Review Article Marijuana Compounds: A Nonconventional...

Review ArticleMarijuana Compounds A Nonconventional Approach toParkinsonrsquos Disease Therapy

Mariana Babayeva Haregewein Assefa Paramita Basu Sanjeda Chumki and Zvi Loewy

Touro College of Pharmacy 230 West 125th Street Room 530 New York NY 10027 USA

Correspondence should be addressed to Mariana Babayeva marianababayevatouroedu

Received 8 June 2016 Revised 29 September 2016 Accepted 10 October 2016

Academic Editor Jan Aasly

Copyright copy 2016 Mariana Babayeva et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Parkinsonrsquos disease (PD) a neurodegenerative disorder is the second most common neurological illness in United StatesNeurologically it is characterized by the selective degeneration of a unique population of cells the nigrostriatal dopamine neuronsThe current treatment is symptomatic and mainly involves replacement of dopamine deficiencyThis therapy improves only motorsymptoms of Parkinsonrsquos disease and is associated with a number of adverse effects including dyskinesia Therefore there is unmetneed for more comprehensive approach in the management of PD Cannabis and related compounds have created significantresearch interest as a promising therapy in neurodegenerative and movement disorders In this review we examine the potentialbenefits of medical marijuana and related compounds in the treatment of bothmotor and nonmotor symptoms as well as in slowingthe progression of the disease The potential for cannabis to enhance the quality of life of Parkinsonrsquos patients is explored

1 Introduction

Marijuana the crude product (dried flowers stems seedsand leaves) derived from the cannabis sativa plant consistsof more than 85 phytocannabinoids [1 2] The term phy-tocannabinoids is used to differentiate these plant-derivedcannabinoids from the synthetic cannabinoids and the struc-turally different endogenous cannabinoids (endocannabi-noids) Among the phytocannabinoids Cannabidiol (CBD)andΔ9-Tetrahydrocannabinol (Δ9-THC THC) are themajorconstituents ofmarijuana [3]Δ9-THC is a psychoactive agentwith analgesic and muscle relaxant property [3 4] WhileCBD is a nonpsychoactive compound and has been shownto have hypnotic anxiolytic antipsychotic antioxidant andneuroprotective effects [5] THC is a partial agonist at thecannabinoid receptor 1 (CB1) and receptor 2 (CB2) UnlikeΔ9-THC CBD has antagonisticinverse agonistic property atCB1 receptor and appears to modulate Δ9-THC-associatedside effects including anxiety tachycardia and hunger [3]CBD also appears to potentiate the effect of endocannabi-noids by inhibiting their inactivation thereby alleviatingpsychotic symptom [6]

Despite the placement of marijuana in the schedule 1category under the US Federal Controlled Substance Act [7]and the US Federal Governmentrsquos continued opposition onits legalization 24 states and Washington DC have enactedlaws allowing marijuana to treat certain medical conditions[8] The range and types of disease conditions for whichmedical marijuana have been approved vary from state tostate The most common disease conditions approved by thestates include cancer HIVAIDS glaucoma chronic andorsevere pain seizureepilepsy cachexia andmultiple sclerosisMoreover two cannabinoids (dronabinol and nabilone) havebeen approved by the FDA for clinical use The syntheticallyproduced Δ9-THC dronabinol (Marinol) is a schedule IIIdrug which is indicated in the treatment of chemotherapy-induced nausea and emesis as well as anorexia associatedwith weight loss in AIDS patients A synthetic cannabinoidnabilone (Cesamet) is a schedule II drug that is indicatedfor the treatment of nausea and vomiting associated withcancer chemotherapy Another cannabinoid Cannabidiol(Epidiolex) is in a clinical trial for the treatment of drug-resistant epilepsy in children [9] A phytocannabinoid prepa-ration nabiximols (Sativex) has been approved for the

Hindawi Publishing CorporationParkinsonrsquos DiseaseVolume 2016 Article ID 1279042 19 pageshttpdxdoiorg10115520161279042

2 Parkinsonrsquos Disease

treatment of spasticity due to multiple sclerosis in a numberof countries outside the United States Nabiximols is anextract of Cannabis sativa L that consists of mainly THC andCBD [10 11]

Although recent studies have provided strong evidencefor the therapeutic benefit of medical marijuana [12ndash16]increasing access to cannabis andor cannabinoids can resultin side effects such as addiction respiratory illness anddecline in cognitive processing Cannabis use has beenindicated as a potential cause aggravator or masker of majorpsychiatric symptoms including psychotic depressive andanxiety disorders particularly in young people [17ndash19] Othernegative effects include working memory deficits reducedattention and processing speed anhedonia abnormal socialbehavior and susceptibility to mood and anxiety disor-ders [20 21] While adult users seem comparatively resis-tant to cannabis-induced behavioral and brain morphologicchanges the individuals who start using cannabis duringtheir early teens can have more severe and more long-lastingeffects [22]

The target of medical marijuana and its constituentsis the endocannabinoid system which is involved in themodulation of a number of physiological functions Theendocannabinoid system includes the endocannabinoids thecannabinoid receptors and the enzymes involved in thebiosynthesis and inactivation of the endocannabinoids [23]The cannabinoid receptors aremainly expressed in the centralnervous system and the immune system but they have alsobeen identified in a number of other parts of the body includ-ing the cardiovascular system the peripheral nervous systemthe reproductive system and the gastrointestinal tract Dueto its wide distribution and effects on a range of biologicalprocess the cannabinoid system has become an attractivetarget for the development of drugs that can potentially beused for the treatment of a number of pathological conditionsincluding mood disorders and movement disorders such asPD [24] Components of the endocannabinoid system areabundant in the striatum and other parts of the basal gangliaand play a crucial role in modulating dopamine activity andmotor functions [25ndash27]

Parkinsonrsquos disease (PD) is the second most commonneurodegenerative disorder following Alzheimerrsquos diseaseand the 14th leading cause of death in all age groups inthe United States [28] The prevalence of PD increases withage and is shown to be higher in males than females insome age groups [29] The number of people with PD isprojected at approximately 9 million by 2030 in the 15 mostpopulous countries in the world [30 31] NeurologicallyPD is characterized by the destruction of dopaminergiccells in the pars compacta region of the substantia nigrain the midbrain resulting in dopamine deficiency in thenerve terminals of the striatum in the forebrain [32] Thesechanges cause impairments not just to the motor systembut also to the cognitive and neuropsychological systems[33] The nigrostriatal pathway is one of the dopaminepathways in the brain that regulates movement The exactcause for the loss of neuronal cells is unknown and the triggerof dopaminergic degeneration seems to be multifactorialincluding environmental factors and genetic susceptibilities

[34ndash36] Clinically PD is characterized by resting tremormuscle rigidity bradykinesia and postural instability [3234 37 38] and it is also associated with a number ofnonmotor symptoms including depression anxiety consti-pation orthostatic hypotension fatigue and sleep disordersas well as in advanced disease dementia [39ndash44] Althoughdopamine deficiency accounts for themajormotor symptomsof the disease loss of noradrenergic and serotoninergic nerveterminals in the limbic system may account for several of thenonmotor features seen in Parkinsonrsquos disease [45 46]

Current therapy involves treatment of motor symptomsof PD through replacement of dopamine deficiency [47]This includes (1) enhancement of the synthesis of braindopamine by administration of levodopa a dopamine pre-cursor (2) direct stimulation of dopamine receptors (3)decreasing dopamine catabolism and (4) stimulation ofdopamine release and inhibition of dopamine reuptake frompresynaptic sites Another therapy involves restoring thenormal balance of cholinergic and dopaminergic actions onthe basal ganglia using anticholinergic drugs [47ndash49]

However these drugs treat only motor symptoms ofParkinsonrsquos disease and are associated with a number ofadverse effects Long-term use of levodopa the mainstaytherapy for PD is associated with motor fluctuations [50]and levodopa-induced dyskinesia [51ndash53] The monoamineoxidase B (MAO-B) inhibitors (selegiline and rasagiline) aswell as inhibitors of catechol-o-methyltransferase COMT(tolcapone and entacapone) are used mostly to reduce themotor fluctuations associated with levodopa therapy dueto their levodopa-sparing effect [54ndash59] Several dopamineagonists including pramipexole ropinirole rotigotine andapomorphine are used as monotherapy in early stage ofParkinson disease or as adjunctive therapy with levodopain patients with advanced PD in order to reduce motorfluctuations [56 60ndash64] In addition to their limited efficacyon motor symptoms and their adverse effects drugs that arecurrently used for the treatment of PD do not have an effecton disease progressionTherefore there is an urgent need forthe development of safer drugs that treat both the motor andnonmotor symptoms of PD as well as drugs that slow theprogression of the disease

