Review ArticleNatural Product-Derived Treatments forAttention-DeficitHyperactivity Disorder Safety Efficacy andTherapeutic Potential of Combination Therapy
James Ahn1 Hyung Seok Ahn2 Jae Hoon Cheong3 and Ike dela Pentildea1
1Department of Pharmaceutical and Administrative Sciences Loma Linda University Loma Linda CA 92350 USA2School of Medicine Chungnam National University Daejeon 301-747 Republic of Korea3Department of Pharmacy Sahmyook University Seoul 139-742 Republic of Korea
Correspondence should be addressed to Ike dela Pena idelapenalluedu
Received 9 November 2015 Revised 30 December 2015 Accepted 10 January 2016
Academic Editor Daniel Fung
Copyright copy 2016 James Ahn et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Typical treatment plans for attention-deficithyperactivity disorder (ADHD) utilize nonpharmacological (behavioralpsychosocial)andor pharmacological interventions Limited accessibility to behavioral therapies and concerns over adverse effects ofpharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments andnutritional supplements In this study we reviewed the herbal preparations and nutritional supplements evaluated in clinicalstudies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials We alsodiscussed some evidence suggesting that adjunct treatment of these agents (with another botanical agent or pharmacological ADHDtreatments) may be a promising approach to treat ADHD The analysis indicated mixed findings with regard to efficacy of naturalproduct-derived ADHD interventions Nevertheless these treatments were considered as a ldquosaferrdquo approach than conventionalADHD medications More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy andsafety of natural product-derived ADHD treatments Studies that replicate encouraging findings on the efficacy of combiningbotanical agents and nutritional supplements with other natural product-derived therapies andwidely usedADHDmedications arealso warranted In conclusion the risk-benefit balance of natural product-derived ADHD treatments should be carefullymonitoredwhen used as standalone treatment or when combined with other conventional ADHD treatments
1 Introduction
Attention-deficithyperactivity disorder (ADHD) a neu-rodevelopmental disorder characterized by the core symp-toms of hyperactivity inattentiveness and impulsivity [1] iscurrently regarded as the most common neuropsychiatricdisorder among children [2] Furthermore while this disor-der is most often diagnosed during childhood it may alsoaffect an individual throughout life [3] It is crucial to developefficacious treatments for ADHD given its serious academicsocial and familial consequences along with the risk ofincurring comorbid conditions and later substance abuse [4]
A number of treatment strategies have been suggestedfor ADHD since its recognition as a specific disorder in the1970s Presently typical treatment plans utilize a nonphar-macological (behavioralpsychosocial) and pharmacological
interventions or a combination of both [5] A prominent non-pharmacological intervention in ADHD is behavioral ther-apy (behavior modification) which showed promise espe-cially in youth and young adult ADHD patients In principlebehavioral therapy operates via rewarding desired behaviorswith positive reinforcement and discouraging problematicbehaviors by introducing limits and consequences [6 7]Another type of behavior modification focuses on socialskills training which is conducted in a group setting whereparticipants are taught by a therapist or qualified teacherappropriateacceptable social behaviors which they (patients)are then encouraged to practice and repeat [7 8] Otherapproaches to ADHD therapy include memory trainingthat employs computer software (Cogmed) neurofeedbackelectroencephalography biofeedback green space medita-tion yoga exercise and acupuncture in order to achieve
Hindawi Publishing CorporationNeural PlasticityVolume 2016 Article ID 1320423 18 pageshttpdxdoiorg10115520161320423
2 Neural Plasticity
symptom management (for reviews see [9ndash11]) However asthese therapies are not widely available only a few patientscan benefit from these treatment approaches Although theyare easy to implement the need for time and professionaltherapists and also the involvement of not only the patient butalso members of the family and teachers during the courseof behavioral therapy limit the use of behavioral ADHDtherapies
ADHD has been associated with abnormalities in cat-echolaminergic function in the brain [12] The use ofmedications that increase levels of catecholamine in thebrain received widespread support as these drugs havebeen demonstrated to alleviate ADHD symptoms [12]Drugs indicated in the management of ADHD are classifiedas stimulant and nonstimulant medications [13 14] Thepredominantly used or prescribed pharmacological inter-ventions for ADHD are stimulant medications [13 14]Methylphenidate and dextroamphetamine are examples ofthese drugs which are structurally similar to endogenouscatecholamines and whose activity increases extracellulardopamine and norepinephrine levels thereby correctingthe underlying abnormalities in catecholaminergic functionsand restoring neurotransmitter imbalance [12]Nonstimulantalternatives include atomoxetine and norepinephrine spe-cific reuptake inhibitors and the antidepressants bupropionimipramine and phenelzine [15 16] Nonstimulant alterna-tives have also been reported to increase catecholamine levelsin the brain resulting in behavioral improvement Howevernonstimulant medications have been found to be inferior tostimulant treatments on efficacy endpoints [13 16 17]
While pharmacological treatments generally improveADHD symptoms for most children 20ndash30 of affectedindividuals are nonresponders or are unable to tolerateadverse side effects of these drugs [11 18] Some of the sideeffects of stimulant medications include headache insomniaand decreased appetite motor tics nausea and abdominalpain [5 15 18] Concerns over long-term exposure risks alsodiscourage parents to medicate their children with stimulantdrugs [17] Furthermore the high likelihood for dependencediversion and abuse particular to drugs classified as scheduleII (ie stimulants) limits the use of stimulant medicationsas ADHD has been also associated with increased risk ofsubstance use disorder [17]
Due to concerns over the safety and efficacy of cur-rent pharmacological ADHD interventions there has beengrowing interest in the development of alternative treatmentssuch as natural product-derived ADHD treatments includingbotanical or herbalmedicines vitamins minerals and aminoacids [9ndash11] These alternative treatments are appealing toparents who desire for more ldquonaturalrdquo interventions for theirchildren [9 10] Approximately 50 of parents of ADHDchildren used these treatments alone or in combination withother drugs or substances [19ndash22] In this study we providea descriptive review of natural product-derived ADHD treat-ments including complementary ADHD interventions suchas vitamins minerals and other nutritional supplementsreport findings of clinical trials which evaluated efficacyand safety of these interventions and discuss the poten-tial mechanism(s) by which these agents improve ADHD
symptoms The botanical agents are enumerated in Table 1and Table 2 summarizes the vitamins minerals and othernutritional supplements evaluated for ADHD treatmentFurthermore we also discuss the findings of studies whichevaluated safety and efficacy of combining botanical agentsor pharmacological ADHD treatments to treat ADHDTheseinformation are summarized in Table 3
2 Methods
Searches were made in the electronic databases PubMedPyschINFO andThe Cochrane Library for English languagearticles from 2001 up to December 1 2015 PubMed wasused to search ADHD search terms in combination withparticular natural product-derived treatments The searchstrategy employed included combining these keywords ldquonat-ural productsrdquo ldquoplantrdquo ldquovitaminsrdquo ldquomineralsrdquo ldquoessentialfatty acidsrdquo ldquoamino acidsrdquo ldquocombination natural prod-uctsrdquo or ldquocombination with methylphenidaterdquo and ldquoADHDrdquoor ldquoattention-deficithyperactivity disorderrdquo This processyielded 671 papers covering a wide range of research articletypes As we were interested only in natural product-derivedADHD treatments which were evaluated in clinical trials weconcentrated on open-label randomized controlled trials aswell as observational studies Moreover the inclusion crite-ria included samples consisting of children and adolescentADHD patients (below 18 years of age) as well as samplesize ge 10 The number of English language articles that werereviewed for this paper was 30
3 Results
31 Pycnogenolreg (French Maritime Pine Bark Extract) Pyc-nogenol is a standardized extract derived from the bark ofthe French maritime pine (Pinus pinaster) This extract isrich in catechin phenolic acids procyanidins and taxifolineach with multiple biologic effects [30 31] Several studieson Pycnogenol showed its potentiality in improving ADHDsymptoms in patients Most notably a double-blind placebo-controlled trial with 61 participants (ages 6ndash14 years) reportedthat Pycnogenol treatment (1mgkgday) for 1 month alle-viated ADHD symptoms particularly episodic hyperactivityand inattentiveness and improved visual-motor coordina-tion [30] One month after termination of Pycnogenol therewas a relapse of symptoms in ADHD participants The latterstudy also assumed that Pycnogenolrsquos therapeutic benefitswere mediated via an increase in nitric oxide productionwhich modulates dopamine and norepinephrine release andintake [30] Pycnogenol reportedly producedmild side effectssuch as gastric discomfort Nevertheless the relatively smallnumber of participants treatedwith Pycnogenol and the shortduration of the study limit the generalization of the studyrsquosfindings It is noteworthy however that significant effectsof Pycnogenol were observed coupled with minimal sideeffects supporting the suggestion that it could be used as analternative ADHD treatment [30]
Another randomized placebo-controlled study inves-tigating efficacy of Pycnogenol reported improvement inattention along with reduction in oxidative DNA damage
Neural Plasticity 3
Table1Clinicaltrialsevaluatin
gsafetyandeffi
cacy
ofbo
tanicalagentsfor
ADHD
Stud
yBo
tanicalagent
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Davee
tal[23]
Bacopa
(Bacopamonnieri)
Standardized
Bacopa
monnieriextract(SBM
E)(225
mgday)for
6mon
ths
Open-labelstudy
31child
ren
6ndash12years
oldwith
ADHD
Redu
ctionof
ADHD
symptom
s(restlessness
poor
self-control
inattention
impu
lsivity
etc)
Neuroprotectio
nregu
lationof
dopamine
andinhibitio
nof
cholinesterase
Safeandwelltolerated
Mild
gastrointestinal
sidee
ffects
Uebel-
von
Sand
ersle
benetal
[24]
Ginkgo
biloba
Ginkgo(EGb761reg)
240m
gdailygiven
for3
to5weeks
Openclinicalpilo
tstudy
20child
renwith
ADHD
Improvem
ento
fADHD
core
symptom
sIm
provem
entin
cerebrovascularb
lood
flow
reversalof
5-HT1
andno
radrenergic
receptor
redu
ctions
Reverseinh
ibition
ofMAO
-AandMAO
-B
Very
lowrateso
fmild
adversee
ventsd
uring
observationalp
eriod
Salehi
etal[25]
Ginkgo
biloba
Ginkgo
biloba
(80ndash
120m
gday)
ormethylphenidate
(20ndash
30mgday)for
6weeks
Rand
omized
doub
le-blin
dcontrolled
trial
50child
ren
6ndash14years
oldwith
ADHD
(119899=25Ginkgo
biloba
versus119899=25
methylphenidate)
Improvem
ento
fADHD
symptom
sLesseffectiv
ethan
methylphenidate
Lesser
sidee
ffects
(headacheinsomnia
andlossof
appetite)than
methylphenidate
Leee
tal[26]
Ginseng
Korean
redginseng
(1000
mgb
id)a
ndplacebotwicea
dayfor8
weeks
Observatio
nalstudy
18child
ren
6ndash14years
oldwith
ADHD
Improvem
entin
attention
Noo
tropice
ffecton
CNS
Increaseddo
paminea
ndno
repineph
rinelevels
Neuroprotectiv
eeffects
Taste
aversio
nand
repu
lsion
toginseng
Koetal[27]
Ginseng
Korean
redginseng
extract(1g
KRG
extractp
ouch)twicea
day
for8
weeks
Rand
omized
doub
le-blin
dplacebo-
controlledtrial
70child
ren
6ndash15years
oldwith
ADHD(119899=33
KRGversus119899=37
placebo)
Improvem
ento
fhyperactivity
and
inattentionsymptom
sDecreased
quantitative
electro
enceph
alograph
ythetabetaratio
Norepo
rted
adverse
events
sidee
ffects
Lietal[28]
Ningdong
Ningdon
g(5mgkgday)
versus
methylphenidate
(1mgkgday)for8
weeks
Rand
omized
doub
le-blin
dmethylphenidate-
controlled
trial
72child
ren
6ndash13years
oldwith
ADHD(119899=36
Ningdon
gversus119899=36
methylphenidate)
Similare
fficacy
tocontrol
(methylphenidate)
Regu
lationof
dopamine
byincreasin
gHVA
concentrationin
thes
era
Hypersomnia
Akh
ondzadeh
etal
[29]
Passion
flowe
rPa
ssiflora
incarnata
Dou
ble-blind
rand
omized
methylphenidate-
controlledclinical
trial
34child
renwith
ADHD
Improvem
ento
fADHD
symptom
sNot
specified
Decreased
appetitea
ndanxietynervou
sness
comparedwith
methylphenidategrou
p
4 Neural Plasticity
Table1Con
tinued
Stud
yBo
tanicalagent
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Trebaticka
etal
[30]
Pycnogenol
Pycnogenol(1mgkgday)
orplacebotre
atmentfor
4weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
61child
ren
6ndash14
years
oldwith
ADHD(119899=44
Pycnogenolversus
119899=17placebo)
Attenu
ationof
hyperactivity
and
improvem
ento
fattention
visual-m
otoric
coordinatio
nand
concentration
Influ
ence
oncatecholam
ineformation
ormetabolism
Increasedprod
uctio
nof
nitricoxidew
hich
mod
ulates
dopamine
andno
repineph
rine
releasea
ndintake
Mild
sidee
ffects
inclu
ding
slownessand
gastric
discom
fort
Chovanovae
tal
[31]
Pycnogenol
Pycnogenol(1mgkgday)
orplacebotre
atmentfor
4weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
61ou
tpatient
child
ren
6ndash14yearso
ldwith
ADHD(119899
=un
specified
Pycnogenolversus
placebo)
Improved
attention
redu
ctionin
oxidative
damage
Antioxidant
prop
ertie
sNorepo
rted
adverse
events
sidee
ffects
Weber
etal[32]
StJohnrsquos
wort
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
56child
ren
6ndash17years
oldwith
ADHD(119899=27
SJW
versus119899=27
placebo)
Nosig
nificant
improvem
entinADHD
symptom
s
Norepo
rted
adverse
events
sidee
ffects
Razlo
getal[33]
Valer
ian(Valeriana
officin
alis)
Dou
ble-blindplacebo-
controlledclinicaltria
l
30child
ren
5ndash11years
oldwith
ADHD
(119899=10Va
leriana