Medical marijuana has been demonstrated to improvemotor symptoms including tremor rigidity and bradykinesiaas well as nonmotor symptoms such as pain and sleepdisorders of PD in observational studies [65] Survey ofPD patients in Colorado USA also indicated the beneficialeffects of marijuana in alleviating nonmotor symptoms ofPD [66] Cannabidiol (CBD) one of the major constituentsof marijuana has been shown to be effective in the treat-ment of psychosis and sleep disorders in PD patients [67ndash69] Another phytocannabinoid Δ9-tetrahydrocannabivarin(Δ9-THCV THCV) was studied in animal disease modelof PD and found to have neuroprotective and symptom-relieving effects [70] Therefore marijuana may provide analternative or add-on therapy for Parkinsonrsquos disease Inaddition Parkinsonrsquos disease has been listed as one of thedisease conditions for which medical marijuana is allowed inConnecticut Illinois Massachusetts New Hampshire New

Parkinsonrsquos Disease 3

Mexico and New York However it may also be coveredunder chronic illnesses in several other states

In this review we seek to investigate any scientific evi-dence that indicates the potential use of marijuana andorits components for the treatment of Parkinsonrsquos disease Thereview aims to (i) examine briefly current treatment andthe unmet need of PD therapy (ii) assess the role of thecannabinoid system in the modulation of movement andneuroprotection (iii) look at the mechanism of action ofmarihuana constituents in the modulation of movement andPD-associated disorders (iv) assess other beneficial effects ofmarihuana that contribute to the amelioration of PD and (v)gather scientific evidence on the clinical benefit of marijuanaandor its constituents in PD patients

2 Marijuana and Its Influence onthe Endocannabinoid System

Cannabis has been used to treat disease since ancient timesMarijuana is derived from the Cannabis sativa L plant Mar-ijuana contains the active chemicals known as cannabinoidsAt least 85 cannabinoids have been identified as unique com-pounds in Cannabis [1] The therapeutic potential of manyof these ligands still remains largely unexplored prompting aneed for further research The chemicals responsible for themedicinal effects of marijuana are D9-Tetrahydrocannabinol(THC) and Cannabidiol (CBD) [71 72] THC is the majorpsychoactive ingredient acting primarily upon the centralnervous system where it affects brain function CBD is themajor nonpsychoactive ingredient in cannabis and producesneuroprotective and anti-inflammatory effects [73] Bothcompounds TCH and CBD have anticonvulsant properties[74] Cannabinoids have also potential to alleviate motordisorders by reducingmotor impairments and neuron degen-eration [75] In addition cannabinoids have been shownto be effective in preclinical studies involving excitotoxicityoxidative stress neuroinflammation and motor complica-tions associated with PD [76]

Some cannabinoids (endocannabinoids or ECBs) arefound in the body Initially ECBswere discovered in the brainand subsequently in the periphery in humans and animalsEndocannabinoids are produced by cultured neurons [77]microglia and astrocytes [78] ECBs interact with the endo-cannabinoid system and aid in regulation of memory plea-sure concentration thinking movement and coordinationsensory and time perception appetite and pain [24 79 80]The ECBs activate two guanine nucleotide-binding protein-(G-protein-) coupled cell membrane receptors consequentlynamed the cannabinoid type 1 (CB1) and type 2 (CB2) recep-tors [81] CB1 receptors are located primarily in the centraland peripheral neurons andCB2 receptors are predominantlyfound in immune cells [82] CB1 receptors are importantmediators in signaling pathways and have been identifiedon both glutamatergic and gamma-aminobutyric (GABA)neurons [83] It is believed that one important role of theneuronal CB1 component is to modulate neurotransmitterrelease in amanner thatmaintains homeostasis by preventingthe development of excessive neuronal activity in the central

nervous system [82] Animal models illustrate that activationof the CB1 receptor by their endogenous ligands can result inprominent neuroprotective effects and may prevent epilepticseizures [84] Other studies suggest that activation of CB1receptors offers neuroprotection against dopaminergic lesionand the development of L-DOPA-induced dyskinesias [85]CB2 receptors are closely related to CB1 and are mainlyexpressed on T cells of the immune system on macrophagesand B cells and in hematopoietic cells [86] They are alsoexpressed on peripheral nerve terminals where these recep-tors play a role in antinociception and the relief of pain[87] In the brain CB2 receptors are mainly expressed bymicroglial cells where their role remains unclear [88]

The major identified ECBs are arachidonoyl ethanola-mide (anandamide AEA) 2-arachidonoyl glycerol (2-AG)O-arachidonoyl ethanolamine (virodhamine) and 2-ara-chidonoyl glyceryl ether (noladin ether) [89] Both AEA and2-AG are specific ligands of CB1 and CB2 receptors Besideshaving activity on CB1 and CB2 receptors AEA also has fullagonistic activity at TRPV1 receptor [90] AEA is localizedin the brain and periphery [91] In the brain AEA showshigh distribution in the hippocampus thalamus striatumand brainstem and to a lesser extent in the cerebral cortex andcerebellum [92] Lower concentrations of AEA are found inhuman serum plasma and cerebrospinal fluid [93] Similarly2-AG is observed in both the brain and periphery although itsconcentration is almost 150 times higher in brain comparedto that of AEA [92 94 95] 2-AGhas greater potency stabilityand agonistic activity at CB1 and CB2 receptors comparedto that of AEA [96 97] Two prominent areas involved inthe control of movement such as the globus pallidus and thesubstantia nigra contain not only the highest densities of CB1receptors [88] but also the highest levels of ECBs especiallyAEA [98 99] Tissue levels of AEA are regulated by fattyacid amide hydrolase (FAAH) [100] It has also been shownthat the basal ganglia contain the precursor of AEA [98 99]supporting the theory of in situ synthesis for this compoundStudies have demonstrated that AEA synthesis is regulated bydopaminergic D2 receptors in the striatum suggesting thatthe endocannabinoid system acts as an inhibitory feedbackmechanism countering the dopamine-induced facilitation ofmotor activity [101]

Marijuana compound THC is CB1 and CB2receptor

partial agonist [82] Due to the structural similarity of naturalcannabinoid THC to the endogenous cannabinoid AEAmany therapeutic advantages of THC have been identifiedsuch as lowering ocular pressure inhibiting smooth musclecontractions and increasing appetite [102] When smokedTHC is rapidly absorbed from the lungs into the bloodstreamand has an effect on the cannabinoid receptors The centralnervous system and specific areas of the brain contain thehighest concentration of cannabinoid receptors Thereforecannabis or THC administration can create an overexcitationof the system that results in altered perceptions pleasure andmood [103]

Unlike THC CBD has little affinity for CB1 and CB2receptors but acts as an indirect antagonist of cannabinoidagonists While this should cause CBD to reduce the effectsof THC it may potentiate THCrsquos effects by increasing CB1


receptor density or through another CB1-related mechanism[73] CBD is also an inverse agonist of CB2 receptors CBDcan counteract some of the functional consequences of CB1activation in the brain possibly by indirect enhancementof adenosine A1 receptors activity through equilibrativenucleoside transporter (ENT) inhibition [73] CBD helps toaugment some of THCrsquos beneficial effects as it reduces thepsychoactivity of THC enhances its tolerability and widensTHCrsquos therapeutic window [104]

Other cannabinoids can also contribute to the cannabismedicinal effects Studies in experimental models and hu-mans have suggested anti-inflammatory neuroprotective anx-iolytic and antipsychotic properties of chemicals extractedfrom marijuana [6 15 82 105 106]

3 Cannabinoids and Parkinsonrsquos Disease

31 Changes in the Cannabinoid System in Parkinsonrsquos DiseaseRecent data from several studies indicate the importantrole of the endocannabinoid system in Parkinsonrsquos diseaseThe components of the endocannabinoid system are highlyexpressed in the neural circuit of basal ganglia which ispart of a complex neuronal system This neuronal systemcoordinates activities from different cortical regions thatdirectly or indirectly participate in the control of movement[107 108] In the basal ganglia the endocannabinoid systembidirectionally interacts with dopaminergic glutamatergicand GABAergic signaling systems [109] Endocannabinoidsplay a dominant role in controlling transmission at synapsesbetween cortical and striatal neurons in mediating theinduction of a particular form of synaptic plasticity and inmodulating basal ganglia activity and motor functions [110]The progressive loss of dopaminergic neurons that occursin PD leads to lower striatal levels of dopamine These lowlevels of dopamine result in the alteration of the equilibriumbetween the direct and the indirect basal ganglia pathwaysand ECB signaling [111]

The cannabinoid signaling system mentioned aboveexperiences a biphasic pattern of changes during the pro-gression of PD [112] Early and presymptomatic PD stagescharacterized by neuronal malfunction with little evidenceof neuronal death are associated with desensitizationdown-regulation of CB1 receptors and aggravation of variouscytotoxic insults such as excitotoxicity oxidative stress andglial activation [113] However intermediate and advancedstages of PD characterized by a deep nigral degenerationand manifestation of major Parkinsonian symptoms areassociated with upregulatory responses of CB1 receptors andthe endocannabinoid ligands [113] This could explain thepotential of CB1 receptor ligands in alleviating common PDsymptoms

In the brain CB1 receptors are expressed by GABAergicneurons innervating the external and internal segments of theglobus pallidus and the substantia nigra [114ndash116] CB1 recep-tors are also present in the corticostriatal glutamatergic ter-minals and in the excitatory projections from the subthalamicnucleus to the internal segment of the globus pallidus and thesubstantia nigra [114ndash116]Within the striatum CB1 receptors

are expressed in parvalbumin immune-reactive interneuronscholinergic interneurons and nitric oxide synthase-positiveneurons [117 118] Animal models of Parkinsonrsquos diseaseshow an increase in the density of CB1 receptors levels ofendogenous ligands and CB1 receptor binding in the basalganglia [119ndash122] Endogenous cannabinoids activate CB1receptors on presynaptic axons and reduce neurotransmitterand glutamate release working as retrograde synaptic mes-sengers released from postsynaptic neurons [123] Similarlyactivation of CB1 receptors inhibits both glutamate releasefrom substantia nigra afferents and GABA release fromstriatal afferents At the same time activation of presynapticCB1 receptors in the external segments of the globus palliduscan increase local GABA levels by reducing GABA reuptakefrom striatal afferents to the nucleus and decrease GABArelease from striatal afferents of the substantia nigra [114116 118] Based on these evidences it is thought that thefunction of the basal ganglia neuronal system is controlled byECB The presence of endocannabinoid systems in differentneural structures and their interaction with dopaminergicglutamatergic and GABAergic neurotransmitter signalingsystems make the components of endocannabinoid systemideal targets for a novel nondopaminergic treatment of PD

Endocannabinoid signaling is also bidirectionally linkedto dopaminergic signaling within the basal ganglia [118]The CB1 D1 and D2 dopamine receptors are localizedin the striatum [114 115] In animal models CB1 and D2dopamine receptors share a common pool of G proteinssuggesting the link of their signal transduction mechanisms[124 125] In addition D2 receptor stimulation resulted inrelease of ECBs in the striatum [101] However stimulationof CB1 receptors completely inhibited D1-dopamine receptormediated activation of adenylyl cyclase and decreased GABArelease from striatal afferents of dopaminergic neurons of thesubstantia nigra resulting in an increased firing of these cells[114ndash116]

Another receptor involved in control of movement istransient receptor potential vanilloid type 1 (TRPV1) whichis expressed in sensory neurons and basal ganglia circuitryof dopaminergic neurons [126 127] TRPV1 receptors aremolecular integrators of nociceptive stimuli activated byendovanilloids [128] TRPV1 also interacts with ECB Inparticular anandamide is one of the major endogenous acti-vators of TRPV1 [129ndash131] Studies have revealed that motorbehavior can be suppressed by the activation of vanilloidreceptors [98 99] suggesting that TRPV1 receptors mightplay a role in the control of motor function

32 Preclinical Data on the Endocannabinoid System as aTarget for Parkinsonrsquos Disease Therapy The association ofcannabinoids with regulation of motor functions is wellestablished [132ndash135]The effect of the cannabinoids onmotoractivity depends on the impact of the endocannabinoidsystem on the dopaminergic glutamatergic and GABAergicsignaling systems throughout the basal ganglia [112 136]The high density of cannabinoid dopamine and vanilloid-like receptors coupled with ECBs within the basal gangliaand cerebellum suggests a potential therapeutic role for the


cannabinoids in the control of voluntary movement andin movement disorders such as Parkinsonrsquos disease [98 99121 137] Additional indications of an important role of theendocannabinoid system in the control of movement involvean inhibitory action of cannabinoids through fine tuning ofvarious classical neurotransmitters activity [138] prominentchanges in transmission of ECBs in the basal ganglia [139]and alteration of the CB1 binding as well as CB1 availabilityin the substantia nigra [85 112 119 120 140 141] These datasupport the idea that cannabinoid- based compounds act onvital pathways of endocannabinoid transmission and there-fore might be of therapeutic interest due to their potential todiminish motor symptoms in extrapyramidal disorders suchas Parkinsonrsquos disease [27 76 142]

Research with cannabinoid agonists and antagonistsdemonstrates that the cannabinoids can modulate motoractivity and produce alterations in corresponding molecularcorrelates [129 143ndash145] It has been widely reported thatsynthetic plant-derived or endogenous cannabinoid ago-nists exert a powerful motor inhibition in laboratory species[129 144 146ndash149] This hypokinetic effect was shown to bemediated by the activation of CB1 receptors in neurons ofthe basal ganglia circuitry [88 137 141 150ndash152] Stimulationof the CB1 receptor by a synthetic cannabinoid HU-210decreased spontaneous glutamatergic activity and reducedthe rotations induced by levodopacarbidopa by 34 in PDrats [153 154] Administration of CB1 receptor agonists THCand two synthetic cannabinoidsWIN 55212-2 and CP 55940increased extracellular dopamine concentrations in rats [152155 156] WIN 55212-2 and CP 55940 also weakenedcontralateral rotations induced by a selective D1D5 receptorpartial agonist SKF38393 without developing catalepsy in PDrats [148] In a gender study THC produced an increase intyrosine hydroxylase activity in parkin-null male mice (amodel of early stages of PD) and caused a motor inhibitionthat was significantly greater compared to wild-type animals[122] Treatment with THC inhibited motor activity andproduced catalepsy in rats [109 144 146 147] and causedantinociception and ring immobility in mice [157] In otherstudies THC diminished the motor inhibition caused by 6-hydroxydopamine [70] and potentiated the hypokinetic effectof reserpine in rats more than 20-fold [135] However ina primate model of Parkinsonrsquos disease THC did not affectlocomotor activity but increased bradykinesia [125]

Administration of WIN 55212-2 increased stimulationof GTP120574S binding in the caudate nucleus putamen globuspallidus and substantia nigra of marmosets indicating aneffective activation of CB1 signaling mechanisms [119 120]WIN 55212-2 produced a dose-dependent reduction of thespontaneous motor activity and catalepsy in mutant Syrianhamsters increased antidystonic efficacy of benzodiazepines[158] and significantly reduced the antikinetic effects ofquinpirole in the reserpine-treated rats [159] Treatmentwith WIN 55212-2 also reduced levodopa-induced dyskine-sias attenuated axial limb and severe orolingual abnormalinvoluntary movements in 6-hyroxydopamine- (6-OHDA-)lesioned rats [160ndash163] An endogenous cannabinoid agonistoleoylethanolamide (OAE) produced reduction in dyskineticcontralateral rotations correlatedwith reduction ofmolecular

associates of L-DOPA-induced dyskinesia reduced FosBstriatal overexpression and phosphoacetylation of hystone3 [164] Another synthetic agonist levonantradol decreasedgeneral and locomotor activity and increased bradykinesiain a primate model of Parkinsonrsquos disease [125] Nabilonea synthetic cannabinoid agonist coadministered with lev-odopa significantly decreased total dyskinesia comparedwithlevodopa alone treatment and increased the duration ofantiparkinsonian action of levodopa by 76 in PD mar-mosets [165 166]

Cannabinoid agonist anandamide (AEA) and its syn-thetic analog methanandamide increased the extracellulardopamine levels in the nucleus accumbens shell of ratsby the activation of the mesolimbic dopaminergic system[167] This dopamine increase was inhibited by the cannabi-noid CB1 receptor antagonist rimonabant [167] Howeverrecent discoveries indicate that AEA is also able to acti-vate vanilloid VR(1) receptors and that the activation ofthese receptors might also be responsible for changes innigrostriatal dopaminergic activity and anandamide-inducedhypokinesia [168ndash170] AEA produced a tonic facilitation ofglutamate release in the substantia nigra via stimulation ofVR1 receptors indicating the involvement of this receptor inmotor and cognitive functions of the dopaminergic system[171] Preclinical data have shown that AEA decreased theactivity of nigrostriatal dopaminergic neurons and producedhypokinesia that was completely reversed by an antagonistof vanilloid-like receptors capsazepine [129] Additionalstudies have demonstrated that AEA inhibited ambulationand stereotypic behavior increased inactivity and occludedthe effects of an agonist of vanilloid VR1 receptors livanilon locomotion in mice suggesting a common mechanismof action for the two compounds [170] Treatment withanandamide lowered motor activity with the maximal inhi-bition by approximately 85 and produced hypothermia andanalgesia inmice increased the inactivity time andmarkedlydecreased the ambulation and the frequency of spontaneousnon-ambulatory activities in rats [146 147 172 173] More-over AEAproduced a decrease in spontaneousmotor activityin laboratory animals similar to the reported actions of THC[129 145 153 170] The hypokinetic actions of AEA wereboosted by coadministration with a selective inhibitor ofendocannabinoid uptake N-(3-furylmethyl) eicosa-581114-tetraenamide UCM707 [174]

Tissue concentrations of endocannabinoids are impor-tant for producing motor effects Levels and activities ofAEA and 2-AG can be manipulated by inhibition of FAAHenzyme the action of which is reduced in experimentalmodels of PD [153 175] Animal studies have shown that theFAAH enzyme inhibitor [3-(3-carbamoylphenyl) phenyl] N-cyclohexylcarbamate (URB597) magnified and prolonged arapid brief dopamine increase that was produced by AEA[167] Additional studies have confirmed that FAAH inhibi-tion remarkably increases AEA tissue levels but reduces 2-AG levels [176 177] To determine whether FAAH inhibitionhas beneficial impact on PD symptoms the effect of theFAAH inhibitor URB597 was studied in MPTP- lesionedmarmosets Treatment with URB597 increased plasma levels


of AEA did not modify the antiparkinsonian actions of L-DOPA and reduced the magnitude of hyperactivity to levelsequivalent to those seen in normal animals [178] In PDmice URB597 prevented induced motor impairment [179]Moreover other FAAH inhibitors JNJ1661010 and TCF2 alsohave anticataleptic properties [179] These results reveal thatFAAH inhibition may represent a new strategy for treatmentof PD