officin
alismother
tincture(VO
MT)
or119899=103x
potencyof
VOMTversus119899=10
placebofor3
weeks)
Improvem
ento
fADHD
symptom
sinVO
MTor
3xpo
tencygrou
pin
comparis
onto
placebo
inparticularinatte
ntion
impu
lsivityand
or
hyperactivity
Inhibitio
nof
the
breakd
ownof
GABA
inthec
entralnervou
ssyste
m
Norepo
rted
adverse
events
sidee
ffects
Neural Plasticity 5
Table2Clinicaltrialsevaluatin
gsafetyandeffi
cacy
ofnu
trition
alsupp
lementsforA
DHD
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Torriolietal[34]
Acetyl-L-carnitin
e(LA
C)LA
C(500
mg2tim
esday)
orplacebofor12mon
ths
Rand
omized
doub
le-blin
dplacebo-
controlledparallel
multic
enterstudy
51child
ren(A
DHDand
Fragile
Xsynd
rome)
6ndash13yearso
ld(119899=24
ALC
versus119899=27
placebo)
Redu
ctionof
ADHD
symptom
sversus
Placeboon
Clinical
GlobalImpressio
nsParentalRa
ting
Mod
ulationof
neural
transm
issionby
increasin
gacetylcholine
synthesis
stim
ulatingits
releasea
ndreleaseo
fdo
pamineinthe
stria
tum
invario
usbrain
region
s
Noadversee
ventssid
eeffectsrepo
rted
Arnoldetal[35]
Acetyl-L-carnitin
e(AL
C)ALC
inweight-b
ased
doses
from
500to
1500
mgb
idor
placebofor16weeks
Multisite
parallel-g
roup
doub
le-blin
drand
omized
pilottria
l
112child
ren
5ndash12years
old(119899=53
Acetyl-L-carnitin
eversus119899=59placebo)
Acetyl-L-carnitin
esuperio
rtoplaceboin
inattentives
ubtype
Noadversee
ventssid
eeffectsrepo
rted
Richardson
and
Puri[36]
Essentialfattyacids
Highlyun
saturatedfatty
acid
(HUFA
)EP
A186m
gday
DHA480m
gday
120574-lino
lenica
cid96
mg
vitamin
E60
IUcis-lin
oleic
acid
864m
gAA42
mgand
thym
eoil8m
gor
oliveo
il(placebo
)for12weeks
Rand
omized
doub
le-blin
dplacebo-
controlledstu
dy
41child
ren
9participantswith
drew
before
thee
ndof
12-w
eekperio
d8ndash12yearso
ld(119899=15
HUFA
versus119899=14
placebo)
Attenu
ationof
ADHD
symptom
sfore
xample
inattention
hyperactivity
improvem
entin
cogn
ition
andem
otion
Influ
ence
onsig
nal
transductio
nrelevant
toneuron
alstructure
developm
entand
functio
ns
Upsetsto
machand
difficulty
swallowing
Stevense
tal[37]
Essentialfattyacids
PUFA
supp
lement
comprise
dof
480m
gDHA
80mgEP
A40m
garachido
nica
cid(A
A)
96mgGLA
and
24mg
alph
a-tocoph
erylacetateo
ran
oliveo
ilplacebofor4
mon
ths
Rand
omized
doub
le-blin
dplacebo-
controlledstu
dy
50child
ren(girlsa
ndbo
ys)119899=25PU
FAsupp
lementatio
n119899=25
placebo
Clearb
enefitfor
all
behaviorsc
haracteristic
ofADHDwas
not
observed
Treatm
enteffectsfor
cond
uctand
attentionas
wellasw
ithclinical
improvem
entsin
oppo
sitionald
efiant
behavior
Mediatio
nof
abno
rmal
neuron
alsig
nalin
gthat
results
inaberrant
behaviors
Not
specified
6 Neural PlasticityTa
ble2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Sinn
andBryan
[38]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omized
doub
le-blin
dcrossover
placebo-controlledstu
dy
132child
ren(data
availablefor
104and87
child
ren)
7ndash12yearso
ld(119899=36PU
FAsv
ersus
119899=41PU
FA+
micronu
trientsv
ersus
119899=27placebo)
Sign
ificant
treatment
effectsbasedon
parental
ratin
gof
core
ADHD
symptom
sinbo
thPU
FAgrou
psversus
placebo
Mod
ulationof
neural
cellsig
nalin
gand
neurotransmitter
processes
PUFA
swith
other
nutrientssuchas
vitC
B 3and
B 6mod
ulates
PUFArsquosrolein
the
synthesis
ofprostaglandins
and
chem
icalsimpo
rtantfor
biologicalandbrain
functio
n
Noadversee
ventssid
eeffects
Sinn
etal[39]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omizedone-w
aycrossoverplacebo-
controlledstu
dyPh
ases
1and
2
Phase1119899=129child
ren
with
ADHD(PUFA
versus
PUFA
+multiv
itaminsminerals
versus
placebofor15
weeks)
Phase2
119899=104
child
renwith
ADHD
(PUFA
PUFA
+multiv
itaminm
inerals
andplacebofor15
weeks)
Improved
abilityon
attentioncontroland
vocabu
lary
perfo
rmance
durin
gph
ase2
Influ
ence
onmetabolic
andneuralactiv
ities
Increasin
gdo
pamine
activ
ityin
thefrontal
lobe
Twocaseso
fnauseaa
ndon
eepisode
ofno
sebleed
Manor
etal[40
]
Essentialfattyacids
2capsules
twicea
dayof
phosph
atidylserin
e(PS
)containing
omega-3(300
mg
ofPS
and120m
gof
EPA+
DHA)o
rcellulose
capsules
asplacebofor15weeks
Rand
omized
doub
le-blin
dsin
gle-centerplacebo
-controlledtrial
200child
ren(6ndash13y
ears
old)
rand
omlyassig
ned
toPS
-omega-3capsules
orplacebo
119873=162child
ren
completed
15weeks
oftre
atment(119899=110PS
-om
ega-3119899=52
placebo)
Improvem
ento
fADHD
symptom
s(im
pulsivity
inattention
moo
dand
behavior
issue)
Maintenance
ofintegrity
ofcellmem
branes
Influ
ence
ondo
paminergica
ndcholinergics
ystems
Increasin
gom
ega-3
LC-PUFA
which
improves
behavioral
sensoryand
neurologicaldysfu
nctio
n
Mild
adversee
vent
profi
leG
Idisc
omfort
atop
icderm
atitis
nauseaticsand
hyperactivity
Raze
tal[41]
Essentialfattyacids
EFAcapsules
containing
240m
gof
linoleica
cid(LA)
60mgof
alph
a-lin
olenicacid
(ALA
)95
mgof
mineraloil
and5m
gof
a-tocoph
erol(as
anantio
xidant)2
timesday
orplacebovitC(500
mg
ascorbicacid)2
timesday
for7
weeks
Rand
omized
doub
le-blin
dplacebo-controlledtrial
73child
ren
7ndash13years
old63
child
ren
completed
thes
tudy
(119899=39EF
Asupp
lement
versus
39placebo
vitamin
C)
Both
treatments
amelioratedsome
ADHDsymptom
sNo
differenceineffi
cacy
betweentre
atments
Improvem
entin
behavioralsensoryand
cogn
itive
functio
ns
Noadversee
ventssid
eeffectsrepo
rted
Neural Plasticity 7
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Voigtetal[42]
Essentialfattyacids
345m
gof
DHAperd
ay(119899=32)o
raplacebocapsule
(119899=31)for
4mon
ths
Rand
omized
doub
le-blin
dplacebo
controlledstu
dy
54child
ren6ndash
12years
old(119899=27
docosahexaenoica
cid
(DHA)v
ersus119899=27
placebo)
DHAsupp
lementatio
ndidno
tsignificantly
improveinanyob
jective
orsubjectiv
emeasure
ofADHDsymptom
s
Welltolerated
andno
adversee
ffectsw
ere
repo
rted
Hira
yamae
tal
[43]
Essentialfattyacids
DHAgrou
pferm
ented
soybeanmilk
(600
mg
DHA12
5mL3week)bread
rolls
(300
mgDHA45g
2week)
andste
amed
bread
(600
mgD
HA60g
2w
eek)
orplacebofood
scon
taining
oliveo
ilinste
adof
DHA-
rich
fishoilfor
2weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
40child
renwith
ADHD
6ndash12yearso
ld(119899=20
docosahexaenoica
cid
(DHA)v
ersus119899=20
placebo)
DHAsupp
lementatio
ndidno
timprove
ADHD-related
symptom
s
Noserio
ussid
eeffects
were
repo
rted
inthe
study
Kono
faletal[44]
Iron
80mgferrou
ssulfatetablets
orplaceboon
cedaily
inthe
morning
for12weeks
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
23ADHDchild
renwith
lowserum
ferritinlevel
(lt30
ngm
L)5ndash8y
ears
old(119899=18iro
nversus
119899=5placebo)
Improvem
ento
fhyperactiveim
pulsive
andinattentive
symptom
sintheA
DHD
ratin
gscale
Iron
isac
ofactorinthe
synthesis
ofbo
thno
repineph
rinea
nddo
pamine
Minor
sidee
ffectsw
ere
repo
rtedsuchas
nausea
constip
ation
and
abdo
minalpain
Mou
sain-Bosce
tal[45]
Vitamin
B6andmagnesiu
mADHDchild
ren
magnesiu
m-vitamin
B6(M
g-B6
)regim
en(6
mgkgd
Mg06m
gkgd
vit-B
6)for
sixmon
thsC
ontro
lsdidno
treceiveM
g-B6
Openstu
dy
76child
ren(m
eanage
69y
ears13girls
and27
boys)(40
ADHD
child
renamp36
healthy
child
ren)
Attenu
ationof
hyperactivity
and
aggressiv
enessS
choo
lattentionwas
also
improved
Vitamin
B6facilitates
thep
rodu
ctionof
the
serotonin
Magnesiu
misa
nonspecific
inhibitoro
fcalcium
andNMDA
channels
Magnesiu
mcan
influ
ence
catecholam
ine
signalin
g
Norepo
rted
sidee
ffects
Bilicietal[46]
Zinc
150m
gzinc
sulfateor
150m
gsucrose(placebo)
daily
for12
weeks
Rand
omized
doub
le-blin
dparallel-g
roup
placebo-controlledtrial
400child
ren6ndash
14years
old(119899=202zinc
versus
119899=198placebo)
Zinc
sulfatebette
rthan
placeboin
decreasin
ghyperactivity
and
impu
lsivityand
improvingsocialization
butn
otinattention
Increasedzinc
levels
necessaryforc
ognitiv
edevelopm
ent
Noserio
ussid
eeffects
repo
rtedM
etallic
taste
was
acom
mon
complaint
8 Neural Plasticity
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Akh
ondzadeh
etal
[47]
Zinc
Zinc
sulfate(55m
gday)
+methylphenidate
(1mgkgday)o
rsucrose
(placebo
)55m
g+
methylphenidate
(1mgkgday)for
6weeks
Rand
omized
doub
le-blin
dclinical
trial
44child
ren
5ndash11years
old(119899=22
methylphenidate+zinc
versus119899=22
methylphenidate+
placebo)
Sign
ificantlygreater
treatmenteffects(as
per
parent
andteacher
ratin
gscales
cores)in
zinc
sulfatewith
methylphenidate
treatmento
verp
lacebo
with
methylphenidate
Zinc
regulates
dopamine
functio
nindirectly
throug
hits
actio
non
melaton
in
Nauseaa
ndmetallic
taste
werec
ommon
complaintsOverallit
was
welltolerated
Arnoldetal[48]
Zinc
Zinc
115mgday(oncea
day)
orZinc
230
mgday
(twicea
day)
orplacebo(8
weeks)am
phetam
ine
5ndash15mgdaily
(based
onthe
weight)
Durationof
experim
entw
as13
weeks
(8weeks
controlled
+5weeks
amph
etam
ine
add-on
)
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
52child
ren6ndash
14years
old(119899=20Zinc
1or
119899=8Zinc
2versus
119899=24placebo)
Noappreciable
differenceb
etweenbo
thdo
sageso
fzinca
ndplacebo
Gastro
intestinal
discom
fortrepo
rted
by1
patie
nt
Neural Plasticity 9
Table3Clinicaltrialsdemon
stratingeffi
cacy
ofcombinatio
ntherapyof
botanicalagentsa
ndherbssupp
lementswith
methylphenidatein
treatingADHD
Stud
yMetho
dsParticipants
Outcomes
Com
ments
Lyon
etal[49]
Ginkgo
biloba
andGinseng
Ginkgo
biloba
extract
(50m
g)plus
American
ginsengPa
nax
quinquefo
lium
(200
mg)
twiceday
(com
binatio
nprod
uct)
Open
pilotstudy
36child
ren
3ndash17years
oldwith
ADHD
Improvem
ento
fADHD
symptom
s(hyperactiv
ity
impu
lsivenessand
anxiety)
Five
participants
repo
rted
adversee
vents
(increasedADHD
symptom
saggressiv
enesssw
eatin
gheadacheand
tiredness)on
ly2
considered
related
tothe
study
Wangetal[50]
Jingling
oralan
dmethylphenidate
Methylphenidate
(10ndash
40mgd)
Rand
omizedblin
ded
study
119899=50ADHDchild
ren
with
transie
nttic
disorder
Sign
ificant
improvem
ent
ofADHDsymptom
sas
wellastics
Com
binatio
ntherapy
moree
ffectivethan
methylphenidatealon
ein
improvingADHD
andtic
symptom
s
Dingetal[51]
Yizhiand
methylphenidate
Rand
omized
methylphenidate-
controlled
trial
210child
renwith
hyperkineticsynd
rome
Sign
ificant
improvem
ent
inADHDsymptom
sin
thosetaking
combinatio
ntherapy
comparedto
either
given
asmon
otherapy
Yizhih
adfewer
side
effectswhengivenalon
eor
incombinatio
nthan
methylphenidate
Akh
ondzadeh
etal
[47]
Zinc
sulfateand
methylphenidate
Rand
omized
doub
le-blindand
methylphenidate+
placebocontrolledtrial
44child
ren(26bo
ys18
girls)5ndash11yearso
ldwith
ADHD
Improved
parent
and
teacherratingscale
scores
fortho
sesupp
lementedwith
zinc
sulfateas
anadjunct
Side
effectsrepo
rted
anxietylossof
appetite
nauseaheadache
abdo
minalpain
insomniaandmetallic
taste
10 Neural Plasticity
and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment
32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary
33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger
number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]
Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy
34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
2 Neural Plasticity
symptom management (for reviews see [9ndash11]) However asthese therapies are not widely available only a few patientscan benefit from these treatment approaches Although theyare easy to implement the need for time and professionaltherapists and also the involvement of not only the patient butalso members of the family and teachers during the courseof behavioral therapy limit the use of behavioral ADHDtherapies
ADHD has been associated with abnormalities in cat-echolaminergic function in the brain [12] The use ofmedications that increase levels of catecholamine in thebrain received widespread support as these drugs havebeen demonstrated to alleviate ADHD symptoms [12]Drugs indicated in the management of ADHD are classifiedas stimulant and nonstimulant medications [13 14] Thepredominantly used or prescribed pharmacological inter-ventions for ADHD are stimulant medications [13 14]Methylphenidate and dextroamphetamine are examples ofthese drugs which are structurally similar to endogenouscatecholamines and whose activity increases extracellulardopamine and norepinephrine levels thereby correctingthe underlying abnormalities in catecholaminergic functionsand restoring neurotransmitter imbalance [12]Nonstimulantalternatives include atomoxetine and norepinephrine spe-cific reuptake inhibitors and the antidepressants bupropionimipramine and phenelzine [15 16] Nonstimulant alterna-tives have also been reported to increase catecholamine levelsin the brain resulting in behavioral improvement Howevernonstimulant medications have been found to be inferior tostimulant treatments on efficacy endpoints [13 16 17]
While pharmacological treatments generally improveADHD symptoms for most children 20ndash30 of affectedindividuals are nonresponders or are unable to tolerateadverse side effects of these drugs [11 18] Some of the sideeffects of stimulant medications include headache insomniaand decreased appetite motor tics nausea and abdominalpain [5 15 18] Concerns over long-term exposure risks alsodiscourage parents to medicate their children with stimulantdrugs [17] Furthermore the high likelihood for dependencediversion and abuse particular to drugs classified as scheduleII (ie stimulants) limits the use of stimulant medicationsas ADHD has been also associated with increased risk ofsubstance use disorder [17]
Due to concerns over the safety and efficacy of cur-rent pharmacological ADHD interventions there has beengrowing interest in the development of alternative treatmentssuch as natural product-derived ADHD treatments includingbotanical or herbalmedicines vitamins minerals and aminoacids [9ndash11] These alternative treatments are appealing toparents who desire for more ldquonaturalrdquo interventions for theirchildren [9 10] Approximately 50 of parents of ADHDchildren used these treatments alone or in combination withother drugs or substances [19ndash22] In this study we providea descriptive review of natural product-derived ADHD treat-ments including complementary ADHD interventions suchas vitamins minerals and other nutritional supplementsreport findings of clinical trials which evaluated efficacyand safety of these interventions and discuss the poten-tial mechanism(s) by which these agents improve ADHD
symptoms The botanical agents are enumerated in Table 1and Table 2 summarizes the vitamins minerals and othernutritional supplements evaluated for ADHD treatmentFurthermore we also discuss the findings of studies whichevaluated safety and efficacy of combining botanical agentsor pharmacological ADHD treatments to treat ADHDTheseinformation are summarized in Table 3
2 Methods
Searches were made in the electronic databases PubMedPyschINFO andThe Cochrane Library for English languagearticles from 2001 up to December 1 2015 PubMed wasused to search ADHD search terms in combination withparticular natural product-derived treatments The searchstrategy employed included combining these keywords ldquonat-ural productsrdquo ldquoplantrdquo ldquovitaminsrdquo ldquomineralsrdquo ldquoessentialfatty acidsrdquo ldquoamino acidsrdquo ldquocombination natural prod-uctsrdquo or ldquocombination with methylphenidaterdquo and ldquoADHDrdquoor ldquoattention-deficithyperactivity disorderrdquo This processyielded 671 papers covering a wide range of research articletypes As we were interested only in natural product-derivedADHD treatments which were evaluated in clinical trials weconcentrated on open-label randomized controlled trials aswell as observational studies Moreover the inclusion crite-ria included samples consisting of children and adolescentADHD patients (below 18 years of age) as well as samplesize ge 10 The number of English language articles that werereviewed for this paper was 30
3 Results
31 Pycnogenolreg (French Maritime Pine Bark Extract) Pyc-nogenol is a standardized extract derived from the bark ofthe French maritime pine (Pinus pinaster) This extract isrich in catechin phenolic acids procyanidins and taxifolineach with multiple biologic effects [30 31] Several studieson Pycnogenol showed its potentiality in improving ADHDsymptoms in patients Most notably a double-blind placebo-controlled trial with 61 participants (ages 6ndash14 years) reportedthat Pycnogenol treatment (1mgkgday) for 1 month alle-viated ADHD symptoms particularly episodic hyperactivityand inattentiveness and improved visual-motor coordina-tion [30] One month after termination of Pycnogenol therewas a relapse of symptoms in ADHD participants The latterstudy also assumed that Pycnogenolrsquos therapeutic benefitswere mediated via an increase in nitric oxide productionwhich modulates dopamine and norepinephrine release andintake [30] Pycnogenol reportedly producedmild side effectssuch as gastric discomfort Nevertheless the relatively smallnumber of participants treatedwith Pycnogenol and the shortduration of the study limit the generalization of the studyrsquosfindings It is noteworthy however that significant effectsof Pycnogenol were observed coupled with minimal sideeffects supporting the suggestion that it could be used as analternative ADHD treatment [30]
Another randomized placebo-controlled study inves-tigating efficacy of Pycnogenol reported improvement inattention along with reduction in oxidative DNA damage
Neural Plasticity 3
Table1Clinicaltrialsevaluatin
gsafetyandeffi
cacy
ofbo
tanicalagentsfor
ADHD
Stud
yBo
tanicalagent
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Davee
tal[23]
Bacopa
(Bacopamonnieri)
Standardized
Bacopa
monnieriextract(SBM
E)(225
mgday)for
6mon
ths
Open-labelstudy
31child
ren
6ndash12years
oldwith
ADHD
Redu
ctionof
ADHD
symptom
s(restlessness
poor
self-control
inattention
impu
lsivity
etc)
Neuroprotectio
nregu
lationof
dopamine
andinhibitio
nof
cholinesterase
Safeandwelltolerated
Mild
gastrointestinal
sidee
ffects
Uebel-
von
Sand
ersle
benetal
[24]
Ginkgo
biloba
Ginkgo(EGb761reg)
240m
gdailygiven
for3
to5weeks
Openclinicalpilo
tstudy
20child
renwith
ADHD
Improvem
ento
fADHD
core
symptom
sIm
provem
entin
cerebrovascularb
lood
flow
reversalof
5-HT1
andno
radrenergic
receptor
redu
ctions
Reverseinh
ibition
ofMAO
-AandMAO
-B
Very
lowrateso
fmild
adversee
ventsd
uring
observationalp
eriod
Salehi
etal[25]
Ginkgo
biloba
Ginkgo
biloba
(80ndash
120m
gday)
ormethylphenidate
(20ndash
30mgday)for
6weeks
Rand
omized
doub
le-blin
dcontrolled
trial
50child
ren
6ndash14years
oldwith
ADHD
(119899=25Ginkgo
biloba
versus119899=25
methylphenidate)
Improvem
ento
fADHD
symptom
sLesseffectiv
ethan
methylphenidate
Lesser
sidee
ffects
(headacheinsomnia
andlossof
appetite)than
methylphenidate
Leee
tal[26]
Ginseng
Korean
redginseng
(1000
mgb
id)a
ndplacebotwicea
dayfor8
weeks
Observatio
nalstudy
18child
ren
6ndash14years
oldwith
ADHD
Improvem
entin
attention
Noo
tropice
ffecton
CNS
Increaseddo
paminea
ndno
repineph
rinelevels
Neuroprotectiv
eeffects
Taste
aversio
nand
repu
lsion
toginseng
Koetal[27]
Ginseng
Korean
redginseng
extract(1g
KRG
extractp
ouch)twicea
day
for8
weeks
Rand
omized
doub
le-blin
dplacebo-
controlledtrial
70child
ren
6ndash15years
oldwith
ADHD(119899=33
KRGversus119899=37
placebo)
Improvem
ento
fhyperactivity
and
inattentionsymptom
sDecreased
quantitative
electro
enceph
alograph
ythetabetaratio
Norepo
rted
adverse
events
sidee
ffects
Lietal[28]
Ningdong
Ningdon
g(5mgkgday)
versus
methylphenidate
(1mgkgday)for8
weeks
Rand
omized
doub
le-blin
dmethylphenidate-
controlled
trial
72child
ren
6ndash13years
oldwith
ADHD(119899=36
Ningdon
gversus119899=36
methylphenidate)
Similare
fficacy
tocontrol
(methylphenidate)
Regu
lationof
dopamine
byincreasin
gHVA
concentrationin
thes
era
Hypersomnia
Akh
ondzadeh
etal
[29]
Passion
flowe
rPa
ssiflora
incarnata
Dou
ble-blind
rand
omized
methylphenidate-
controlledclinical
trial
34child
renwith
ADHD
Improvem
ento
fADHD
symptom
sNot
specified
Decreased
appetitea
ndanxietynervou
sness
comparedwith
methylphenidategrou
p
4 Neural Plasticity
Table1Con
tinued
Stud
yBo
tanicalagent
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Trebaticka
etal
[30]
Pycnogenol
Pycnogenol(1mgkgday)
orplacebotre
atmentfor
4weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
61child
ren
6ndash14
years
oldwith
ADHD(119899=44
Pycnogenolversus
119899=17placebo)
Attenu
ationof
hyperactivity
and
improvem
ento
fattention
visual-m
otoric
coordinatio
nand
concentration
Influ
ence
oncatecholam
ineformation
ormetabolism
Increasedprod
uctio
nof
nitricoxidew
hich
mod
ulates
dopamine
andno
repineph
rine
releasea
ndintake
Mild
sidee
ffects
inclu
ding
slownessand
gastric
discom
fort
Chovanovae
tal
[31]
Pycnogenol
Pycnogenol(1mgkgday)
orplacebotre
atmentfor
4weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
61ou
tpatient
child
ren
6ndash14yearso
ldwith
ADHD(119899
=un
specified
Pycnogenolversus
placebo)
Improved
attention
redu
ctionin
oxidative
damage
Antioxidant
prop
ertie
sNorepo
rted
adverse
events
sidee
ffects
Weber
etal[32]
StJohnrsquos
wort
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
56child
ren
6ndash17years
oldwith
ADHD(119899=27
SJW
versus119899=27
placebo)
Nosig
nificant
improvem
entinADHD
symptom
s
Norepo
rted
adverse
events
sidee
ffects
Razlo
getal[33]
Valer
ian(Valeriana
officin
alis)
Dou
ble-blindplacebo-
controlledclinicaltria
l
30child
ren
5ndash11years
oldwith
ADHD
(119899=10Va
leriana
officin
alismother
tincture(VO
MT)
or119899=103x
potencyof
VOMTversus119899=10
placebofor3
weeks)
Improvem
ento
fADHD
symptom
sinVO
MTor
3xpo
tencygrou
pin
comparis
onto
placebo
inparticularinatte
ntion
impu
lsivityand
or
hyperactivity
Inhibitio
nof
the
breakd
ownof
GABA
inthec
entralnervou
ssyste
m
Norepo
rted
adverse
events
sidee
ffects
Neural Plasticity 5
Table2Clinicaltrialsevaluatin
gsafetyandeffi
cacy
ofnu
trition
alsupp
lementsforA
DHD
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Torriolietal[34]
Acetyl-L-carnitin
e(LA
C)LA
C(500
mg2tim
esday)
orplacebofor12mon
ths
Rand
omized
doub
le-blin
dplacebo-
controlledparallel
multic
enterstudy
51child
ren(A
DHDand
Fragile
Xsynd
rome)
6ndash13yearso
ld(119899=24
ALC
versus119899=27
placebo)
Redu
ctionof
ADHD
symptom
sversus
Placeboon
Clinical
GlobalImpressio
nsParentalRa
ting
Mod
ulationof
neural
transm
issionby
increasin
gacetylcholine
synthesis
stim
ulatingits
releasea
ndreleaseo
fdo
pamineinthe
stria
tum
invario
usbrain
region
s
Noadversee
ventssid
eeffectsrepo
rted
Arnoldetal[35]
Acetyl-L-carnitin
e(AL
C)ALC
inweight-b
ased
doses
from
500to
1500
mgb
idor
placebofor16weeks
Multisite
parallel-g
roup
doub
le-blin
drand
omized
pilottria
l
112child
ren
5ndash12years
old(119899=53
Acetyl-L-carnitin
eversus119899=59placebo)
Acetyl-L-carnitin
esuperio
rtoplaceboin
inattentives
ubtype
Noadversee
ventssid
eeffectsrepo
rted
Richardson
and
Puri[36]
Essentialfattyacids
Highlyun
saturatedfatty
acid
(HUFA
)EP
A186m
gday
DHA480m
gday
120574-lino
lenica
cid96
mg
vitamin
E60
IUcis-lin
oleic
acid
864m
gAA42
mgand
thym
eoil8m
gor
oliveo
il(placebo
)for12weeks
Rand
omized
doub
le-blin
dplacebo-
controlledstu
dy
41child
ren
9participantswith
drew
before
thee
ndof
12-w
eekperio
d8ndash12yearso
ld(119899=15
HUFA
versus119899=14
placebo)
Attenu
ationof
ADHD
symptom
sfore
xample
inattention
hyperactivity
improvem
entin
cogn
ition
andem
otion
Influ
ence
onsig
nal
transductio
nrelevant
toneuron
alstructure
developm
entand
functio
ns
Upsetsto
machand
difficulty
swallowing
Stevense
tal[37]
Essentialfattyacids
PUFA
supp
lement
comprise
dof
480m
gDHA
80mgEP
A40m
garachido
nica
cid(A
A)
96mgGLA
and
24mg
alph
a-tocoph
erylacetateo
ran
oliveo
ilplacebofor4
mon
ths
Rand
omized
doub
le-blin
dplacebo-
controlledstu
dy
50child
ren(girlsa
ndbo
ys)119899=25PU
FAsupp
lementatio
n119899=25
placebo
Clearb
enefitfor
all
behaviorsc
haracteristic
ofADHDwas
not
observed
Treatm
enteffectsfor
cond
uctand
attentionas
wellasw
ithclinical
improvem
entsin
oppo
sitionald
efiant
behavior
Mediatio
nof
abno
rmal
neuron
alsig
nalin
gthat
results
inaberrant
behaviors
Not
specified
6 Neural PlasticityTa
ble2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Sinn
andBryan
[38]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omized
doub
le-blin
dcrossover
placebo-controlledstu
dy
132child
ren(data
availablefor
104and87
child
ren)
7ndash12yearso
ld(119899=36PU
FAsv
ersus
119899=41PU
FA+
micronu
trientsv
ersus
119899=27placebo)
Sign
ificant
treatment
effectsbasedon
parental
ratin
gof
core
ADHD
symptom
sinbo
thPU
FAgrou
psversus
placebo
Mod
ulationof
neural
cellsig
nalin
gand
neurotransmitter
processes
PUFA
swith
other
nutrientssuchas
vitC
B 3and
B 6mod
ulates
PUFArsquosrolein
the
synthesis
ofprostaglandins
and
chem
icalsimpo
rtantfor
biologicalandbrain
functio
n
Noadversee
ventssid
eeffects
Sinn
etal[39]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omizedone-w
aycrossoverplacebo-
controlledstu
dyPh
ases
1and
2
Phase1119899=129child
ren
with
ADHD(PUFA
versus
PUFA
+multiv
itaminsminerals
versus
placebofor15
weeks)
Phase2
119899=104
child
renwith
ADHD
(PUFA
PUFA
+multiv
itaminm
inerals
andplacebofor15
weeks)
Improved
abilityon
attentioncontroland
vocabu
lary
perfo
rmance
durin
gph
ase2
Influ
ence
onmetabolic
andneuralactiv
ities
Increasin
gdo
pamine
activ
ityin
thefrontal
lobe
Twocaseso
fnauseaa
ndon
eepisode
ofno
sebleed
Manor
etal[40
]
Essentialfattyacids
2capsules
twicea
dayof
phosph
atidylserin
e(PS
)containing
omega-3(300
mg
ofPS
and120m
gof
EPA+
DHA)o
rcellulose
capsules
asplacebofor15weeks
Rand
omized
doub
le-blin
dsin
gle-centerplacebo
-controlledtrial
200child
ren(6ndash13y
ears
old)
rand
omlyassig
ned
toPS
-omega-3capsules
orplacebo
119873=162child
ren
completed
15weeks
oftre
atment(119899=110PS
-om
ega-3119899=52
placebo)
Improvem
ento
fADHD
symptom
s(im
pulsivity
inattention
moo
dand
behavior
issue)
Maintenance
ofintegrity
ofcellmem
branes
Influ
ence
ondo
paminergica
ndcholinergics
ystems
Increasin
gom
ega-3
LC-PUFA
which
improves
behavioral
sensoryand
neurologicaldysfu
nctio
n
Mild
adversee
vent
profi
leG
Idisc
omfort
atop
icderm
atitis
nauseaticsand
hyperactivity
Raze
tal[41]
Essentialfattyacids
EFAcapsules
containing
240m
gof
linoleica
cid(LA)
60mgof
alph
a-lin
olenicacid
(ALA
)95
mgof
mineraloil
and5m
gof
a-tocoph
erol(as
anantio
xidant)2
timesday
orplacebovitC(500
mg
ascorbicacid)2
timesday
for7
weeks
Rand
omized
doub
le-blin
dplacebo-controlledtrial
73child
ren
7ndash13years
old63
child
ren
completed
thes
tudy
(119899=39EF
Asupp
lement
versus
39placebo
vitamin
C)
Both
treatments
amelioratedsome
ADHDsymptom
sNo
differenceineffi
cacy
betweentre
atments
Improvem
entin
behavioralsensoryand
cogn
itive
functio
ns
Noadversee
ventssid
eeffectsrepo
rted
Neural Plasticity 7
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Voigtetal[42]
Essentialfattyacids
345m
gof
DHAperd
ay(119899=32)o
raplacebocapsule
(119899=31)for
4mon
ths
Rand
omized
doub
le-blin
dplacebo
controlledstu
dy
54child
ren6ndash
12years
old(119899=27
docosahexaenoica
cid
(DHA)v
ersus119899=27
placebo)
DHAsupp
lementatio
ndidno
tsignificantly
improveinanyob
jective
orsubjectiv
emeasure
ofADHDsymptom
s
Welltolerated
andno
adversee
ffectsw
ere
repo
rted
Hira
yamae
tal
[43]
Essentialfattyacids
DHAgrou
pferm
ented
soybeanmilk
(600
mg
DHA12
5mL3week)bread
rolls
(300
mgDHA45g
2week)
andste
amed
bread
(600
mgD
HA60g
2w
eek)
orplacebofood
scon
taining
oliveo
ilinste
adof
DHA-
rich
fishoilfor
2weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
40child
renwith
ADHD
6ndash12yearso
ld(119899=20
docosahexaenoica
cid
(DHA)v
ersus119899=20
placebo)
DHAsupp
lementatio
ndidno
timprove
ADHD-related
symptom
s
Noserio
ussid
eeffects
were
repo
rted
inthe
study
Kono
faletal[44]
Iron
80mgferrou
ssulfatetablets
orplaceboon
cedaily
inthe
morning
for12weeks
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
23ADHDchild
renwith
lowserum
ferritinlevel
(lt30
ngm
L)5ndash8y
ears
old(119899=18iro
nversus
119899=5placebo)
Improvem
ento
fhyperactiveim
pulsive
andinattentive
symptom
sintheA
DHD
ratin
gscale
Iron
isac
ofactorinthe
synthesis
ofbo
thno
repineph
rinea
nddo
pamine
Minor
sidee
ffectsw
ere
repo
rtedsuchas
nausea
constip
ation
and
abdo
minalpain
Mou
sain-Bosce
tal[45]
Vitamin
B6andmagnesiu
mADHDchild
ren
magnesiu
m-vitamin
B6(M
g-B6
)regim
en(6
mgkgd
Mg06m
gkgd
vit-B
6)for
sixmon
thsC
ontro
lsdidno
treceiveM
g-B6
Openstu
dy
76child
ren(m
eanage
69y
ears13girls
and27
boys)(40
ADHD
child
renamp36
healthy
child
ren)
Attenu
ationof
hyperactivity
and
aggressiv
enessS
choo
lattentionwas
also
improved
Vitamin
B6facilitates
thep
rodu
ctionof
the
serotonin
Magnesiu
misa
nonspecific
inhibitoro
fcalcium
andNMDA
channels
Magnesiu
mcan
influ
ence
catecholam
ine
signalin
g
Norepo
rted
sidee
ffects
Bilicietal[46]
Zinc
150m
gzinc
sulfateor
150m
gsucrose(placebo)
daily
for12