Overall these results indicate that endogenous or exoge-nous cannabinoid agonists activate the dopaminergic systemand play a very important role in modulation of motorbehavior [180] In addition to the effects on movementactivity cannabinoid agonists have demonstrated neuropro-tective properties suggesting that the cannabinoids have apromising pharmacological profile for not only improvingParkinsonian symptoms but also delaying PD progression[70 85 181ndash183]

The CB1 receptor antagonists can also influence move-ment syndromes of Parkinsonrsquos disease suggesting that mod-ulation of the CB1 signaling system might be valuable intreatment of motor disorders In a study with PD rats rimon-abant (SR141716A) a selective antagonist of CB1 receptors hasshown the potential to act as an antihypokinetic agent byenhancing glutamate release from excitatory afferents to thestriatum [184] Moreover SR141716A prevented the effects ofTHC on dopamine release [156 167] and also increased thelocomotor activity in mice and rats preexposed to THC [170185] SR141716A produced a 71 increase in motor activityin MPTP-lesioned marmosets with LID [136] Coadminis-tration of SR141716A with levodopa resulted in significantlyless dyskinesia than administration of levodopa alone [136160] SR141716A also reversed effect of the cannabinoidagonist WIN 55212-2 and increased the locomotor activityin 6-OHDA-lesioned animals [159 163] Coadministration ofSR141716A with a selective D2D3 receptor agonist quinpirolereduced levels of AEA and 2AG by sevenfold in the globuspallidus boosted the locomotive effects of quinpirole andproduced restoration of locomotion in animal models ofParkinsonrsquos disease [98 99 101 136 186] In parkin-nullmice SR141716A produced a decrease in tyrosine hydroxylaseactivity in the caudatendashputamen and as result formed ahyperkinetic response [122] However SR141716A did notalleviate the motor deficits in a primate model of Parkinsonrsquosdisease [125]

Another CB1 receptor antagonist AM251 and SR141716Aproduced antiparkinsonian effects in rats with very severenigral degeneration (gt95 cell loss) [187] Local adminis-tration of these antagonists into denervated striatum globuspallidus and subthalamic nucleus reducedmotor asymmetryin Parkinsonian rats [187 188] which was inhibited by CB1receptor agonist AM404 [187] Another CB1 antagonist CE-178253 produced a 30 increase in motor behavior responsesto L-DOPA in MPTP-treated rhesus monkeys but did notmodify levodopa-induced dyskinesias [189] THCV causedchanges in glutamatergic transmission and attenuated themotor inhibition in PD rats [70] Overall these findingssuggest that cannabinoid CB1 antagonists might be thera-peutically effective in the control of Parkinsonrsquos disease andlevodopa-induced dyskinesia [114 190]

The activation of CB2 receptors might also contribute tosome extent to the potential of cannabinoids in PD [191]THCV which is not only a CB1 antagonist but also a CB2 par-tial agonist reduced the loss of tyrosine hydroxylase-positiveneurons in the substantia nigra with preservation of theseneurons in CB2 receptor-deficient mice [70] CBD has alsoreduced the loss of tyrosine hydroxylase-positive neurons inthe substantia nigra of PD rats Both compounds THCV andCBD have acted via neuroprotective and antioxidant mech-anisms [70 182 191] CBD has also demonstrated significanteffects in preclinical models of neurodegenerative disordersin combination with other cannabinoids [15 70 192] CB2receptor agonists display a promising pharmacological profilefor delaying disease progression

The cannabinoid pharmacologicmanipulation representsa promising therapy to alleviate movement disorders andlevodopa-induced dyskinesias Thus CB1 antagonists appearto have antiparkinsonian effects while cannabinoid receptoragonists may be useful in the treatment of motor complica-tions in Parkinsonrsquos disease

33 Effect of Cannabinoids on Patients with Movement Dis-orders Cannabis and related compounds have created sig-nificant research interest as a promising therapy in neurode-generative and movement disorders The successful use oftincture of Cannabis indica in treating PD was first describedin Europe by Gowers [193] Despite the lack of controlledstudies there is evidence that cannabinoids are of therapeuticvalue in the treatment of tics in Tourette syndrome someforms of tremor and dystonia chorea inHuntingtonrsquos diseasethe reduction of levodopa-induced dyskinesia in Parkinsonrsquosdisease and Parkinsonian syndromes [194ndash201]

A study with smoked cannabis queried 339 PD patientsindicated that marijuana produced significant improvementof general PD symptoms in 46 of the patients 31 of themreported improvement in resting tremor 38 reported relieffrom rigidity 45 defined reduced bradykinesia and 14of the patients reported alleviated dyskinesias [202] Highurine concentration (gt50 ngml) of the THC primary activemetabolite 11-HO-THC was associated with relief from PDsymptoms [202] The dose and frequency of the cannabisadministrations were important in relieving PD symptomsSmoked cannabis also produced a statistically significantimprovement in tremor rigidity and bradykinesia as wellas improvement in sleep and pain scores in 22 PD patients[65] In another study smoked cannabis was responsible fora significant improvement in the mean total motor UnifiedParkinsonrsquos Disease Rating Scale (UPDRS) score tremorrigidity and bradykinesia in 17 patients with PD [203] Onedose of smoked marijuana provided symptoms relief for upto 3 hours [203] Moreover both studies reported significantimprovement of nonmotor symptoms of PD such as painand sleep [65 203] However smoked marijuana did notreduce Parkinsonian symptoms in 5 patients with idiopathicParkinsonrsquos disease and severe tremor [204] A clinical trialin 19 PD and 6 patients with levodopa-induced dyskinesiademonstrated that oral cannabis extract was ineffective foralleviating parkinsonism or dyskinesia [205]


Few studies have evaluated the effects of CBD on PDsymptoms In a pilot study CBD lowered total UPDRSscores and significantly reduced psychotic symptoms in 6 PDpatients with psychosis [67] In another study CBD admin-istration produced no improvement in measures of motorand general symptoms in 21 PD patients [68 69] Howeverthe group treated with CBD had significantly different meantotal scores in the Parkinsonrsquos Disease Questionnaire 39compared to the placebo group [68 69] Oral CBD improveddyskinesia by up to 30 without a significant worseningof the parkinsonism in PD patients [206] CBD withdrawalcaused severe generalized dystonia [206]

Clinical studies have been conducted to evaluate theeffect of a synthetic cannabinoid nabilone Oral nabilonesignificantly reduced dyskinesia without aggravating parkin-sonism in seven PD patients with severe L-DOPA-induceddyskinesia [207] In another study nabilone produced a 22reduction in levodopa-induced dyskinesia in PD patients[208] Nabilone showed efficacy not only against LID butalso against bradykinesia in PD patients [209] Some othercannabinoid related compounds such as CE178253 OEA andHU-210 have also been reported to be efficacious againstL-DOPA-induced dyskinesia and bradykinesia in PD [199209] However SR 141716 did not improve Parkinsonianmotor disability in PDpatients [210]TheAmericanAcademyof Neurology (AAN) review deemed marijuana ldquoprobablyineffectiverdquo for treating L-DOPA-induced dyskinesia [211]These conflicting results indicate the need for more researchin this area

Several clinical studies have been performed to evaluatethe effect of marijuana on dystonia Inhaled cannabis hasprovided a marked reduction in dystonia and complete painrelief in patients with right hemiplegic painful dystoniaMoreover the patients have been able to completely dis-continue opioid use [212] Smoked cannabis also improvedidiopathic dystonia and generalized dystonia due to Wilsonrsquosdisease [213 214] In a preliminary study administration ofCBD resulted in a 50 improvement in spasm severity andfrequency in a patient with blepharospasm-oromandibulardystonia [215] and amelioration of the dystonic movementswithin 2-3 hours in patients with dystonic movement dis-orders [201] CBD also improved dystonia by 20ndash50 indystonic patients and stopped tremor and hypokinesia in2 patients with Parkinsonrsquos disease [200] Another cannabiscompound THC produced a reduction of abnormal move-ment patterns in a 14-year-old girl withmarked dystonia [216]and decreased intensity of myoclonic movements in a 13-year-old boy with athetosis and myoclonic movements [216]In contrast to these findings one study found no significantreduction in dystonia following treatment with nabilone [165166]

Studies have looked at the potential benefits of medicalmarijuana and cannabinoids for the treatment of Hunt-ingtonrsquos disease (HD) Nabilone versus placebo showed atreatment difference of 086 for total motor score 168 forchorea 357 for Unified Huntingtonrsquos Disease Rating Scale(UHDRS) cognition 401 for UHDRS behavior and 643for the neuropsychiatric inventory in HD patients [217]However in previous study nabilone was found to increase

choreatic movements in patients with HD [197 198] AANguideline examining the efficacy of marijuana for treatingchorea in HD stated nabilone can be used for modestdecreases in HD chorea [218] Available data regarding theeffect of CBD on HD symptoms are inconsistent CBDproduced improvement (20ndash40) in the choreic movementsin HD patients [219] However a latter study did not confirmthe earlier finding [220] A comparison of the effects ofCBD and placebo on chorea severity in neuroleptic-freeHD patients indicated no significant or clinically importantdifferences [220]