weeks
Rand
omized
doub
le-blin
dparallel-g
roup
placebo-controlledtrial
400child
ren6ndash
14years
old(119899=202zinc
versus
119899=198placebo)
Zinc
sulfatebette
rthan
placeboin
decreasin
ghyperactivity
and
impu
lsivityand
improvingsocialization
butn
otinattention
Increasedzinc
levels
necessaryforc
ognitiv
edevelopm
ent
Noserio
ussid
eeffects
repo
rtedM
etallic
taste
was
acom
mon
complaint
8 Neural Plasticity
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Akh
ondzadeh
etal
[47]
Zinc
Zinc
sulfate(55m
gday)
+methylphenidate
(1mgkgday)o
rsucrose
(placebo
)55m
g+
methylphenidate
(1mgkgday)for
6weeks
Rand
omized
doub
le-blin
dclinical
trial
44child
ren
5ndash11years
old(119899=22
methylphenidate+zinc
versus119899=22
methylphenidate+
placebo)
Sign
ificantlygreater
treatmenteffects(as
per
parent
andteacher
ratin
gscales
cores)in
zinc
sulfatewith
methylphenidate
treatmento
verp
lacebo
with
methylphenidate
Zinc
regulates
dopamine
functio
nindirectly
throug
hits
actio
non
melaton
in
Nauseaa
ndmetallic
taste
werec
ommon
complaintsOverallit
was
welltolerated
Arnoldetal[48]
Zinc
Zinc
115mgday(oncea
day)
orZinc
230
mgday
(twicea
day)
orplacebo(8
weeks)am
phetam
ine
5ndash15mgdaily
(based
onthe
weight)
Durationof
experim
entw
as13
weeks
(8weeks
controlled
+5weeks
amph
etam
ine
add-on
)
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
52child
ren6ndash
14years
old(119899=20Zinc
1or
119899=8Zinc
2versus
119899=24placebo)
Noappreciable
differenceb
etweenbo
thdo
sageso
fzinca
ndplacebo
Gastro
intestinal
discom
fortrepo
rted
by1
patie
nt
Neural Plasticity 9
Table3Clinicaltrialsdemon
stratingeffi
cacy
ofcombinatio
ntherapyof
botanicalagentsa
ndherbssupp
lementswith
methylphenidatein
treatingADHD
Stud
yMetho
dsParticipants
Outcomes
Com
ments
Lyon
etal[49]
Ginkgo
biloba
andGinseng
Ginkgo
biloba
extract
(50m
g)plus
American
ginsengPa
nax
quinquefo
lium
(200
mg)
twiceday
(com
binatio
nprod
uct)
Open
pilotstudy
36child
ren
3ndash17years
oldwith
ADHD
Improvem
ento
fADHD
symptom
s(hyperactiv
ity
impu
lsivenessand
anxiety)
Five
participants
repo
rted
adversee
vents
(increasedADHD
symptom
saggressiv
enesssw
eatin
gheadacheand
tiredness)on
ly2
considered
related
tothe
study
Wangetal[50]
Jingling
oralan
dmethylphenidate
Methylphenidate
(10ndash
40mgd)
Rand
omizedblin
ded
study
119899=50ADHDchild
ren
with
transie
nttic
disorder
Sign
ificant
improvem
ent
ofADHDsymptom
sas
wellastics
Com
binatio
ntherapy
moree
ffectivethan
methylphenidatealon
ein
improvingADHD
andtic
symptom
s
Dingetal[51]
Yizhiand
methylphenidate
Rand
omized
methylphenidate-
controlled
trial
210child
renwith
hyperkineticsynd
rome
Sign
ificant
improvem
ent
inADHDsymptom
sin
thosetaking
combinatio
ntherapy
comparedto
either
given
asmon
otherapy
Yizhih
adfewer
side
effectswhengivenalon
eor
incombinatio
nthan
methylphenidate
Akh
ondzadeh
etal
[47]
Zinc
sulfateand
methylphenidate
Rand
omized
doub
le-blindand
methylphenidate+
placebocontrolledtrial
44child
ren(26bo
ys18
girls)5ndash11yearso
ldwith
ADHD
Improved
parent
and
teacherratingscale
scores
fortho
sesupp
lementedwith
zinc
sulfateas
anadjunct
Side
effectsrepo
rted
anxietylossof
appetite
nauseaheadache
abdo
minalpain
insomniaandmetallic
taste
10 Neural Plasticity
and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment
32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary
33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger
number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]
Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy
34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
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Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Neural Plasticity
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Parkinsonrsquos Disease
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Research and TreatmentAutism
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Neural Plasticity 3
Table1Clinicaltrialsevaluatin
gsafetyandeffi
cacy
ofbo
tanicalagentsfor
ADHD
Stud
yBo
tanicalagent
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Davee
tal[23]
Bacopa
(Bacopamonnieri)
Standardized
Bacopa
monnieriextract(SBM
E)(225
mgday)for
6mon
ths
Open-labelstudy
31child
ren
6ndash12years
oldwith
ADHD
Redu
ctionof
ADHD
symptom
s(restlessness
poor
self-control
inattention
impu
lsivity
etc)
Neuroprotectio
nregu
lationof
dopamine
andinhibitio
nof
cholinesterase
Safeandwelltolerated
Mild
gastrointestinal
sidee
ffects
Uebel-
von
Sand
ersle
benetal
[24]
Ginkgo
biloba
Ginkgo(EGb761reg)
240m
gdailygiven
for3
to5weeks
Openclinicalpilo
tstudy
20child
renwith
ADHD
Improvem
ento
fADHD
core
symptom
sIm
provem
entin
cerebrovascularb
lood
flow
reversalof
5-HT1
andno
radrenergic
receptor
redu
ctions
Reverseinh
ibition
ofMAO
-AandMAO
-B
Very
lowrateso
fmild
adversee
ventsd
uring
observationalp
eriod
Salehi
etal[25]
Ginkgo
biloba
Ginkgo
biloba
(80ndash
120m
gday)
ormethylphenidate
(20ndash
30mgday)for
6weeks
Rand
omized
doub
le-blin
dcontrolled
trial
50child
ren
6ndash14years
oldwith
ADHD
(119899=25Ginkgo
biloba
versus119899=25
methylphenidate)
Improvem
ento
fADHD
symptom
sLesseffectiv
ethan
methylphenidate
Lesser
sidee
ffects
(headacheinsomnia
andlossof
appetite)than
methylphenidate
Leee
tal[26]
Ginseng
Korean
redginseng
(1000
mgb
id)a
ndplacebotwicea
dayfor8
weeks
Observatio
nalstudy
18child
ren
6ndash14years
oldwith
ADHD
Improvem
entin
attention
Noo
tropice
ffecton
CNS
Increaseddo
paminea
ndno
repineph
rinelevels
Neuroprotectiv
eeffects
Taste
aversio
nand
repu
lsion
toginseng
Koetal[27]
Ginseng
Korean
redginseng
extract(1g
KRG
extractp
ouch)twicea
day
for8
weeks
Rand
omized
doub
le-blin
dplacebo-
controlledtrial
70child
ren
6ndash15years
oldwith
ADHD(119899=33
KRGversus119899=37
placebo)
Improvem
ento
fhyperactivity
and
inattentionsymptom
sDecreased
quantitative
electro
enceph
alograph
ythetabetaratio
Norepo
rted
adverse
events
sidee
ffects
Lietal[28]
Ningdong
Ningdon
g(5mgkgday)
versus
methylphenidate
(1mgkgday)for8
weeks
Rand
omized
doub
le-blin
dmethylphenidate-
controlled
trial
72child
ren
6ndash13years
oldwith
ADHD(119899=36
Ningdon
gversus119899=36
methylphenidate)
Similare
fficacy
tocontrol
(methylphenidate)
Regu
lationof
dopamine
byincreasin
gHVA
concentrationin
thes
era
Hypersomnia
Akh
ondzadeh
etal
[29]
Passion
flowe
rPa
ssiflora
incarnata
Dou
ble-blind
rand
omized
methylphenidate-
controlledclinical
trial
34child
renwith
ADHD
Improvem
ento
fADHD
symptom
sNot
specified
Decreased
appetitea
ndanxietynervou
sness
comparedwith
methylphenidategrou
p
4 Neural Plasticity
Table1Con
tinued
Stud
yBo
tanicalagent
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Trebaticka
etal
[30]
Pycnogenol
Pycnogenol(1mgkgday)
orplacebotre
atmentfor
4weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
61child
ren
6ndash14
years
oldwith
ADHD(119899=44
Pycnogenolversus
119899=17placebo)
Attenu
ationof
hyperactivity
and
improvem
ento
fattention
visual-m
otoric
coordinatio
nand
concentration
Influ
ence
oncatecholam
ineformation
ormetabolism
Increasedprod
uctio
nof
nitricoxidew
hich
mod
ulates
dopamine
andno
repineph
rine
releasea
ndintake
Mild
sidee
ffects
inclu
ding
slownessand
gastric
discom
fort
Chovanovae
tal
[31]
Pycnogenol
Pycnogenol(1mgkgday)
orplacebotre
atmentfor
4weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
61ou
tpatient
child
ren
6ndash14yearso
ldwith
ADHD(119899
=un
specified
Pycnogenolversus
placebo)
Improved
attention
redu
ctionin
oxidative
damage
Antioxidant
prop
ertie
sNorepo
rted
adverse
events
sidee
ffects
Weber
etal[32]
StJohnrsquos
wort
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
56child
ren
6ndash17years
oldwith
ADHD(119899=27
SJW
versus119899=27
placebo)
Nosig
nificant
improvem
entinADHD
symptom
s
Norepo
rted
adverse
events
sidee
ffects
Razlo
getal[33]
Valer
ian(Valeriana
officin
alis)
Dou
ble-blindplacebo-
controlledclinicaltria
l
30child
ren
5ndash11years
oldwith
ADHD
(119899=10Va
leriana
officin
alismother
tincture(VO
MT)
or119899=103x
potencyof
VOMTversus119899=10
placebofor3
weeks)
Improvem
ento
fADHD
symptom
sinVO
MTor
3xpo
tencygrou
pin
comparis
onto
placebo
inparticularinatte
ntion
impu
lsivityand
or
hyperactivity
Inhibitio
nof
the
breakd
ownof
GABA
inthec
entralnervou
ssyste
m
Norepo
rted
adverse
events
sidee
ffects
Neural Plasticity 5
Table2Clinicaltrialsevaluatin
gsafetyandeffi
cacy
ofnu
trition
alsupp
lementsforA
DHD
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Torriolietal[34]
Acetyl-L-carnitin
e(LA
C)LA
C(500
mg2tim
esday)
orplacebofor12mon
ths
Rand
omized
doub
le-blin
dplacebo-
controlledparallel
multic
enterstudy
51child
ren(A
DHDand
Fragile
Xsynd
rome)
6ndash13yearso
ld(119899=24
ALC
versus119899=27
placebo)
Redu
ctionof
ADHD
symptom
sversus
Placeboon
Clinical
GlobalImpressio
nsParentalRa
ting
Mod
ulationof
neural
transm
issionby
increasin
gacetylcholine
synthesis
stim
ulatingits
releasea
ndreleaseo
fdo
pamineinthe
stria
tum
invario
usbrain
region
s
Noadversee
ventssid
eeffectsrepo
rted
Arnoldetal[35]
Acetyl-L-carnitin
e(AL
C)ALC
inweight-b
ased
doses
from
500to
1500
mgb
idor
placebofor16weeks
Multisite
parallel-g
roup
doub
le-blin
drand
omized
pilottria
l
112child
ren
5ndash12years
old(119899=53
Acetyl-L-carnitin
eversus119899=59placebo)
Acetyl-L-carnitin
esuperio
rtoplaceboin
inattentives
ubtype
Noadversee
ventssid
eeffectsrepo
rted
Richardson
and
Puri[36]
Essentialfattyacids
Highlyun
saturatedfatty
acid
(HUFA
)EP
A186m
gday
DHA480m
gday
120574-lino
lenica
cid96
mg
vitamin
E60
IUcis-lin
oleic
acid
864m
gAA42
mgand
thym
eoil8m
gor
oliveo
il(placebo
)for12weeks
Rand
omized
doub
le-blin
dplacebo-
controlledstu
dy
41child
ren
9participantswith
drew
before
thee
ndof
12-w
eekperio
d8ndash12yearso
ld(119899=15
HUFA
versus119899=14
placebo)
Attenu
ationof
ADHD
symptom
sfore
xample
inattention
hyperactivity
improvem
entin
cogn
ition
andem
otion
Influ
ence
onsig
nal
transductio
nrelevant
toneuron
alstructure
developm
entand
functio
ns
Upsetsto
machand
difficulty
swallowing
Stevense
tal[37]
Essentialfattyacids
PUFA
supp
lement
comprise
dof
480m
gDHA
80mgEP
A40m
garachido
nica
cid(A
A)
96mgGLA
and
24mg
alph
a-tocoph
erylacetateo
ran
oliveo
ilplacebofor4
mon
ths
Rand
omized
doub
le-blin
dplacebo-
controlledstu
dy
50child
ren(girlsa
ndbo
ys)119899=25PU
FAsupp
lementatio
n119899=25
placebo
Clearb
enefitfor
all
behaviorsc
haracteristic
ofADHDwas
not
observed
Treatm
enteffectsfor
cond
uctand
attentionas
wellasw
ithclinical
improvem
entsin
oppo
sitionald
efiant
behavior
Mediatio
nof
abno
rmal
neuron
alsig
nalin
gthat
results
inaberrant
behaviors
Not
specified
6 Neural PlasticityTa
ble2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Sinn
andBryan
[38]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omized
doub
le-blin
dcrossover
placebo-controlledstu
dy
132child
ren(data
availablefor
104and87
child
ren)
7ndash12yearso
ld(119899=36PU
FAsv
ersus
119899=41PU
FA+
micronu
trientsv
ersus
119899=27placebo)
Sign
ificant
treatment
effectsbasedon
parental
ratin
gof
core
ADHD
symptom
sinbo
thPU
FAgrou
psversus
placebo
Mod
ulationof
neural
cellsig
nalin
gand
neurotransmitter
processes
PUFA
swith
other
nutrientssuchas
vitC
B 3and
B 6mod
ulates
PUFArsquosrolein
the
synthesis
ofprostaglandins
and
chem
icalsimpo
rtantfor
biologicalandbrain
functio
n
Noadversee
ventssid
eeffects
Sinn
etal[39]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omizedone-w
aycrossoverplacebo-
controlledstu
dyPh
ases
1and
2
Phase1119899=129child
ren
with
ADHD(PUFA
versus
PUFA
+multiv
itaminsminerals
versus
placebofor15
weeks)
Phase2
119899=104
child
renwith
ADHD
(PUFA
PUFA
+multiv
itaminm
inerals
andplacebofor15
weeks)
Improved
abilityon
attentioncontroland
vocabu
lary
perfo
rmance
durin
gph
ase2
Influ
ence
onmetabolic
andneuralactiv
ities
Increasin
gdo
pamine
activ
ityin
thefrontal
lobe
Twocaseso
fnauseaa
ndon
eepisode
ofno
sebleed
Manor
etal[40
]
Essentialfattyacids
2capsules
twicea
dayof
phosph
atidylserin
e(PS
)containing
omega-3(300
mg
ofPS
and120m
gof
EPA+
DHA)o
rcellulose
capsules
asplacebofor15weeks
Rand
omized
doub
le-blin
dsin
gle-centerplacebo
-controlledtrial
200child
ren(6ndash13y
ears
old)
rand
omlyassig
ned
toPS
-omega-3capsules
orplacebo
119873=162child
ren
completed
15weeks
oftre
atment(119899=110PS
-om
ega-3119899=52
placebo)
Improvem
ento
fADHD
symptom
s(im
pulsivity
inattention
moo
dand
behavior
issue)
Maintenance
ofintegrity
ofcellmem
branes
Influ
ence
ondo
paminergica
ndcholinergics
ystems
Increasin
gom
ega-3
LC-PUFA
which
improves
behavioral
sensoryand
neurologicaldysfu
nctio
n
Mild
adversee
vent
profi
leG
Idisc
omfort
atop
icderm
atitis
nauseaticsand
hyperactivity
Raze
tal[41]
Essentialfattyacids
EFAcapsules
containing
240m
gof
linoleica
cid(LA)
60mgof
alph
a-lin
olenicacid
(ALA
)95
mgof
mineraloil
and5m
gof
a-tocoph
erol(as
anantio
xidant)2
timesday
orplacebovitC(500
mg
ascorbicacid)2
timesday
for7
weeks
Rand
omized
doub
le-blin
dplacebo-controlledtrial
73child
ren
7ndash13years
old63
child
ren
completed
thes
tudy
(119899=39EF
Asupp
lement
versus
39placebo
vitamin
C)
Both
treatments
amelioratedsome
ADHDsymptom
sNo
differenceineffi
cacy
betweentre
atments
Improvem
entin
behavioralsensoryand
cogn
itive
functio
ns
Noadversee
ventssid
eeffectsrepo
rted
Neural Plasticity 7
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Voigtetal[42]
Essentialfattyacids
345m
gof
DHAperd
ay(119899=32)o
raplacebocapsule
(119899=31)for
4mon
ths
Rand
omized
doub
le-blin
dplacebo
controlledstu
dy
54child
ren6ndash
12years
old(119899=27
docosahexaenoica
cid
(DHA)v
ersus119899=27
placebo)
DHAsupp
lementatio
ndidno
tsignificantly
improveinanyob
jective
orsubjectiv
emeasure
ofADHDsymptom
s
Welltolerated
andno
adversee
ffectsw
ere
repo
rted
Hira
yamae
tal
[43]
Essentialfattyacids
DHAgrou
pferm
ented
soybeanmilk
(600
mg
DHA12
5mL3week)bread
rolls
(300
mgDHA45g
2week)
andste
amed
bread
(600
mgD
HA60g
2w
eek)
orplacebofood
scon
taining
oliveo
ilinste
adof
DHA-
rich
fishoilfor
2weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
40child
renwith
ADHD
6ndash12yearso
ld(119899=20
docosahexaenoica
cid
(DHA)v
ersus119899=20
placebo)
DHAsupp
lementatio
ndidno
timprove
ADHD-related
symptom
s
Noserio
ussid
eeffects
were
repo
rted
inthe
study
Kono
faletal[44]
Iron
80mgferrou
ssulfatetablets
orplaceboon
cedaily
inthe
morning
for12weeks
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
23ADHDchild
renwith
lowserum
ferritinlevel
(lt30
ngm
L)5ndash8y
ears
old(119899=18iro
nversus
119899=5placebo)
Improvem
ento
fhyperactiveim
pulsive
andinattentive
symptom
sintheA
DHD
ratin
gscale
Iron
isac
ofactorinthe
synthesis
ofbo
thno
repineph
rinea
nddo
pamine
Minor
sidee
ffectsw
ere
repo
rtedsuchas
nausea
constip
ation
and
abdo
minalpain
Mou
sain-Bosce
tal[45]
Vitamin
B6andmagnesiu
mADHDchild
ren
magnesiu
m-vitamin
B6(M
g-B6
)regim
en(6
mgkgd
Mg06m
gkgd
vit-B
6)for
sixmon
thsC
ontro
lsdidno
treceiveM
g-B6
Openstu
dy
76child
ren(m
eanage
69y
ears13girls
and27
boys)(40
ADHD
child
renamp36
healthy
child
ren)
Attenu
ationof
hyperactivity
and
aggressiv
enessS
choo
lattentionwas
also
improved
Vitamin
B6facilitates
thep
rodu
ctionof
the
serotonin
Magnesiu
misa
nonspecific
inhibitoro
fcalcium
andNMDA
channels
Magnesiu
mcan
influ
ence
catecholam
ine
signalin
g
Norepo
rted
sidee
ffects
Bilicietal[46]
Zinc
150m
gzinc
sulfateor
150m
gsucrose(placebo)
daily
for12
weeks
Rand
omized
doub
le-blin
dparallel-g
roup
placebo-controlledtrial
400child
ren6ndash
14years
old(119899=202zinc
versus
119899=198placebo)
Zinc
sulfatebette
rthan
placeboin
decreasin
ghyperactivity
and
impu
lsivityand
improvingsocialization
butn
otinattention
Increasedzinc
levels
necessaryforc
ognitiv
edevelopm
ent
Noserio
ussid
eeffects
repo
rtedM
etallic
taste
was
acom
mon
complaint
8 Neural Plasticity
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Akh
ondzadeh
etal
[47]
Zinc
Zinc
sulfate(55m
gday)
+methylphenidate
(1mgkgday)o
rsucrose
(placebo
)55m
g+
methylphenidate
(1mgkgday)for
6weeks
Rand
omized
doub
le-blin
dclinical
trial
44child
ren
5ndash11years
old(119899=22
methylphenidate+zinc
versus119899=22
methylphenidate+
placebo)
Sign
ificantlygreater
treatmenteffects(as
per
parent
andteacher
ratin
gscales
cores)in
zinc
sulfatewith
methylphenidate
treatmento
verp
lacebo
with
methylphenidate
Zinc
regulates
dopamine
functio
nindirectly
throug
hits
actio
non
melaton
in
Nauseaa
ndmetallic
taste
werec
ommon
complaintsOverallit
was
welltolerated
Arnoldetal[48]
Zinc
Zinc
115mgday(oncea
day)
orZinc
230
mgday
(twicea
day)
orplacebo(8
weeks)am
phetam
ine
5ndash15mgdaily
(based
onthe
weight)
Durationof
experim
entw
as13
weeks
(8weeks
controlled
+5weeks
amph
etam
ine
add-on
)
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
52child
ren6ndash
14years
old(119899=20Zinc
1or
119899=8Zinc
2versus
119899=24placebo)
Noappreciable
differenceb
etweenbo
thdo
sageso
fzinca
ndplacebo
Gastro
intestinal
discom
fortrepo
rted
by1
patie
nt
Neural Plasticity 9
Table3Clinicaltrialsdemon
stratingeffi
cacy
ofcombinatio
ntherapyof
botanicalagentsa
ndherbssupp
lementswith
methylphenidatein
treatingADHD
Stud
yMetho
dsParticipants
Outcomes
Com
ments
Lyon
etal[49]
Ginkgo
biloba
andGinseng
Ginkgo
biloba
extract
(50m
g)plus
American
ginsengPa
nax
quinquefo
lium
(200
mg)
twiceday
(com
binatio
nprod
uct)
Open
pilotstudy
36child
ren
3ndash17years
oldwith
ADHD
Improvem
ento
fADHD
symptom
s(hyperactiv
ity
impu
lsivenessand
anxiety)
Five
participants
repo
rted
adversee
vents
(increasedADHD
symptom
saggressiv
enesssw
eatin
gheadacheand
tiredness)on
ly2
considered
related
tothe
study
Wangetal[50]
Jingling
oralan
dmethylphenidate
Methylphenidate
(10ndash
40mgd)
Rand
omizedblin
ded
study
119899=50ADHDchild
ren
with
transie
nttic
disorder
Sign
ificant
improvem
ent
ofADHDsymptom
sas
wellastics
Com
binatio
ntherapy
moree
ffectivethan
methylphenidatealon
ein
improvingADHD
andtic
symptom
s
Dingetal[51]
Yizhiand
methylphenidate
Rand
omized
methylphenidate-
controlled
trial
210child
renwith
hyperkineticsynd
rome
Sign
ificant
improvem
ent
inADHDsymptom
sin
thosetaking
combinatio
ntherapy
comparedto
either
given
asmon
otherapy
Yizhih
adfewer
side
effectswhengivenalon
eor
incombinatio
nthan
methylphenidate
Akh
ondzadeh
etal
[47]
Zinc
sulfateand
methylphenidate
Rand
omized
doub
le-blindand
methylphenidate+
placebocontrolledtrial
44child
ren(26bo
ys18
girls)5ndash11yearso
ldwith
ADHD
Improved
parent
and
teacherratingscale
scores
fortho
sesupp
lementedwith
zinc
sulfateas
anadjunct
Side
effectsrepo
rted
anxietylossof
appetite
nauseaheadache
abdo
minalpain
insomniaandmetallic
taste
10 Neural Plasticity
and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment
32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary
33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger
number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]
Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy
34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Brain ScienceInternational Journal of
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Neurodegenerative Diseases
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Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
4 Neural Plasticity
Table1Con
tinued
Stud
yBo
tanicalagent
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Trebaticka
etal
[30]
Pycnogenol
Pycnogenol(1mgkgday)
orplacebotre
atmentfor
4weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
61child
ren
6ndash14
years
oldwith
ADHD(119899=44
Pycnogenolversus
119899=17placebo)
Attenu
ationof
hyperactivity
and
improvem
ento
fattention
visual-m
otoric
coordinatio
nand
concentration
Influ
ence
oncatecholam
ineformation
ormetabolism
Increasedprod
uctio
nof
nitricoxidew
hich
mod
ulates
dopamine
andno
repineph
rine
releasea
ndintake
Mild
sidee
ffects
inclu
ding
slownessand
gastric
discom
fort
Chovanovae
tal
[31]
Pycnogenol
Pycnogenol(1mgkgday)
orplacebotre
atmentfor
4weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
61ou
tpatient
child
ren
6ndash14yearso
ldwith
ADHD(119899
=un
specified
Pycnogenolversus
placebo)
Improved
attention
redu
ctionin
oxidative
damage
Antioxidant
prop
ertie
sNorepo
rted
adverse
events
sidee
ffects
Weber
etal[32]
StJohnrsquos
wort
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
56child
ren
6ndash17years
oldwith
ADHD(119899=27
SJW
versus119899=27
placebo)
Nosig
nificant
improvem
entinADHD
symptom
s
Norepo
rted
adverse
events
sidee
ffects
Razlo
getal[33]
Valer
ian(Valeriana
officin
alis)
Dou
ble-blindplacebo-
controlledclinicaltria
l
30child
ren
5ndash11years
oldwith
ADHD
(119899=10Va
leriana
officin
alismother
tincture(VO
MT)
or119899=103x
potencyof
VOMTversus119899=10
placebofor3
weeks)
Improvem
ento
fADHD
symptom
sinVO
MTor
3xpo
tencygrou
pin
comparis
onto
placebo
inparticularinatte
ntion
impu
lsivityand
or
hyperactivity
Inhibitio
nof
the
breakd
ownof
GABA
inthec
entralnervou
ssyste
m
Norepo
rted
adverse
events
sidee
ffects
Neural Plasticity 5
Table2Clinicaltrialsevaluatin
gsafetyandeffi
cacy
ofnu
trition
alsupp
lementsforA
DHD
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Torriolietal[34]
Acetyl-L-carnitin
e(LA
C)LA
C(500
mg2tim
esday)
orplacebofor12mon
ths
Rand
omized
doub
le-blin
dplacebo-
controlledparallel
multic
enterstudy
51child
ren(A
DHDand
Fragile
Xsynd
rome)
6ndash13yearso
ld(119899=24
ALC
versus119899=27
placebo)
Redu
ctionof
ADHD
symptom
sversus
Placeboon
Clinical
GlobalImpressio
nsParentalRa
ting
Mod
ulationof
neural
transm
issionby
increasin
gacetylcholine
synthesis
stim
ulatingits
releasea
ndreleaseo
fdo
pamineinthe
stria
tum
invario
usbrain
region
s
Noadversee
ventssid
eeffectsrepo
rted
Arnoldetal[35]
Acetyl-L-carnitin
e(AL
C)ALC
inweight-b
ased
doses
from
500to
1500
mgb
idor
placebofor16weeks
Multisite
parallel-g
roup
doub
le-blin
drand
omized
pilottria
l
112child
ren
5ndash12years
old(119899=53
Acetyl-L-carnitin
eversus119899=59placebo)
Acetyl-L-carnitin
esuperio
rtoplaceboin
inattentives
ubtype
Noadversee
ventssid
eeffectsrepo
rted
Richardson
and
Puri[36]
Essentialfattyacids
Highlyun
saturatedfatty
acid
(HUFA
)EP
A186m
gday
DHA480m
gday
120574-lino
lenica
cid96
mg
vitamin
E60
IUcis-lin
oleic
acid
864m
gAA42
mgand
thym
eoil8m
gor
oliveo
il(placebo
)for12weeks
Rand
omized
doub
le-blin
dplacebo-
controlledstu
dy
41child
ren
9participantswith
drew
before
thee
ndof
12-w
eekperio
d8ndash12yearso
ld(119899=15
HUFA
versus119899=14
placebo)
Attenu
ationof
ADHD
symptom
sfore
xample
inattention
hyperactivity
improvem
entin
cogn
ition
andem
otion
Influ
ence
onsig
nal
transductio
nrelevant
toneuron
alstructure
developm
entand
functio
ns
Upsetsto
machand
difficulty
swallowing
Stevense
tal[37]
Essentialfattyacids
PUFA
supp
lement
comprise
dof
480m
gDHA
80mgEP
A40m
garachido
nica
cid(A
A)
96mgGLA
and
24mg
alph
a-tocoph
erylacetateo
ran
oliveo
ilplacebofor4
mon
ths
Rand
omized
doub
le-blin
dplacebo-
controlledstu
dy
50child
ren(girlsa
ndbo
ys)119899=25PU
FAsupp
lementatio
n119899=25
placebo
Clearb
enefitfor
all
behaviorsc
haracteristic
ofADHDwas
not
observed
Treatm
enteffectsfor
cond
uctand
attentionas
wellasw
ithclinical
improvem
entsin
oppo
sitionald
efiant
behavior
Mediatio
nof
abno
rmal
neuron
alsig
nalin
gthat
results
inaberrant
behaviors
Not
specified
6 Neural PlasticityTa
ble2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Sinn
andBryan
[38]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omized
doub
le-blin
dcrossover
placebo-controlledstu
dy
132child
ren(data
availablefor
104and87
child
ren)
7ndash12yearso
ld(119899=36PU
FAsv
ersus
119899=41PU
FA+
micronu
trientsv
ersus
119899=27placebo)
Sign
ificant
treatment
effectsbasedon
parental
ratin
gof
core
ADHD
symptom
sinbo
thPU
FAgrou
psversus
placebo
Mod
ulationof
neural
cellsig
nalin
gand
neurotransmitter
processes
PUFA
swith
other
nutrientssuchas
vitC
B 3and
B 6mod
ulates
PUFArsquosrolein
the
synthesis
ofprostaglandins
and
chem
icalsimpo
rtantfor
biologicalandbrain
functio
n
Noadversee
ventssid
eeffects
Sinn
etal[39]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omizedone-w
aycrossoverplacebo-
controlledstu
dyPh
ases
1and
2
Phase1119899=129child
ren
with
ADHD(PUFA
versus
PUFA
+multiv
itaminsminerals
versus
placebofor15
weeks)
Phase2
119899=104
child
renwith
ADHD
(PUFA
PUFA
+multiv
itaminm
inerals
andplacebofor15
weeks)
Improved
abilityon
attentioncontroland
vocabu
lary
perfo
rmance
durin
gph
ase2
Influ
ence
onmetabolic
andneuralactiv
ities
Increasin
gdo
pamine
activ
ityin
thefrontal
lobe
Twocaseso
fnauseaa
ndon
eepisode
ofno
sebleed
Manor
etal[40
]
Essentialfattyacids
2capsules
twicea
dayof
phosph
atidylserin
e(PS
)containing
omega-3(300
mg
ofPS
and120m
gof
EPA+
DHA)o
rcellulose
capsules
asplacebofor15weeks
Rand
omized
doub
le-blin
dsin
gle-centerplacebo
-controlledtrial
200child
ren(6ndash13y
ears
old)
rand
omlyassig
ned
toPS
-omega-3capsules
orplacebo
119873=162child
ren
completed
15weeks
oftre
atment(119899=110PS
-om
ega-3119899=52
placebo)
Improvem
ento
fADHD
symptom
s(im
pulsivity
inattention
moo
dand
behavior
issue)
Maintenance
ofintegrity
ofcellmem
branes
Influ
ence
ondo
paminergica
ndcholinergics
ystems
Increasin
gom
ega-3
LC-PUFA
which
improves
behavioral
sensoryand
neurologicaldysfu
nctio
n
Mild
adversee
vent
profi
leG
Idisc
omfort
atop
icderm
atitis
nauseaticsand
hyperactivity
Raze
tal[41]
Essentialfattyacids
EFAcapsules
containing
240m
gof
linoleica
cid(LA)
60mgof
alph
a-lin
olenicacid
(ALA
)95
mgof
mineraloil
and5m
gof
a-tocoph
erol(as
anantio
xidant)2
timesday
orplacebovitC(500
mg
ascorbicacid)2
timesday
for7
weeks
Rand
omized
doub
le-blin
dplacebo-controlledtrial
73child
ren
7ndash13years
old63
child
ren
completed
thes
tudy
(119899=39EF
Asupp
lement
versus
39placebo
vitamin
C)
Both
treatments
amelioratedsome
ADHDsymptom
sNo
differenceineffi
cacy
betweentre
atments
Improvem
entin
behavioralsensoryand
cogn
itive
functio
ns
Noadversee
ventssid
eeffectsrepo
rted
Neural Plasticity 7
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Voigtetal[42]
Essentialfattyacids
345m
gof
DHAperd
ay(119899=32)o
raplacebocapsule
(119899=31)for
4mon
ths
Rand
omized
doub
le-blin
dplacebo
controlledstu
dy
54child
ren6ndash
12years
old(119899=27
docosahexaenoica
cid
(DHA)v
ersus119899=27
placebo)
DHAsupp
lementatio
ndidno
tsignificantly
improveinanyob
jective
orsubjectiv
emeasure
ofADHDsymptom
s
Welltolerated
andno
adversee
ffectsw
ere
repo
rted
Hira
yamae
tal
[43]
Essentialfattyacids
DHAgrou
pferm
ented
soybeanmilk
(600
mg
DHA12
5mL3week)bread
rolls
(300
mgDHA45g
2week)
andste
amed
bread
(600
mgD
HA60g
2w
eek)
orplacebofood
scon
taining
oliveo
ilinste
adof
DHA-
rich
fishoilfor
2weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
40child
renwith
ADHD
6ndash12yearso
ld(119899=20
docosahexaenoica
cid
(DHA)v
ersus119899=20
placebo)
DHAsupp
lementatio
ndidno
timprove
ADHD-related
symptom
s
Noserio
ussid
eeffects
were
repo
rted
inthe
study
Kono
faletal[44]
Iron
80mgferrou
ssulfatetablets
orplaceboon
cedaily
inthe
morning
for12weeks
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
23ADHDchild
renwith
lowserum
ferritinlevel
(lt30
ngm
L)5ndash8y
ears
old(119899=18iro
nversus
119899=5placebo)
Improvem
ento
fhyperactiveim
pulsive
andinattentive
symptom
sintheA
DHD
ratin
gscale
Iron
isac
ofactorinthe
synthesis
ofbo
thno
repineph
rinea
nddo
pamine
Minor
sidee
ffectsw
ere
repo
rtedsuchas
nausea
constip
ation
and
abdo
minalpain
Mou
sain-Bosce
tal[45]
Vitamin
B6andmagnesiu
mADHDchild
ren
magnesiu
m-vitamin
B6(M
g-B6
)regim
en(6
mgkgd
Mg06m
gkgd
vit-B
6)for
sixmon
thsC
ontro
lsdidno
treceiveM
g-B6
Openstu
dy
76child
ren(m
eanage
69y
ears13girls
and27
boys)(40
ADHD
child
renamp36
healthy
child
ren)
Attenu
ationof
hyperactivity
and
aggressiv
enessS
choo
lattentionwas
also
improved
Vitamin
B6facilitates
thep
rodu
ctionof
the
serotonin
Magnesiu
misa
nonspecific
inhibitoro
fcalcium
andNMDA
channels
Magnesiu
mcan
influ
ence
catecholam
ine
signalin
g
Norepo
rted
sidee
ffects
Bilicietal[46]
Zinc
150m
gzinc
sulfateor
150m
gsucrose(placebo)
daily
for12
weeks
Rand
omized
doub
le-blin
dparallel-g
roup
placebo-controlledtrial
400child
ren6ndash
14years
old(119899=202zinc
versus
119899=198placebo)
Zinc
sulfatebette
rthan
placeboin
decreasin
ghyperactivity
and
impu
lsivityand
improvingsocialization
butn
otinattention
Increasedzinc
levels
necessaryforc
ognitiv
edevelopm
ent
Noserio
ussid
eeffects
repo
rtedM
etallic
taste
was
acom
mon
complaint
8 Neural Plasticity
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Akh
ondzadeh
etal
[47]
Zinc
Zinc
sulfate(55m
gday)
+methylphenidate
(1mgkgday)o
rsucrose
(placebo
)55m
g+
methylphenidate
(1mgkgday)for
6weeks
Rand
omized
doub
le-blin
dclinical
trial
44child
ren
5ndash11years
old(119899=22
methylphenidate+zinc
versus119899=22
methylphenidate+
placebo)
Sign
ificantlygreater
treatmenteffects(as