Few studies have indicated that marijuana and THC canreduce tics and associated behavioral disorders in patientswith Tourettersquos syndrome (TS) [221] Cannabis inhalationsproduced a significant amelioration of TS symptoms [222]Followingmarijuana administration 82 of TS patients (119873 =64) reported a reduction or complete remission of motorand vocal tics and an amelioration of premonitory urgesand obsessive-compulsive symptoms (OCB) [199] Smokedmarijuana also eliminated TS symptoms in one case study[223] Administration of THC to a boy with TS improvedtics and enhanced short-interval intracortical inhibition andthe prolongation of the cortical silent period [224] TCHsignificantly reduced tics and improve driving ability in aTourettersquos patient [225] Treatment with THC lowered themean C1 specific over nonspecific binding ratio (11988110158401015840

3) from

030 to 025 in six TS patients although the difference was notsignificant However 11988110158401015840

3clearly declined in a patient with a

marked clinical response [226] To date there have been onlytwo controlled trials that investigated the effect of THC onTS [194] both of which reported a significant improvementof tics and OCB after THC administration [195 196]

Considering the relevance of these data the need for alter-native treatments for PD motor and nonmotor symptomsmedical marijuana or related compoundsmay provide a newapproach to the treatment of Parkinsonrsquos disease

4 Beneficial Effects of Cannabinoids in theAmelioration of Nonmotor Symptoms andProgression of Parkinsonrsquos Disease

41 Neuroprotective Actions of Cannabinoids Cannabinoidshave been shown to have neuroprotective effect due to theirantioxidative anti-inflammatory actions and their ability tosuppress exitotoxicity Plant-derived cannabinoids such asTHC and CBD can provide neuroprotection against the invivo and in vitro toxicity of 6-hydroxydopamine and this wasthought to be due to their antioxidative property or modula-tion of glial cell function or a combination of both [182] Stud-ies found that CBD was able to recover 6-hydroxydopamine-induced dopamine depletion and also induced upregulationof Cu Zn-superoxide dismutase which is a key enzyme inendogenous defense against oxidative stress [70 191 227]The reported data suggest that CBD also diminishes theincrease in nicotinamide adenine dinucleotide phosphate(NADPH) oxidase expression and decreases the markersof oxidative stress inflammation and cell death in thekidneys [228] Another study has also emphasized a role for


superoxide anion produced by microglial NADPH oxidasein augmenting the demise of dopaminergic neurons in thePD brain [229] The mechanism by which CBD acts toreduce NADPH oxidase expression and inhibit oxidativeinjury within the PD brain has yet to be confirmed butit seems to act through mechanisms independent of CB1or CB2 receptors [76] However data obtained from recentstudies have hinted towards a direct relationship betweenthe CB1 receptor and mitochondrial functions in the brain[230] The phenolic ring moieties in cannabinoids displayantioxidant activity guarding against glutamate-induced neu-rotoxicity in a cellular model [231] CBD produced reduc-tion of hydroperoxide-induced oxidative damage and wasmore protective against glutamate neurotoxicity compared toascorbate and a-tocopherol indicating that CBD is a potentantioxidant [232] Taken together these discoveries supportthe hypothesis that treatment with cannabinoids havingantioxidant effects may modulate mitochondrial reactiveoxygen species production [233] in the PD brain

Inflammation has been shown to be a crucial patho-logical factor responsible for the demise of dopaminergicneurons in PD [234ndash236] Glial cells appear to play a keyrole in neuroinflammation since higher levels of activatedmicroglia are reported in the substantia nigra of patientswith PD compared to brains of control subjects [237 238]Cannabinoids demonstrate anti-inflammatory activities bysuppressing toxic cytokine release and microglia activation[181ndash183] Increased CB2 receptor expression in nigral cellsand stimulation of these receptors protect dopaminergicneurons from microglia-induced inflammation and regulateneuronal survival [70] The cannabinoids are known to beable to activate the CB2 receptor which mediate the anti-inflammatory effects of the compounds and preserve cellsfrom excessive apoptosis Recent evidence substantiates thatsome cannabinoids may attenuate the neuroinflammationassociatedwith PD [191 239ndash241] Several studies showed thatCBD has anti-inflammatory properties [242ndash246] and canproduce beneficial effect in acute inflammation and chronicneuropathic states [5 247 248] THC demonstrates anti-inflammatory effect via activation of the CB1 receptor [249ndash251] In addition cannabinoids provide anti-inflammationeffect by reducing the vasoconstriction and restoring bloodsupply to the injured area [252] All these data supportthat cannabinoids are potentially effective compounds forthe treatment of neuroinflammatory conditions includingneurodegenerative diseases like PD

Marijuana may prevent brain damage by protectingagainst neuronal injuryThere are a fewmechanisms bywhichcannabinoids provide neuroprotection One of the mech-anisms involves an inductionupregulation of cannabinoidCB2 receptors mainly in reactivemicroglia and regulates theinfluence of these glial cells on homeostasis of surroundingneurons [253] In combination with the increased antitoxiceffects observed in cell cultures containing glia this sug-gests that immunomodulation produced by CB2 receptoractivation may play a primary role in the neuroprotectiveproperties of cannabinoids [182] Anothermechanismof neu-roprotection is activation of CB1 receptors Loss of dopamin-ergic neurons and greater degree of motor impairment in

CB1 knockout mice have been reported [85] Cannabinoidsactivating the CB1 receptor are antiexcitotoxic due to sup-pression of glutamatergic activity with a subsequent decreasein calcium ion influx and eventual nitric oxide production[254ndash256] Sativex-like combination of phytocannabinoidshas been demonstrated to produce neuroprotective effectvia interaction with both CB1 and CB2 receptors [134 257]In addition THC reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra [70] and exhibitedneuroprotective effect by activation of the PPAR120574 receptors[258] Overall these data suggest that cannabinoids areneuroprotective in acute and chronic neurodegeneration andcan delay or even stop progressive degeneration of braindopaminergic system a process that cannot be preventedcurrently

42 Analgesic Effect of Cannabinoids Pain is a relevant andoften underestimated nonmotor symptom of PD [259 260]Pain affects more that 50 of people with this disorderand can cause extreme physical psychological and socialdisorders and worsen Parkinsonian disability [261 262]Different treatment options are used to treat PD pain [262ndash265] However these medications have significant side effectsand do not provide universal efficacy [264 265] Cannabisis well known as a pain-relieving plant The cannabinoidreceptors in the central and peripheral nervous systems havebeen shown to modulate pain perception [266 267]

Several clinical studies have been performed to inves-tigate the effect of marijuana or cannabinoids on painSmoked cannabis significantly reduced neuropathic painintensity as well as significantly improved mood disturbancephysical disability and quality of life in HIV-patients [268]Cannabis was effective at ameliorating neuropathic pain inpatients with central and peripheral neuropathic pain [269]Inhaled cannabis significantly reduced pain intensity (34)compared to placebo in a clinical trial of painful distal sym-metric polyneuropathy (DSPN) [270] Whole plant extractsof Cannabis sativa produced statistically significant improve-ments on the mean pain severity score [271] Cannabis-basedmedicine significantly decreased chronic pain intensity aswell as sleep disturbance in multiple sclerosis patients [272273] Oromucosal nabiximols (1 1 combination of the THCand CBD) produced a reduction in pain intensity scores inpatients with neuropathic pain [274]

These findings are consistent with other discoveriessupporting the efficacy of cannabis in relieving pain Theanalgesic effect of cannabinoids has been reviewed [75 211275ndash281]The review of the literature suggests that marijuanaandor cannabinoids may be efficacious for pain relieving invarious disease states including PD

43 Antidepressant Effect of Cannabinoids Depression isone of the common nonmotor symptoms of PD and theestimated rate varies widely with an average prevalence of upto 50 [282ndash284] Despite its association with poor healthoutcomes and quality of life depression in PD patients isunderdiagnosed and undertreated [285ndash287] Studies haveindicated that the endocannabinoid system is involved in


the regulation of mood and emotional behavior and theloss or blockade of the endocannabinoid signaling systemresults in depressive symptoms [288] For example the CB1receptor antagonist rimonabant has been shown to inducesymptoms of anxiety and depression [289ndash291] In additionpolymorphism of the gene that encodes the CB1 receptorhas been associated with depression in PD [292] In animalmodels low level of THC produced antidepressant activityand increased serotogenic activity via activation of the CB1receptor [293] Animal studies have also shown that inhibi-tion of hydrolysis of the endocannabinoid anandamide exertsantidepressive effect [294] and resulted in an increased sero-tonergic andnoradrenergic neuronal activity in themidbrainCurrently available antidepressant drugs act via increasingserotonin andor noradrenaline levelsThese andmany otherstudies indicate that the cannabinoid system is a potentialtarget for the development of novel antidepressant drugsEpidemiological studies have demonstrated that people whoused cannabis daily or weekly exhibit less depressed moodand more positive effect than nonusers of cannabis [295]Other studies have shown an association between heavycannabis use and depressive symptoms However it is notclear whether the increased depressive symptoms are dueto cannabis use or other factors that increased the risk ofboth depression and heavy use of cannabis [296] Thereforemoderate use of cannabis in PD patients may help alleviatedepressive symptoms and improve quality of life