per
parent
andteacher
ratin
gscales
cores)in
zinc
sulfatewith
methylphenidate
treatmento
verp
lacebo
with
methylphenidate
Zinc
regulates
dopamine
functio
nindirectly
throug
hits
actio
non
melaton
in
Nauseaa
ndmetallic
taste
werec
ommon
complaintsOverallit
was
welltolerated
Arnoldetal[48]
Zinc
Zinc
115mgday(oncea
day)
orZinc
230
mgday
(twicea
day)
orplacebo(8
weeks)am
phetam
ine
5ndash15mgdaily
(based
onthe
weight)
Durationof
experim
entw
as13
weeks
(8weeks
controlled
+5weeks
amph
etam
ine
add-on
)
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
52child
ren6ndash
14years
old(119899=20Zinc
1or
119899=8Zinc
2versus
119899=24placebo)
Noappreciable
differenceb
etweenbo
thdo
sageso
fzinca
ndplacebo
Gastro
intestinal
discom
fortrepo
rted
by1
patie
nt
Neural Plasticity 9
Table3Clinicaltrialsdemon
stratingeffi
cacy
ofcombinatio
ntherapyof
botanicalagentsa
ndherbssupp
lementswith
methylphenidatein
treatingADHD
Stud
yMetho
dsParticipants
Outcomes
Com
ments
Lyon
etal[49]
Ginkgo
biloba
andGinseng
Ginkgo
biloba
extract
(50m
g)plus
American
ginsengPa
nax
quinquefo
lium
(200
mg)
twiceday
(com
binatio
nprod
uct)
Open
pilotstudy
36child
ren
3ndash17years
oldwith
ADHD
Improvem
ento
fADHD
symptom
s(hyperactiv
ity
impu
lsivenessand
anxiety)
Five
participants
repo
rted
adversee
vents
(increasedADHD
symptom
saggressiv
enesssw
eatin
gheadacheand
tiredness)on
ly2
considered
related
tothe
study
Wangetal[50]
Jingling
oralan
dmethylphenidate
Methylphenidate
(10ndash
40mgd)
Rand
omizedblin
ded
study
119899=50ADHDchild
ren
with
transie
nttic
disorder
Sign
ificant
improvem
ent
ofADHDsymptom
sas
wellastics
Com
binatio
ntherapy
moree
ffectivethan
methylphenidatealon
ein
improvingADHD
andtic
symptom
s
Dingetal[51]
Yizhiand
methylphenidate
Rand
omized
methylphenidate-
controlled
trial
210child
renwith
hyperkineticsynd
rome
Sign
ificant
improvem
ent
inADHDsymptom
sin
thosetaking
combinatio
ntherapy
comparedto
either
given
asmon
otherapy
Yizhih
adfewer
side
effectswhengivenalon
eor
incombinatio
nthan
methylphenidate
Akh
ondzadeh
etal
[47]
Zinc
sulfateand
methylphenidate
Rand
omized
doub
le-blindand
methylphenidate+
placebocontrolledtrial
44child
ren(26bo
ys18
girls)5ndash11yearso
ldwith
ADHD
Improved
parent
and
teacherratingscale
scores
fortho
sesupp
lementedwith
zinc
sulfateas
anadjunct
Side
effectsrepo
rted
anxietylossof
appetite
nauseaheadache
abdo
minalpain
insomniaandmetallic
taste
10 Neural Plasticity
and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment
32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary
33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger
number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]
Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy
34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
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[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity 5
Table2Clinicaltrialsevaluatin
gsafetyandeffi
cacy
ofnu
trition
alsupp
lementsforA
DHD
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Torriolietal[34]
Acetyl-L-carnitin
e(LA
C)LA
C(500
mg2tim
esday)
orplacebofor12mon
ths
Rand
omized
doub
le-blin
dplacebo-
controlledparallel
multic
enterstudy
51child
ren(A
DHDand
Fragile
Xsynd
rome)
6ndash13yearso
ld(119899=24
ALC
versus119899=27
placebo)
Redu
ctionof
ADHD
symptom
sversus
Placeboon
Clinical
GlobalImpressio
nsParentalRa
ting
Mod
ulationof
neural
transm
issionby
increasin
gacetylcholine
synthesis
stim
ulatingits
releasea
ndreleaseo
fdo
pamineinthe
stria
tum
invario
usbrain
region
s
Noadversee
ventssid
eeffectsrepo
rted
Arnoldetal[35]
Acetyl-L-carnitin
e(AL
C)ALC
inweight-b
ased
doses
from
500to
1500
mgb
idor
placebofor16weeks
Multisite
parallel-g
roup
doub
le-blin
drand
omized
pilottria
l
112child
ren
5ndash12years
old(119899=53
Acetyl-L-carnitin
eversus119899=59placebo)
Acetyl-L-carnitin
esuperio
rtoplaceboin
inattentives
ubtype
Noadversee
ventssid
eeffectsrepo
rted
Richardson
and
Puri[36]
Essentialfattyacids
Highlyun
saturatedfatty
acid
(HUFA
)EP
A186m
gday
DHA480m
gday
120574-lino
lenica
cid96
mg
vitamin
E60
IUcis-lin
oleic
acid
864m
gAA42
mgand
thym
eoil8m
gor
oliveo
il(placebo
)for12weeks
Rand
omized
doub
le-blin
dplacebo-
controlledstu
dy
41child
ren
9participantswith
drew
before
thee
ndof
12-w
eekperio
d8ndash12yearso
ld(119899=15
HUFA
versus119899=14
placebo)
Attenu
ationof
ADHD
symptom
sfore
xample
inattention
hyperactivity
improvem
entin
cogn
ition
andem
otion
Influ
ence
onsig
nal
transductio
nrelevant
toneuron
alstructure
developm
entand
functio
ns
Upsetsto
machand
difficulty
swallowing
Stevense
tal[37]
Essentialfattyacids
PUFA
supp
lement
comprise
dof
480m
gDHA
80mgEP
A40m
garachido
nica
cid(A
A)
96mgGLA
and
24mg
alph
a-tocoph
erylacetateo
ran
oliveo
ilplacebofor4
mon
ths
Rand
omized
doub
le-blin
dplacebo-
controlledstu
dy
50child
ren(girlsa
ndbo
ys)119899=25PU
FAsupp
lementatio
n119899=25
placebo
Clearb
enefitfor
all
behaviorsc
haracteristic
ofADHDwas
not
observed
Treatm
enteffectsfor
cond
uctand
attentionas
wellasw
ithclinical
improvem
entsin
oppo
sitionald
efiant
behavior
Mediatio
nof
abno
rmal
neuron
alsig
nalin
gthat
results
inaberrant
behaviors
Not
specified
6 Neural PlasticityTa
ble2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Sinn
andBryan
[38]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omized
doub
le-blin
dcrossover
placebo-controlledstu
dy
132child
ren(data
availablefor
104and87
child
ren)
7ndash12yearso
ld(119899=36PU
FAsv
ersus
119899=41PU
FA+
micronu
trientsv
ersus
119899=27placebo)
Sign
ificant
treatment
effectsbasedon
parental
ratin
gof
core
ADHD
symptom
sinbo
thPU
FAgrou
psversus
placebo
Mod
ulationof
neural
cellsig
nalin
gand
neurotransmitter
processes
PUFA
swith
other
nutrientssuchas
vitC
B 3and
B 6mod
ulates
PUFArsquosrolein
the
synthesis
ofprostaglandins
and
chem
icalsimpo
rtantfor
biologicalandbrain
functio
n
Noadversee
ventssid
eeffects
Sinn
etal[39]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omizedone-w
aycrossoverplacebo-
controlledstu
dyPh
ases
1and
2
Phase1119899=129child
ren
with
ADHD(PUFA
versus
PUFA
+multiv
itaminsminerals
versus
placebofor15
weeks)
Phase2
119899=104
child
renwith
ADHD
(PUFA
PUFA
+multiv
itaminm
inerals
andplacebofor15
weeks)
Improved
abilityon
attentioncontroland
vocabu
lary
perfo
rmance
durin
gph
ase2
Influ
ence
onmetabolic
andneuralactiv
ities
Increasin
gdo
pamine
activ
ityin
thefrontal
lobe
Twocaseso
fnauseaa
ndon
eepisode
ofno
sebleed
Manor
etal[40
]
Essentialfattyacids
2capsules
twicea
dayof
phosph
atidylserin
e(PS
)containing
omega-3(300
mg
ofPS
and120m
gof
EPA+
DHA)o
rcellulose
capsules
asplacebofor15weeks
Rand
omized
doub
le-blin
dsin
gle-centerplacebo
-controlledtrial
200child
ren(6ndash13y
ears
old)
rand
omlyassig
ned
toPS
-omega-3capsules
orplacebo
119873=162child
ren
completed
15weeks
oftre
atment(119899=110PS
-om
ega-3119899=52
placebo)
Improvem
ento
fADHD
symptom
s(im
pulsivity
inattention
moo
dand
behavior
issue)
Maintenance
ofintegrity
ofcellmem
branes
Influ
ence
ondo
paminergica
ndcholinergics
ystems
Increasin
gom
ega-3
LC-PUFA
which
improves
behavioral
sensoryand
neurologicaldysfu
nctio
n
Mild
adversee
vent
profi
leG
Idisc
omfort
atop
icderm
atitis
nauseaticsand
hyperactivity
Raze
tal[41]
Essentialfattyacids
EFAcapsules
containing
240m
gof
linoleica
cid(LA)
60mgof
alph
a-lin
olenicacid
(ALA
)95
mgof
mineraloil
and5m
gof
a-tocoph
erol(as
anantio
xidant)2
timesday
orplacebovitC(500
mg
ascorbicacid)2
timesday
for7
weeks
Rand
omized
doub
le-blin
dplacebo-controlledtrial
73child
ren
7ndash13years
old63
child
ren
completed
thes
tudy
(119899=39EF
Asupp
lement
versus
39placebo
vitamin
C)
Both
treatments
amelioratedsome
ADHDsymptom
sNo
differenceineffi
cacy
betweentre
atments
Improvem
entin
behavioralsensoryand
cogn
itive
functio
ns
Noadversee
ventssid
eeffectsrepo
rted
Neural Plasticity 7
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Voigtetal[42]
Essentialfattyacids
345m
gof
DHAperd
ay(119899=32)o
raplacebocapsule
(119899=31)for
4mon
ths
Rand
omized
doub
le-blin
dplacebo
controlledstu
dy
54child
ren6ndash
12years
old(119899=27
docosahexaenoica
cid
(DHA)v
ersus119899=27
placebo)
DHAsupp
lementatio
ndidno
tsignificantly
improveinanyob
jective
orsubjectiv
emeasure
ofADHDsymptom
s
Welltolerated
andno
adversee
ffectsw
ere
repo
rted
Hira
yamae
tal
[43]
Essentialfattyacids
DHAgrou
pferm
ented
soybeanmilk
(600
mg
DHA12
5mL3week)bread
rolls
(300
mgDHA45g
2week)
andste
amed
bread
(600
mgD
HA60g
2w
eek)
orplacebofood
scon
taining
oliveo
ilinste
adof
DHA-
rich
fishoilfor
2weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
40child
renwith
ADHD
6ndash12yearso
ld(119899=20
docosahexaenoica
cid
(DHA)v
ersus119899=20
placebo)
DHAsupp
lementatio
ndidno
timprove
ADHD-related
symptom
s
Noserio
ussid
eeffects
were
repo
rted
inthe
study
Kono
faletal[44]
Iron
80mgferrou
ssulfatetablets
orplaceboon
cedaily
inthe
morning
for12weeks
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
23ADHDchild
renwith
lowserum
ferritinlevel
(lt30
ngm
L)5ndash8y
ears
old(119899=18iro
nversus
119899=5placebo)
Improvem
ento
fhyperactiveim
pulsive
andinattentive
symptom
sintheA
DHD
ratin
gscale
Iron
isac
ofactorinthe
synthesis
ofbo
thno
repineph
rinea
nddo
pamine
Minor
sidee
ffectsw
ere
repo
rtedsuchas
nausea
constip
ation
and
abdo
minalpain
Mou
sain-Bosce
tal[45]
Vitamin
B6andmagnesiu
mADHDchild
ren
magnesiu
m-vitamin
B6(M
g-B6
)regim
en(6
mgkgd
Mg06m
gkgd
vit-B
6)for
sixmon
thsC
ontro
lsdidno
treceiveM
g-B6
Openstu
dy
76child
ren(m
eanage
69y
ears13girls
and27
boys)(40
ADHD
child
renamp36
healthy
child
ren)
Attenu
ationof
hyperactivity
and
aggressiv
enessS
choo
lattentionwas
also
improved
Vitamin
B6facilitates
thep
rodu
ctionof
the
serotonin
Magnesiu
misa
nonspecific
inhibitoro
fcalcium
andNMDA
channels
Magnesiu
mcan
influ
ence
catecholam
ine
signalin
g
Norepo
rted
sidee
ffects
Bilicietal[46]
Zinc
150m
gzinc
sulfateor
150m
gsucrose(placebo)
daily
for12
weeks
Rand
omized
doub
le-blin
dparallel-g
roup
placebo-controlledtrial
400child
ren6ndash
14years
old(119899=202zinc
versus
119899=198placebo)
Zinc
sulfatebette
rthan
placeboin
decreasin
ghyperactivity
and
impu
lsivityand
improvingsocialization
butn
otinattention
Increasedzinc
levels
necessaryforc
ognitiv
edevelopm
ent
Noserio
ussid
eeffects
repo
rtedM
etallic
taste
was
acom
mon
complaint
8 Neural Plasticity
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Akh
ondzadeh
etal
[47]
Zinc
Zinc
sulfate(55m
gday)
+methylphenidate
(1mgkgday)o
rsucrose
(placebo
)55m
g+
methylphenidate
(1mgkgday)for
6weeks
Rand
omized
doub
le-blin
dclinical
trial
44child
ren
5ndash11years
old(119899=22
methylphenidate+zinc
versus119899=22
methylphenidate+
placebo)
Sign
ificantlygreater
treatmenteffects(as
per
parent
andteacher
ratin
gscales
cores)in
zinc
sulfatewith
methylphenidate
treatmento
verp
lacebo
with
methylphenidate
Zinc
regulates
dopamine
functio
nindirectly
throug
hits
actio
non
melaton
in
Nauseaa
ndmetallic
taste
werec
ommon
complaintsOverallit
was
welltolerated
Arnoldetal[48]
Zinc
Zinc
115mgday(oncea
day)
orZinc
230
mgday
(twicea
day)
orplacebo(8
weeks)am
phetam
ine
5ndash15mgdaily
(based
onthe
weight)
Durationof
experim
entw
as13
weeks
(8weeks
controlled
+5weeks
amph
etam
ine
add-on
)
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
52child
ren6ndash
14years
old(119899=20Zinc
1or
119899=8Zinc
2versus
119899=24placebo)
Noappreciable
differenceb
etweenbo
thdo
sageso
fzinca
ndplacebo
Gastro
intestinal
discom
fortrepo
rted
by1
patie
nt
Neural Plasticity 9
Table3Clinicaltrialsdemon
stratingeffi
cacy
ofcombinatio
ntherapyof
botanicalagentsa
ndherbssupp
lementswith
methylphenidatein
treatingADHD
Stud
yMetho
dsParticipants
Outcomes
Com
ments
Lyon
etal[49]
Ginkgo
biloba
andGinseng
Ginkgo
biloba
extract
(50m
g)plus
American
ginsengPa
nax
quinquefo
lium
(200
mg)
twiceday
(com
binatio
nprod
uct)
Open
pilotstudy
36child
ren
3ndash17years
oldwith
ADHD
Improvem
ento
fADHD
symptom
s(hyperactiv
ity
impu
lsivenessand
anxiety)
Five
participants
repo
rted
adversee
vents
(increasedADHD
symptom
saggressiv
enesssw
eatin
gheadacheand
tiredness)on
ly2
considered
related
tothe
study
Wangetal[50]
Jingling
oralan
dmethylphenidate
Methylphenidate
(10ndash
40mgd)
Rand
omizedblin
ded
study
119899=50ADHDchild
ren
with
transie
nttic
disorder
Sign
ificant
improvem
ent
ofADHDsymptom
sas
wellastics
Com
binatio
ntherapy
moree
ffectivethan
methylphenidatealon
ein
improvingADHD
andtic
symptom
s
Dingetal[51]
Yizhiand
methylphenidate
Rand
omized
methylphenidate-
controlled
trial
210child
renwith
hyperkineticsynd
rome
Sign
ificant
improvem
ent
inADHDsymptom
sin
thosetaking
combinatio
ntherapy
comparedto
either
given
asmon
otherapy
Yizhih
adfewer
side
effectswhengivenalon
eor
incombinatio
nthan
methylphenidate
Akh
ondzadeh
etal
[47]
Zinc
sulfateand
methylphenidate
Rand
omized
doub
le-blindand
methylphenidate+
placebocontrolledtrial
44child
ren(26bo
ys18
girls)5ndash11yearso
ldwith
ADHD
Improved
parent
and
teacherratingscale
scores
fortho
sesupp
lementedwith
zinc
sulfateas
anadjunct
Side
effectsrepo
rted
anxietylossof
appetite
nauseaheadache
abdo
minalpain
insomniaandmetallic
taste
10 Neural Plasticity
and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment
32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary
33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger
number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]
Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy
34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
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Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
6 Neural PlasticityTa
ble2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Sinn
andBryan
[38]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omized
doub
le-blin
dcrossover
placebo-controlledstu
dy
132child
ren(data
availablefor
104and87
child
ren)
7ndash12yearso
ld(119899=36PU
FAsv
ersus
119899=41PU
FA+
micronu
trientsv
ersus
119899=27placebo)
Sign
ificant
treatment
effectsbasedon
parental
ratin
gof
core
ADHD
symptom
sinbo
thPU
FAgrou
psversus
placebo
Mod
ulationof
neural
cellsig
nalin
gand
neurotransmitter
processes
PUFA
swith
other
nutrientssuchas
vitC
B 3and
B 6mod
ulates
PUFArsquosrolein
the
synthesis
ofprostaglandins
and
chem
icalsimpo
rtantfor
biologicalandbrain
functio
n
Noadversee
ventssid
eeffects
Sinn
etal[39]