44 Effect of Cannabinoids on Sleep Disorders Sleep disor-ders are common in PD patients and negatively affect thequality of life The reported prevalence ranges from 25to 98 and this wide variation could be due to differ-ences in study design and diagnostic tools used [297] Thecauses of the sleep disturbances in PD are multifactorialand include neurodegeneration and the medications usedto treat motor symptoms of PD [298] Various sleep disor-ders including rapid eye movement sleep behavior disorderinsomnia sleep fragmentation excessive daytime sleepinessrestless legs syndrome and obstructive sleep apnea have beendescribed in PD patients [299 300] Cannabidiol the majornonpsychotic component of marijuana has been reported toimprove rapid eye movement sleep behavior disorder in PDpatients [68 69] Marijuana has also been shown to improvenonmotor symptoms of PD including sleep [65] In clinicaltrials involving 2000 patients with various pain conditionsnabiximols has been demonstrated to improve subjectivesleep parameters [301] Thus marijuana could be used toenhance the quality of life of PD patients by alleviating sleepdisorders and pain

5 Summary

Cannabis and related compounds have recently been studiedas promising therapeutic agents in treatment of neurode-generative and movement disorders including Parkinsonrsquosdisease In this review we have examined the potentialbenefits of medical marijuana and cannabinoids in thetreatment of both motor and nonmotor symptoms as well as

in slowing the progression of the disease We have lookedinto any scientific evidence that indicates the potential useof marijuana andor related compounds for the treatment ofPD Current treatments of PD provide only relief of motorsymptoms and are associated with adverse effects such asdyskinesia In addition these therapies do not slow theprogression of the disease Therefore there is an urgent needfor safer drugs that can treat both motor and nonmotorsymptoms of PD as well as drugs that slow the progressionof the disease

In spite of the placement of marijuana in schedule 1category under the US Federal Controlled Substance Act 24states andWashingtonDChave enacted laws allowing the useof marijuana to treat a range of medical conditions Parkin-sonrsquos disease has been listed as one of the disease conditionsfor whichmedical marijuana is allowed in a number of statesResearch studies have provided evidence for the potentialeffectiveness of medical marijuana and its components in thetreatment of PD as cannabinoids act on the sameneurologicalpathway that is disrupted in Parkinsonrsquos disease Involvementof the endocannabinoid system in the regulation of motorbehavior the localization of the cannabinoid receptors inareas that control movement and the effect of cannabi-noids on motor activity indicate that cannabinoids can bepotentially used in the treatment of movement disordersCannabinoid agonists and antagonists have been shown tomodulate the endocannabinoid system and modify motoractivity Cannabinoid receptor antagonists appear to produceantiparkinsonian effects while cannabinoid receptor agonistsexert a powerful motor inhibition and may be useful inthe treatment of motor complications In addition we haveassessed the role of the cannabinoid system and marijuanaconstituents in neuroprotection as well as considered otherbeneficial effects of marijuana Marijuana has been shownto improve nonmotor symptoms of PD such as depressionpain sleep and anxiety Moreover components of cannabishave been demonstrated to have neuroprotective effect dueto their anti-inflammatory antioxidative and antiexcitotoxicproperties Due to combination of the above mentionedbeneficial effects cannabis may provide a viable alternativeor addition to the current treatment of Parkinsonrsquos diseaseHowever there are concerns regarding the use of medicalmarijuana including lack of standardization and regulationimprecise dosing possible adverse effects and medicationinteractions Further studies are needed to provide moredata on efficacy safety pharmacokinetics and interactions ofcannabinoids

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

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[2] M A ElSohly and D Slade ldquoChemical constituents of mar-ijuana the complex mixture of natural cannabinoidsrdquo LifeSciences vol 78 no 5 pp 539ndash548 2005

[3] E B Russo ldquoTaming THC potential cannabis synergy andphytocannabinoid-terpenoid entourage effectsrdquo British Journalof Pharmacology vol 163 no 7 pp 1344ndash1364 2011

[4] E J Rahn and A G Hohmann ldquoCannabinoids as Phar-macotherapies for neuropathic pain from the bench to thebedsiderdquo Neurotherapeutics vol 6 no 4 pp 713ndash737 2009

[5] A W Zuardi ldquoCannabidiol from an inactive cannabinoid toa drug with wide spectrum of actionrdquo Revista Brasileira dePsiquiatria vol 30 no 3 pp 271ndash280 2008

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[7] DEA (Drug Enforcement Administration) Drug Fact SheetMarijuana httpwwwdeagovdruginfodrug data sheetsMar-ijuanapdf

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[9] Y Park ldquoGeorgia Regents University Epidiolex and DrugResistant Epilepsy in Children (CBD)rdquo In ClinicalTrialsgovBethesda (MD) National Library of Medicine (US) NLMIdentifier NCT02397863 httpsclinicaltrialsgovct2showNCT02397863

[10] W Notcutt R Langford P Davies S Ratcliffe and R PottsldquoA placebo-controlled parallel-group randomized withdrawalstudy of subjects with symptoms of spasticity due to multiplesclerosis who are receiving long-term Sativex (nabiximols)rdquoMultiple Sclerosis Journal vol 18 no 2 pp 219ndash228 2012

[11] A Novotna J Mares S Ratcliffe et al ldquoA randomizeddouble-blind placebo-controlled parallel-group enriched-design study of nabiximolslowast (Sativex) as add-on therapy insubjects with refractory spasticity caused by multiple sclerosisrdquoEuropean Journal of Neurology vol 18 no 9 pp 1122ndash1131 2011

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agonistsrdquo Recent Patents on CNS Drug Discovery vol 5 no 1pp 46ndash52 2010

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[21] M Schneider ldquoPuberty as a highly vulnerable developmentalperiod for the consequences of cannabis exposurerdquo AddictionBiology vol 13 no 2 pp 253ndash263 2008

[22] F Grotenhermen ldquoThe toxicology of cannabis and cannabisprohibitionrdquo Chemistry amp Biodiversity vol 4 no 8 pp 1744ndash1769 2007

[23] F R de Fonseca I del Arco F J Bermudez-Silva A BilbaoA Cippitelli and M Navarro ldquoThe endocannabinoid systemphysiology and pharmacologyrdquoAlcohol and Alcoholism vol 40no 1 pp 2ndash14 2005

[24] P Pacher S Batkai and G Kunos ldquoThe endocannabinoidsystem as an emerging target of pharmacotherapyrdquo Pharmaco-logical Reviews vol 58 no 3 pp 389ndash462 2006

[25] TMorera-Herreras CMiguelez AAristieta J A Ruiz-Ortegaand L Ugedo ldquoEndocannabinoid modulation of dopaminergicmotor circuitsrdquo Frontiers in Pharmacology vol 3 article 1102012

[26] A El Manira and A Kyriakatos ldquoThe role of endocannabinoidsignaling in motor controlrdquo Physiology vol 25 no 4 pp 230ndash238 2010

[27] J Fernandez-Ruiz and S Gonzalez ldquoCannabinoid control ofmotor function at the Basal GangliardquoHandbook of ExperimentalPharmacology vol 168 pp 479ndash507 2005

[28] J XuKDKochanek and S LMurphy ldquoNational vital statisticsreports deaths final data for 2007rdquo Statistics vol 58 no 3 p 1352010

[29] T Pringsheim N Jette A Frolkis and T D L Steeves ldquoTheprevalence of Parkinsonrsquos disease a systematic review andmeta-analysisrdquo Movement Disorders vol 29 no 13 pp 1583ndash15902014

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[33] L C Kwan and T L Whitehill ldquoPerception of speech by indi-viduals with Parkinsonrsquos disease a reviewrdquo Parkinsonrsquos Diseasevol 2011 Article ID 389767 11 pages 2011

[34] B Thomas and M F Beal ldquoParkinsonrsquos diseaserdquo HumanMolecular Genetics vol 16 no 2 pp R183ndashR194 2007

[35] G E Alexander ldquoBiology of Parkinsonrsquos disease pathogenesisand pathophysiology of a multisystem neurodegenerative dis-orderrdquo Dialogues in Clinical Neuroscience vol 6 no 3 pp 259ndash280 2004

[36] W Dauer and S Przedborski ldquoParkinsonrsquos disease mechanismsand modelsrdquo Neuron vol 39 no 6 pp 889ndash909 2003


[37] M C Rodriguez-Oroz M Jahanshahi P Krack et al ldquoInitialclinical manifestations of Parkinsonrsquos disease features andpathophysiological mechanismsrdquo The Lancet Neurology vol 8no 12 pp 1128ndash1139 2009