Essentialfattyacids
LC-PUFA
capsules
containing
400m
gfishoil
and100m
gevening
prim
rose
oilw
ithEP
A(93m
g)D
HA(29m
g)G
LA(10m
g)and
vitamin
E(18mg)
orplaceboSix
activ
eor6
placebocapsules
perd
ayfor15weeks
Rand
omizedone-w
aycrossoverplacebo-
controlledstu
dyPh
ases
1and
2
Phase1119899=129child
ren
with
ADHD(PUFA
versus
PUFA
+multiv
itaminsminerals
versus
placebofor15
weeks)
Phase2
119899=104
child
renwith
ADHD
(PUFA
PUFA
+multiv
itaminm
inerals
andplacebofor15
weeks)
Improved
abilityon
attentioncontroland
vocabu
lary
perfo
rmance
durin
gph
ase2
Influ
ence
onmetabolic
andneuralactiv
ities
Increasin
gdo
pamine
activ
ityin
thefrontal
lobe
Twocaseso
fnauseaa
ndon
eepisode
ofno
sebleed
Manor
etal[40
]
Essentialfattyacids
2capsules
twicea
dayof
phosph
atidylserin
e(PS
)containing
omega-3(300
mg
ofPS
and120m
gof
EPA+
DHA)o
rcellulose
capsules
asplacebofor15weeks
Rand
omized
doub
le-blin
dsin
gle-centerplacebo
-controlledtrial
200child
ren(6ndash13y
ears
old)
rand
omlyassig
ned
toPS
-omega-3capsules
orplacebo
119873=162child
ren
completed
15weeks
oftre
atment(119899=110PS
-om
ega-3119899=52
placebo)
Improvem
ento
fADHD
symptom
s(im
pulsivity
inattention
moo
dand
behavior
issue)
Maintenance
ofintegrity
ofcellmem
branes
Influ
ence
ondo
paminergica
ndcholinergics
ystems
Increasin
gom
ega-3
LC-PUFA
which
improves
behavioral
sensoryand
neurologicaldysfu
nctio
n
Mild
adversee
vent
profi
leG
Idisc
omfort
atop
icderm
atitis
nauseaticsand
hyperactivity
Raze
tal[41]
Essentialfattyacids
EFAcapsules
containing
240m
gof
linoleica
cid(LA)
60mgof
alph
a-lin
olenicacid
(ALA
)95
mgof
mineraloil
and5m
gof
a-tocoph
erol(as
anantio
xidant)2
timesday
orplacebovitC(500
mg
ascorbicacid)2
timesday
for7
weeks
Rand
omized
doub
le-blin
dplacebo-controlledtrial
73child
ren
7ndash13years
old63
child
ren
completed
thes
tudy
(119899=39EF
Asupp
lement
versus
39placebo
vitamin
C)
Both
treatments
amelioratedsome
ADHDsymptom
sNo
differenceineffi
cacy
betweentre
atments
Improvem
entin
behavioralsensoryand
cogn
itive
functio
ns
Noadversee
ventssid
eeffectsrepo
rted
Neural Plasticity 7
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Voigtetal[42]
Essentialfattyacids
345m
gof
DHAperd
ay(119899=32)o
raplacebocapsule
(119899=31)for
4mon
ths
Rand
omized
doub
le-blin
dplacebo
controlledstu
dy
54child
ren6ndash
12years
old(119899=27
docosahexaenoica
cid
(DHA)v
ersus119899=27
placebo)
DHAsupp
lementatio
ndidno
tsignificantly
improveinanyob
jective
orsubjectiv
emeasure
ofADHDsymptom
s
Welltolerated
andno
adversee
ffectsw
ere
repo
rted
Hira
yamae
tal
[43]
Essentialfattyacids
DHAgrou
pferm
ented
soybeanmilk
(600
mg
DHA12
5mL3week)bread
rolls
(300
mgDHA45g
2week)
andste
amed
bread
(600
mgD
HA60g
2w
eek)
orplacebofood
scon
taining
oliveo
ilinste
adof
DHA-
rich
fishoilfor
2weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
40child
renwith
ADHD
6ndash12yearso
ld(119899=20
docosahexaenoica
cid
(DHA)v
ersus119899=20
placebo)
DHAsupp
lementatio
ndidno
timprove
ADHD-related
symptom
s
Noserio
ussid
eeffects
were
repo
rted
inthe
study
Kono
faletal[44]
Iron
80mgferrou
ssulfatetablets
orplaceboon
cedaily
inthe
morning
for12weeks
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
23ADHDchild
renwith
lowserum
ferritinlevel
(lt30
ngm
L)5ndash8y
ears
old(119899=18iro
nversus
119899=5placebo)
Improvem
ento
fhyperactiveim
pulsive
andinattentive
symptom
sintheA
DHD
ratin
gscale
Iron
isac
ofactorinthe
synthesis
ofbo
thno
repineph
rinea
nddo
pamine
Minor
sidee
ffectsw
ere
repo
rtedsuchas
nausea
constip
ation
and
abdo
minalpain
Mou
sain-Bosce
tal[45]
Vitamin
B6andmagnesiu
mADHDchild
ren
magnesiu
m-vitamin
B6(M
g-B6
)regim
en(6
mgkgd
Mg06m
gkgd
vit-B
6)for
sixmon
thsC
ontro
lsdidno
treceiveM
g-B6
Openstu
dy
76child
ren(m
eanage
69y
ears13girls
and27
boys)(40
ADHD
child
renamp36
healthy
child
ren)
Attenu
ationof
hyperactivity
and
aggressiv
enessS
choo
lattentionwas
also
improved
Vitamin
B6facilitates
thep
rodu
ctionof
the
serotonin
Magnesiu
misa
nonspecific
inhibitoro
fcalcium
andNMDA
channels
Magnesiu
mcan
influ
ence
catecholam
ine
signalin
g
Norepo
rted
sidee
ffects
Bilicietal[46]
Zinc
150m
gzinc
sulfateor
150m
gsucrose(placebo)
daily
for12
weeks
Rand
omized
doub
le-blin
dparallel-g
roup
placebo-controlledtrial
400child
ren6ndash
14years
old(119899=202zinc
versus
119899=198placebo)
Zinc
sulfatebette
rthan
placeboin
decreasin
ghyperactivity
and
impu
lsivityand
improvingsocialization
butn
otinattention
Increasedzinc
levels
necessaryforc
ognitiv
edevelopm
ent
Noserio
ussid
eeffects
repo
rtedM
etallic
taste
was
acom
mon
complaint
8 Neural Plasticity
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Akh
ondzadeh
etal
[47]
Zinc
Zinc
sulfate(55m
gday)
+methylphenidate
(1mgkgday)o
rsucrose
(placebo
)55m
g+
methylphenidate
(1mgkgday)for
6weeks
Rand
omized
doub
le-blin
dclinical
trial
44child
ren
5ndash11years
old(119899=22
methylphenidate+zinc
versus119899=22
methylphenidate+
placebo)
Sign
ificantlygreater
treatmenteffects(as
per
parent
andteacher
ratin
gscales
cores)in
zinc
sulfatewith
methylphenidate
treatmento
verp
lacebo
with
methylphenidate
Zinc
regulates
dopamine
functio
nindirectly
throug
hits
actio
non
melaton
in
Nauseaa
ndmetallic
taste
werec
ommon
complaintsOverallit
was
welltolerated
Arnoldetal[48]
Zinc
Zinc
115mgday(oncea
day)
orZinc
230
mgday
(twicea
day)
orplacebo(8
weeks)am
phetam
ine
5ndash15mgdaily
(based
onthe
weight)
Durationof
experim
entw
as13
weeks
(8weeks
controlled
+5weeks
amph
etam
ine
add-on
)
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
52child
ren6ndash
14years
old(119899=20Zinc
1or
119899=8Zinc
2versus
119899=24placebo)
Noappreciable
differenceb
etweenbo
thdo
sageso
fzinca
ndplacebo
Gastro
intestinal
discom
fortrepo
rted
by1
patie
nt
Neural Plasticity 9
Table3Clinicaltrialsdemon
stratingeffi
cacy
ofcombinatio
ntherapyof
botanicalagentsa
ndherbssupp
lementswith
methylphenidatein
treatingADHD
Stud
yMetho
dsParticipants
Outcomes
Com
ments
Lyon
etal[49]
Ginkgo
biloba
andGinseng
Ginkgo
biloba
extract
(50m
g)plus
American
ginsengPa
nax
quinquefo
lium
(200
mg)
twiceday
(com
binatio
nprod
uct)
Open
pilotstudy
36child
ren
3ndash17years
oldwith
ADHD
Improvem
ento
fADHD
symptom
s(hyperactiv
ity
impu
lsivenessand
anxiety)
Five
participants
repo
rted
adversee
vents
(increasedADHD
symptom
saggressiv
enesssw
eatin
gheadacheand
tiredness)on
ly2
considered
related
tothe
study
Wangetal[50]
Jingling
oralan
dmethylphenidate
Methylphenidate
(10ndash
40mgd)
Rand
omizedblin
ded
study
119899=50ADHDchild
ren
with
transie
nttic
disorder
Sign
ificant
improvem
ent
ofADHDsymptom
sas
wellastics
Com
binatio
ntherapy
moree
ffectivethan
methylphenidatealon
ein
improvingADHD
andtic
symptom
s
Dingetal[51]
Yizhiand
methylphenidate
Rand
omized
methylphenidate-
controlled
trial
210child
renwith
hyperkineticsynd
rome
Sign
ificant
improvem
ent
inADHDsymptom
sin
thosetaking
combinatio
ntherapy
comparedto
either
given
asmon
otherapy
Yizhih
adfewer
side
effectswhengivenalon
eor
incombinatio
nthan
methylphenidate
Akh
ondzadeh
etal
[47]
Zinc
sulfateand
methylphenidate
Rand
omized
doub
le-blindand
methylphenidate+
placebocontrolledtrial
44child
ren(26bo
ys18
girls)5ndash11yearso
ldwith
ADHD
Improved
parent
and
teacherratingscale
scores
fortho
sesupp
lementedwith
zinc
sulfateas
anadjunct
Side
effectsrepo
rted
anxietylossof
appetite
nauseaheadache
abdo
minalpain
insomniaandmetallic
taste
10 Neural Plasticity
and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment
32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary
33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger
number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]
Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy
34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
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Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Neural Plasticity
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Parkinsonrsquos Disease
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Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Neural Plasticity 7
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Voigtetal[42]
Essentialfattyacids
345m
gof
DHAperd
ay(119899=32)o
raplacebocapsule
(119899=31)for
4mon
ths
Rand
omized
doub
le-blin
dplacebo
controlledstu
dy
54child
ren6ndash
12years
old(119899=27
docosahexaenoica
cid
(DHA)v
ersus119899=27
placebo)
DHAsupp
lementatio
ndidno
tsignificantly
improveinanyob
jective
orsubjectiv
emeasure
ofADHDsymptom
s
Welltolerated
andno
adversee
ffectsw
ere
repo
rted
Hira
yamae
tal
[43]
Essentialfattyacids
DHAgrou
pferm
ented
soybeanmilk
(600
mg
DHA12
5mL3week)bread
rolls
(300
mgDHA45g
2week)
andste
amed
bread
(600
mgD
HA60g
2w
eek)
orplacebofood
scon
taining
oliveo
ilinste
adof
DHA-
rich
fishoilfor
2weeks
Rand
omized
doub
le-blin
dplacebo-controlledstu
dy
40child
renwith
ADHD
6ndash12yearso
ld(119899=20
docosahexaenoica
cid
(DHA)v
ersus119899=20
placebo)
DHAsupp
lementatio
ndidno
timprove
ADHD-related
symptom
s
Noserio
ussid
eeffects
were
repo
rted
inthe
study
Kono
faletal[44]
Iron
80mgferrou
ssulfatetablets
orplaceboon
cedaily
inthe
morning
for12weeks
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
23ADHDchild
renwith
lowserum
ferritinlevel
(lt30
ngm
L)5ndash8y
ears
old(119899=18iro
nversus
119899=5placebo)
Improvem
ento
fhyperactiveim
pulsive
andinattentive
symptom
sintheA
DHD
ratin
gscale
Iron
isac
ofactorinthe
synthesis
ofbo
thno
repineph
rinea
nddo
pamine
Minor
sidee
ffectsw
ere
repo
rtedsuchas
nausea
constip
ation
and
abdo
minalpain
Mou
sain-Bosce
tal[45]
Vitamin
B6andmagnesiu
mADHDchild
ren
magnesiu
m-vitamin
B6(M
g-B6
)regim
en(6
mgkgd
Mg06m
gkgd
vit-B
6)for
sixmon
thsC
ontro
lsdidno
treceiveM
g-B6
Openstu
dy
76child
ren(m
eanage
69y
ears13girls
and27
boys)(40
ADHD
child
renamp36
healthy
child
ren)
Attenu
ationof
hyperactivity
and
aggressiv
enessS
choo
lattentionwas
also
improved
Vitamin
B6facilitates
thep
rodu
ctionof
the
serotonin
Magnesiu
misa
nonspecific
inhibitoro
fcalcium
andNMDA
channels
Magnesiu
mcan
influ
ence
catecholam
ine
signalin
g
Norepo
rted
sidee
ffects
Bilicietal[46]
Zinc
150m
gzinc
sulfateor
150m
gsucrose(placebo)
daily
for12
weeks
Rand
omized
doub
le-blin
dparallel-g
roup
placebo-controlledtrial
400child
ren6ndash
14years
old(119899=202zinc
versus
119899=198placebo)
Zinc
sulfatebette
rthan
placeboin
decreasin
ghyperactivity
and
impu
lsivityand
improvingsocialization
butn
otinattention
Increasedzinc
levels
necessaryforc
ognitiv
edevelopm
ent
Noserio
ussid
eeffects
repo
rtedM
etallic
taste
was
acom
mon
complaint
8 Neural Plasticity
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Akh
ondzadeh
etal
[47]
Zinc
Zinc
sulfate(55m
gday)
+methylphenidate
(1mgkgday)o
rsucrose
(placebo
)55m
g+
methylphenidate
(1mgkgday)for
6weeks
Rand
omized
doub
le-blin
dclinical
trial
44child
ren
5ndash11years
old(119899=22
methylphenidate+zinc
versus119899=22
methylphenidate+
placebo)
Sign
ificantlygreater
treatmenteffects(as
per
parent
andteacher
ratin
gscales
cores)in
zinc
sulfatewith
methylphenidate
treatmento
verp
lacebo
with
methylphenidate
Zinc
regulates
dopamine
functio
nindirectly
throug
hits
actio
non
melaton
in
Nauseaa
ndmetallic
taste
werec
ommon
complaintsOverallit
was
welltolerated
Arnoldetal[48]
Zinc
Zinc
115mgday(oncea
day)
orZinc
230
mgday
(twicea
day)
orplacebo(8
weeks)am
phetam
ine
5ndash15mgdaily
(based
onthe
weight)
Durationof
experim
entw
as13
weeks
(8weeks
controlled
+5weeks
amph
etam
ine
add-on
)
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
52child
ren6ndash
14years
old(119899=20Zinc
1or
119899=8Zinc
2versus
119899=24placebo)
Noappreciable
differenceb
etweenbo
thdo
sageso
fzinca
ndplacebo
Gastro
intestinal
discom
fortrepo
rted
by1
patie
nt
Neural Plasticity 9
Table3Clinicaltrialsdemon
stratingeffi
cacy
ofcombinatio
ntherapyof
botanicalagentsa
ndherbssupp
lementswith
methylphenidatein
treatingADHD
Stud
yMetho
dsParticipants
Outcomes
Com
ments
Lyon
etal[49]
Ginkgo
biloba
andGinseng
Ginkgo
biloba
extract
(50m
g)plus
American
ginsengPa
nax
quinquefo
lium
(200
mg)
twiceday
(com
binatio
nprod
uct)
Open
pilotstudy
36child
ren
3ndash17years
oldwith
ADHD
Improvem
ento
fADHD
symptom
s(hyperactiv
ity
impu
lsivenessand
anxiety)
Five
participants
repo
rted
adversee
vents
(increasedADHD
symptom
saggressiv
enesssw
eatin
gheadacheand
tiredness)on
ly2
considered
related
tothe
study
Wangetal[50]
Jingling
oralan
dmethylphenidate
Methylphenidate
(10ndash
40mgd)
Rand
omizedblin
ded
study
119899=50ADHDchild
ren
with
transie
nttic
disorder
Sign
ificant
improvem
ent
ofADHDsymptom
sas
wellastics
Com
binatio
ntherapy
moree
ffectivethan
methylphenidatealon
ein
improvingADHD
andtic
symptom
s
Dingetal[51]
Yizhiand
methylphenidate
Rand
omized
methylphenidate-
controlled
trial
210child
renwith
hyperkineticsynd
rome
Sign
ificant
improvem
ent
inADHDsymptom
sin
thosetaking
combinatio
ntherapy
comparedto
either
given
asmon
otherapy
Yizhih
adfewer
side
effectswhengivenalon
eor
incombinatio
nthan
methylphenidate
Akh
ondzadeh
etal
[47]
Zinc
sulfateand
methylphenidate
Rand
omized
doub
le-blindand
methylphenidate+
placebocontrolledtrial
44child
ren(26bo
ys18
girls)5ndash11yearso
ldwith
ADHD
Improved
parent
and
teacherratingscale
scores
fortho
sesupp
lementedwith
zinc
sulfateas
anadjunct
Side
effectsrepo
rted
anxietylossof
appetite
nauseaheadache
abdo
minalpain
insomniaandmetallic
taste
10 Neural Plasticity
and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment
32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary
33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger
number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]
Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy
34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
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Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
8 Neural Plasticity
Table2Con
tinued
Stud
ySupp
lement
Metho
dParticipants
Outcomes
Prop
osed
mechanism
ofactio
nCom
ments(sidee
ffects
etc)
Akh
ondzadeh
etal
[47]
Zinc
Zinc
sulfate(55m
gday)
+methylphenidate
(1mgkgday)o
rsucrose
(placebo
)55m
g+
methylphenidate
(1mgkgday)for
6weeks
Rand
omized
doub
le-blin
dclinical
trial
44child
ren
5ndash11years
old(119899=22
methylphenidate+zinc
versus119899=22
methylphenidate+
placebo)
Sign
ificantlygreater
treatmenteffects(as
per
parent
andteacher
ratin
gscales