[38] T Patel and F Chang ldquoParkinsonrsquos disease guidelines forpharmacistsrdquo Canadian Pharmacists Journal vol 147 no 3 pp161ndash170 2014

[39] K R Chaudhuri D G Healy and A H V Schapira ldquoNon-motor symptoms of Parkinsonrsquos disease diagnosis andmanage-mentrdquoThe Lancet Neurology vol 5 no 3 pp 235ndash245 2006

[40] BMuller J AssmusKHerlofson J P Larsen andO-B TysnesldquoImportance of motor vs non-motor symptoms for health-related quality of life in early Parkinsonrsquos diseaserdquo Parkinsonismand Related Disorders vol 19 no 11 pp 1027ndash1032 2013

[41] J Latoo M Mistry and F J Dunne ldquoOften overlooked neu-ropsychiatric syndromes in Parkinsonrsquos diseaserdquo British Journalof Medical Practitioners vol 6 no 1 pp 23ndash30 2013

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[44] B Connolly and S H Fox ldquoTreatment of cognitive psychiatricand affective disorders associated with Parkinsonrsquos diseaserdquoNeurotherapeutics vol 11 no 1 pp 78ndash91 2014

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[46] F Gasparini T Di Paolo and B Gomez-MancillaldquoMetabotropic glutamate receptors for Parkinsonrsquos diseasetherapyrdquo Parkinsonrsquos Disease vol 2013 Article ID 196028 11pages 2013

[47] C G Goetz and G Pal ldquoInitial management of Parkinsonrsquosdiseaserdquo British Medical Journal vol 349 Article ID 6258 2014

[48] A Lees ldquoAlternatives to levodopa in the initial treatment ofearly Parkinsonrsquos diseaserdquo Drugs and Aging vol 22 no 9 pp731ndash740 2005

[49] R Katzenschlager C Sampaio J Costa and A Lees ldquoAnti-cholinergics for symptomatic management of Parkinsonrsquos dis-easerdquo Cochrane Database of Systematic Reviews no 2 ArticleID CD003735 2003

[50] S Maranis S Tsouli and S Konitsiotis ldquoTreatment ofmotor symptoms in advanced Parkinsonrsquos disease a practicalapproachrdquo Progress in Neuro-Psychopharmacology and Biologi-cal Psychiatry vol 35 no 8 pp 1795ndash1807 2011

[51] R Heumann R Moratalla M T Herrero et al ldquoDyski-nesia in Parkinsonrsquos disease mechanisms and current non-pharmacological interventionsrdquo Journal of Neurochemistry vol130 no 4 pp 472ndash489 2014

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[53] G Porras P De Deurwaerdere Q Li et al ldquoL-dopa-induceddyskinesia beyond an excessive dopamine tone in the striatumrdquoScientific Reports vol 4 article 3730 2014

[54] J J Chen D M Swope and K Dashtipour ldquoComprehensivereview of rasagiline a second-generation monoamine oxidase

inhibitor for the treatment of Parkinsonrsquos Diseaserdquo ClinicalTherapeutics vol 29 no 9 pp 1825ndash1849 2007

[55] S Lecht S Haroutiunian A Hoffman and P Lazarovici ldquoRasa-gilinemdashanovelMAOB inhibitor in Parkinsonrsquos disease therapyrdquoTherapeutics and Clinical Risk Management vol 3 no 3 pp467ndash474 2007

[56] R Pahwa S A Factor K E Lyons et al ldquoPractice parameterTreatment of Parkinson disease with motor fluctuations anddyskinesia (an evidence-based review) report of the QualityStandards Subcommittee of the American Academy of Neurol-ogyrdquo Neurology vol 66 no 7 pp 983ndash995 2006

[57] F Stocchi and J M Rabey ldquoEffect of rasagiline as adjuncttherapy to levodopa on severity of OFF in Parkinsonrsquos diseaserdquoEuropean Journal of Neurology vol 18 no 12 pp 1373ndash13782011

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[59] E Tolosa and M B Stern ldquoEfficacy safety and tolerabilityof rasagiline as adjunctive therapy in elderly patients withParkinsonrsquos diseaserdquo European Journal of Neurology vol 19 no2 pp 258ndash264 2012

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[61] Parkinson Study Group ldquoPramipexole vs levodopa as initialtreatment for Parkinson disease A randomized controlled trialParkinson Study Grouprdquo The Journal of the American MedicalAssociation vol 284 no 15 pp 1931ndash1938 2000

[62] S Perez-Lloret M V Rey P L Ratti and O Rascol ldquoRotigotinetransdermal patch for the treatment of Parkinsonrsquos diseaserdquoFundamental and Clinical Pharmacology vol 27 no 1 pp 81ndash95 2013

[63] J-P Elshoff W Cawello J-O Andreas F-X Mathy and MBraun ldquoAn update on pharmacological pharmacokinetic prop-erties and drug-drug interactions of rotigotine transdermalsystem in Parkinsonrsquos disease and restless legs syndromerdquoDrugs vol 75 no 5 pp 487ndash501 2015

[64] D Deleu Y Hanssens and M G Northway ldquoSubcutaneousapomorphine an evidence-based reviewof its use in Parkinsonrsquosdiseaserdquo Drugs and Aging vol 21 no 11 pp 687ndash709 2004

[65] I Lotan T A Treves Y Roditi and R Djaldetti ldquoCannabis(medicalmarijuana) treatment formotor andnon-motor symp-toms of Parkinson diseaserdquoClinical Neuropharmacology vol 37no 2 pp 41ndash44 2014

[66] T A Finseth J L Hedeman R P Brown K I Johnson MS Binder and B M Kluger ldquoSelf-reported efficacy of cannabisand other complementary medicine modalities by Parkinsonrsquosdisease patients in Coloradordquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 874849 6 pages2015

[67] A W Zuardi J A S Crippa J E C Hallak et al ldquoCannabidiolfor the treatment of psychosis in Parkinsonrsquos diseaserdquo Journal ofPsychopharmacology vol 23 no 8 pp 979ndash983 2009

[68] M H N Chagas A W Zuardi V Tumas et al ldquoEffectsof cannabidiol in the treatment of patients with Parkinsonrsquosdisease an exploratory double-blind trialrdquo Journal of Psy-chopharmacology vol 28 no 11 pp 1088ndash1092 2014


[69] M H N Chagas A L Eckeli A W Zuardi et al ldquoCannabidiolcan improve complex sleep-related behaviours associated withrapid eye movement sleep behaviour disorder in Parkinsonrsquosdisease patients a case seriesrdquo Journal of Clinical Pharmacy andTherapeutics vol 39 no 5 pp 564ndash566 2014

[70] C Garcıa C Palomo-Garo M Garcıa-Arencibia J A RamosR G Pertwee and J Fernandez-Ruiz ldquoSymptom-relievingand neuroprotective effects of the phytocannabinoid Δ9-THCVin animal models of Parkinsonrsquos diseaserdquo British Journal ofPharmacology vol 163 no 7 pp 1495ndash1506 2011

[71] M Shen and S A Thayer ldquoΔ9-Tetrahydrocannabinol acts as apartial agonist tomodulate glutamatergic synaptic transmissionbetween rat hippocampal neurons in culturerdquo Molecular Phar-macology vol 55 no 1 pp 8ndash13 1999

[72] R Murase R Kawamura E Singer et al ldquoTargeting multiplecannabinoid anti-tumour pathways with a resorcinol derivativeleads to inhibition of advanced stages of breast cancerrdquo BritishJournal of Pharmacology vol 171 no 19 pp 4464ndash4477 2014

[73] O Devinsky M R Cilio H Cross et al ldquoCannabidiol phar-macology and potential therapeutic role in epilepsy and otherneuropsychiatric disordersrdquo Epilepsia vol 55 no 6 pp 791ndash802 2014

[74] M Babayeva M Fuzailov P Rozenfeld and P Basu ldquoMari-juana compounds a non-conventional therapeutic approach toepilepsy in childrenrdquo Journal of Addiction Neuropharmacologyvol 1 pp 2ndash36 2014

[75] J L Croxford ldquoTherapeutic potential of cannabinoids in CNSdiseaserdquo CNS Drugs vol 17 no 3 pp 179ndash202 2003

[76] J Fernandez-Ruiz O Sagredo M R Pazos et al ldquoCannabidiolfor neurodegenerative disorders important new clinical appli-cations for this phytocannabinoidrdquo British Journal of ClinicalPharmacology vol 75 no 2 pp 323ndash333 2013

[77] Y Hashimotodani T Ohno-Shosaku M Watanabe and MKano ldquoRoles of phospholipase C120573 and NMDA receptor inactivity-dependent endocannabinoid releaserdquo The Journal ofPhysiology vol 584 no 2 pp 373ndash380 2007

[78] Z Hegyi K Hollo G Kis K Mackie and M Antal ldquoDiffer-ential distribution of diacylglycerol lipase-alpha and N-acyl-phosphatidylethanolamine-specific phospholipase d immuno-reactivity in the superficial spinal dorsal horn of ratsrdquo Glia vol60 no 9 pp 1316ndash1329 2012