cores)in
zinc
sulfatewith
methylphenidate
treatmento
verp
lacebo
with
methylphenidate
Zinc
regulates
dopamine
functio
nindirectly
throug
hits
actio
non
melaton
in
Nauseaa
ndmetallic
taste
werec
ommon
complaintsOverallit
was
welltolerated
Arnoldetal[48]
Zinc
Zinc
115mgday(oncea
day)
orZinc
230
mgday
(twicea
day)
orplacebo(8
weeks)am
phetam
ine
5ndash15mgdaily
(based
onthe
weight)
Durationof
experim
entw
as13
weeks
(8weeks
controlled
+5weeks
amph
etam
ine
add-on
)
Rand
omized
doub
le-blin
dplacebo-controlledpilot
trial
52child
ren6ndash
14years
old(119899=20Zinc
1or
119899=8Zinc
2versus
119899=24placebo)
Noappreciable
differenceb
etweenbo
thdo
sageso
fzinca
ndplacebo
Gastro
intestinal
discom
fortrepo
rted
by1
patie
nt
Neural Plasticity 9
Table3Clinicaltrialsdemon
stratingeffi
cacy
ofcombinatio
ntherapyof
botanicalagentsa
ndherbssupp
lementswith
methylphenidatein
treatingADHD
Stud
yMetho
dsParticipants
Outcomes
Com
ments
Lyon
etal[49]
Ginkgo
biloba
andGinseng
Ginkgo
biloba
extract
(50m
g)plus
American
ginsengPa
nax
quinquefo
lium
(200
mg)
twiceday
(com
binatio
nprod
uct)
Open
pilotstudy
36child
ren
3ndash17years
oldwith
ADHD
Improvem
ento
fADHD
symptom
s(hyperactiv
ity
impu
lsivenessand
anxiety)
Five
participants
repo
rted
adversee
vents
(increasedADHD
symptom
saggressiv
enesssw
eatin
gheadacheand
tiredness)on
ly2
considered
related
tothe
study
Wangetal[50]
Jingling
oralan
dmethylphenidate
Methylphenidate
(10ndash
40mgd)
Rand
omizedblin
ded
study
119899=50ADHDchild
ren
with
transie
nttic
disorder
Sign
ificant
improvem
ent
ofADHDsymptom
sas
wellastics
Com
binatio
ntherapy
moree
ffectivethan
methylphenidatealon
ein
improvingADHD
andtic
symptom
s
Dingetal[51]
Yizhiand
methylphenidate
Rand
omized
methylphenidate-
controlled
trial
210child
renwith
hyperkineticsynd
rome
Sign
ificant
improvem
ent
inADHDsymptom
sin
thosetaking
combinatio
ntherapy
comparedto
either
given
asmon
otherapy
Yizhih
adfewer
side
effectswhengivenalon
eor
incombinatio
nthan
methylphenidate
Akh
ondzadeh
etal
[47]
Zinc
sulfateand
methylphenidate
Rand
omized
doub
le-blindand
methylphenidate+
placebocontrolledtrial
44child
ren(26bo
ys18
girls)5ndash11yearso
ldwith
ADHD
Improved
parent
and
teacherratingscale
scores
fortho
sesupp
lementedwith
zinc
sulfateas
anadjunct
Side
effectsrepo
rted
anxietylossof
appetite
nauseaheadache
abdo
minalpain
insomniaandmetallic
taste
10 Neural Plasticity
and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment
32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary
33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger
number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]
Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy
34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
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Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
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Parkinsonrsquos Disease
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Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity 9
Table3Clinicaltrialsdemon
stratingeffi
cacy
ofcombinatio
ntherapyof
botanicalagentsa
ndherbssupp
lementswith
methylphenidatein
treatingADHD
Stud
yMetho
dsParticipants
Outcomes
Com
ments
Lyon
etal[49]
Ginkgo
biloba
andGinseng
Ginkgo
biloba
extract
(50m
g)plus
American
ginsengPa
nax
quinquefo
lium
(200
mg)
twiceday
(com
binatio
nprod
uct)
Open
pilotstudy
36child
ren
3ndash17years
oldwith
ADHD
Improvem
ento
fADHD
symptom
s(hyperactiv
ity
impu
lsivenessand
anxiety)
Five
participants
repo
rted
adversee
vents
(increasedADHD
symptom
saggressiv
enesssw
eatin
gheadacheand
tiredness)on
ly2
considered
related
tothe
study
Wangetal[50]
Jingling
oralan
dmethylphenidate
Methylphenidate
(10ndash
40mgd)
Rand
omizedblin
ded
study
119899=50ADHDchild
ren
with
transie
nttic
disorder
Sign
ificant
improvem
ent
ofADHDsymptom
sas
wellastics
Com
binatio
ntherapy
moree
ffectivethan
methylphenidatealon
ein
improvingADHD
andtic
symptom
s
Dingetal[51]
Yizhiand
methylphenidate
Rand
omized
methylphenidate-
controlled
trial
210child
renwith
hyperkineticsynd
rome
Sign
ificant
improvem
ent
inADHDsymptom
sin
thosetaking
combinatio
ntherapy
comparedto
either
given
asmon
otherapy
Yizhih
adfewer
side
effectswhengivenalon
eor
incombinatio
nthan
methylphenidate
Akh
ondzadeh
etal
[47]
Zinc
sulfateand
methylphenidate
Rand
omized
doub
le-blindand
methylphenidate+
placebocontrolledtrial
44child
ren(26bo
ys18
girls)5ndash11yearso
ldwith
ADHD
Improved
parent
and
teacherratingscale
scores
fortho
sesupp
lementedwith
zinc
sulfateas
anadjunct
Side
effectsrepo
rted
anxietylossof
appetite
nauseaheadache
abdo
minalpain
insomniaandmetallic
taste
10 Neural Plasticity
and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment
32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary
33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger
number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]
Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy
34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
10 Neural Plasticity
and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment
32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary
33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger
number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]
Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy
34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity 11
35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD
36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]
37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant
improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment
38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials
39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies
391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients
392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254
12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
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Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
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Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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12 Neural Plasticity
in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication
393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted
394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD
310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]
3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms
recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]
The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]
Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]
While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD
3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])
A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation
Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
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[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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International Journal of
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BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Neural Plasticity 13
of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]
Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]
Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]
In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms
conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]
3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]
Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders
3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
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Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
14 Neural Plasticity
vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]
In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]
4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug
Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]
Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)
study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]
In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies
41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate
In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments
42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity 15
that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach
5 Conclusion
There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy
Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments
The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
James Ahn and Hyung Seok Ahn contributed equally to thiswork
Acknowledgments
This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)
References
[1] J M Swanson J A Sergeant E Taylor E J S Sonuga-BarkeP S Jensen and D P Cantwell ldquoAttention-deficit hyperactivitydisorder and hyperkinetic disorderrdquo The Lancet vol 351 no9100 pp 429ndash433 1998
[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007
[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005
[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015
[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005
[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010
[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm
[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011
[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011
[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012
[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
16 Neural Plasticity
pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012
[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008
[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004
[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005
[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012
[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010
[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009
[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011
[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003
[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999
[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005
[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001
[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014
[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014
[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in
Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010
[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011
[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014
[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011
[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005
[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006
[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006
[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008
[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012
[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008
[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007
[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002
[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003
[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity 17
[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008
[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012
[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009
[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001
[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004
[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008
[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006
[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004
[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004
[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011
[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001
[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011
[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002
[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006
[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007
[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011
[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013
[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010
[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012
[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003
[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013
[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011
[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013
[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013
[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014
[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013
[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010
[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
18 Neural Plasticity
natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011
[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009
[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008
[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007
[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009
[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004
[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006
[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015
[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007
[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000
[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014
[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999
[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009
[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997
[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015
[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014
[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011
[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007
[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009
[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012
[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012
[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013
[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001
[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014