[79] P G Fine and M J Rosenfeld ldquoThe endocannabinoid systemcannabinoids and painrdquoRambamMaimonidesMedical Journalvol 4 no 4 Article ID e0022 2013

[80] E M Marco S Y Romero-Zerbo M-P Viveros and F JBermudez-Silva ldquoThe role of the endocannabinoid system ineating disorders pharmacological implicationsrdquo BehaviouralPharmacology vol 23 no 5-6 pp 526ndash536 2012

[81] C R Hiley ldquoEndocannabinoids and the heartrdquo Journal ofCardiovascular Pharmacology vol 53 no 4 pp 267ndash276 2009

[82] R G Pertwee ldquoThe diverse CB 1 and CB 2 receptor pharma-cology of three plant cannabinoids Δ 9-tetrahydrocannabinolcannabidiol and Δ 9-tetrahydrocannabivarinrdquo British Journal ofPharmacology vol 153 no 2 pp 199ndash215 2008

[83] J-Y Xu and C Chen ldquoEndocannabinoids in synaptic plasticityand neuroprotectionrdquo Neuroscientist vol 21 no 2 pp 152ndash1682015

[84] V L Hegde M Nagarkatti and P S Nagarkatti ldquoCannabinoidreceptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive prop-ertiesrdquo European Journal of Immunology vol 40 no 12 pp3358ndash3371 2010

[85] S Perez-Rial M S Garcıa-Gutierrez J A Molina et alldquoIncreased vulnerability to 6-hydroxydopamine lesion andreduced development of dyskinesias in mice lacking CB1cannabinoid receptorsrdquoNeurobiology of Aging vol 32 no 4 pp631ndash645 2011

[86] D Piomelli ldquoThe molecular logic of endocannabinoid sig-nallingrdquoNature ReviewsNeuroscience vol 4 no 11 pp 873ndash8842003

[87] L A Matsuda S J Lolait M J Brownstein A C Young and TI Bonner ldquoStructure of a cannabinoid receptor and functionalexpression of the cloned cDNArdquo Nature vol 346 no 6284 pp561ndash564 1990

[88] M Herkenham A B Lynn M D Little et al ldquoCannabinoidreceptor localization in brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 87 no5 pp 1932ndash1936 1990

[89] I Ivanov P Borchert and B Hinz ldquoA simple method for simul-taneous determination of N-arachidonoylethanolamine N-oleoylethanolamine N-palmitoylethanolamine and 2-arachid-onoylglycerol in human cellsrdquo Analytical and BioanalyticalChemistry vol 407 no 6 pp 1781ndash1787 2015

[90] R G Pertwee A C Howlett M E Abood et al ldquoInter-national Union of Basic and Clinical Pharmacology LXXIXCannabinoid receptors and their ligands BeyondCB1 andCB2rdquoPharmacological Reviews vol 62 no 4 pp 588ndash631 2010

[91] N T Snider V J Walker and P F Hollenberg ldquoOxidationof the endogenous cannabinoid arachidonoyl ethanolamideby the cytochrome P450 monooxygenases physiological andpharmacological implicationsrdquo Pharmacological Reviews vol62 no 1 pp 136ndash154 2010

[92] M W Buczynski and L H Parsons ldquoQuantification of brainendocannabinoid levels methods interpretations and pitfallsrdquoBritish Journal of Pharmacology vol 160 no 3 pp 423ndash4422010

[93] C C Felder A Nielsen E M Briley et al ldquoIsolation andmeasurement of the endogenous cannabinoid receptor agonistanandamide in brain and peripheral tissues of human and ratrdquoFEBS Letters vol 393 no 2-3 pp 231ndash235 1996

[94] T Sugiura S Kondo S Kishimoto et al ldquoEvidence that2-arachidonoylglycerol but not N-palmitoylethanolamine oranandamide is the physiological ligand for the cannabinoidCB2 receptor Comparison of the agonistic activities of variouscannabinoid receptor ligands in HL-60 cellsrdquo Journal of Biolog-ical Chemistry vol 275 no 1 pp 605ndash612 2000

[95] T Bisogno F Berrendero G Ambrosino et al ldquoBrainregional distribution of endocannabinoids implications fortheir biosynthesis and biological functionrdquo Biochemical andBiophysical Research Communications vol 256 no 2 pp 377ndash380 1999

[96] R Mechoulam S Ben-Shabat L Hanus et al ldquoIdentificationof an endogenous 2-monoglyceride present in canine gut thatbinds to cannabinoid receptorsrdquo Biochemical Pharmacologyvol 50 no 1 pp 83ndash90 1995

[97] W Gonsiorek C Lunn X Fan S Narula D Lundell andR W Hipkin ldquoEndocannabinoid 2-arachidonyl glycerol isa full agonist through human type 2 cannabinoid receptorantagonism by anandamiderdquo Molecular Pharmacology vol 57no 5 pp 1045ndash1050 2000

[98] V Di Marzo F Berrendero T Bisogno et al ldquoEnhance-ment of anandamide formation in the limbic forebrain andreduction of endocannabinoid contents in the striatum of Δ9-


tetrahydrocannabinol-tolerant ratsrdquo Journal of Neurochemistryvol 74 no 4 pp 1627ndash1635 2000

[99] V Di Marzo M P Hill T Bisogno A R Crossman and J MBrotchie ldquoEnhanced levels of endogenous cannabinoids in theglobus pallidus are associated with a reduction in movement inan animal model of Parkinsonrsquos diseaserdquo FASEB Journal vol 14no 10 pp 1432ndash1438 2000

[100] G Palermo I Bauer P Campomanes et al ldquoKeys to lipidselection in fatty acid amide hydrolase catalysis structuralflexibility gating residues and multiple binding pocketsrdquo PLoSComputational Biology vol 11 no 6 article e1004231 2015

[101] A Giuffrida L H Parsons T M Kerr F Rodrıguez DeFonseca M Navarro and D Piomelli ldquoDopamine activation ofendogenous cannabinoid signaling in dorsal striatumrdquo NatureNeuroscience vol 2 no 4 pp 358ndash363 1999

[102] L De Petrocellis M G Cascio and V Di Marzo ldquoTheendocannabinoid system a general view and latest additionsrdquoBritish Journal of Pharmacology vol 141 no 5 pp 765ndash7742004

[103] B S Basavarajappa ldquoNeuropharmacology of the endocanna-binoid signaling system-molecular mechanisms biologicalactions and synaptic plasticityrdquo Current Neuropharmacologyvol 5 no 2 pp 81ndash97 2007

[104] I G Karniol and E A Carlini ldquoPharmacological interac-tion between cannabidiol and 1205759-tetrahydrocannabinolrdquo Psy-chopharmacologia vol 33 no 1 pp 53ndash70 1973

[105] R Mechoulam and Y Shvo ldquoHashishmdashI the structure ofcannabidiolrdquo Tetrahedron vol 19 pp 2073ndash2078 1963

[106] V Di Marzo and A Fontana ldquoAnandamide an endogenouscannabinomimetic eicosanoid lsquokilling two birds with onestonersquordquo Prostaglandins Leukotrienes and Essential Fatty Acidsvol 53 no 1 pp 1ndash11 1995

[107] H J Groenewegen ldquoThe basal ganglia and motor controlrdquoNeural Plasticity vol 10 no 1-2 pp 107ndash120 2003

[108] P Calabresi B Picconi A Tozzi V Ghiglieri and M DiFilippo ldquoDirect and indirect pathways of basal ganglia a criticalreappraisalrdquo Nature Neuroscience vol 17 no 8 pp 1022ndash10302014

[109] J Fernandez-Ruiz ldquoThe endocannabinoid system as a targetfor the treatment of motor dysfunctionrdquo British Journal ofPharmacology vol 156 no 7 pp 1029ndash1040 2009

[110] B D Heifets and P E Castillo ldquoEndocannabinoid signaling andlong-term synaptic plasticityrdquo Annual Review of Physiology vol71 pp 283ndash306 2009

[111] E Bezard J M Brotchie and C E Gross ldquoPathophysiologyof levodopa-induced dyskinesia potential for new therapiesrdquoNature Reviews Neuroscience vol 2 no 8 pp 577ndash588 2001

[112] S V More and D-K Choi ldquoPromising cannabinoid-basedtherapies for Parkinsonrsquos diseasemotor symptoms to neuropro-tectionrdquo Molecular Neurodegeneration vol 10 no 1 article 172015

[113] M Garcıa-Arencibia C Garcıa and J Fernandez-RuizldquoCannabinoids and Parkinsonrsquos diseaserdquo CNS and NeurologicalDisordersmdashDrug Targets vol 8 no 6 pp 432ndash439 2009

[114] J M Brotchie ldquoCB1 cannabinoid receptor signalling in Parkin-sonrsquos diseaserdquoCurrent Opinion in Pharmacology vol 3 no 1 pp54ndash61 2003

[115] M van der Stelt andVDiMarzo ldquoThe endocannabinoid systemin the basal ganglia and in themesolimbic reward system impli-cations for neurological and psychiatric disordersrdquo EuropeanJournal of Pharmacology vol 480 no 1ndash3 pp 133ndash150 2003

[116] E Benarroch ldquoEndocannabinoids in basal ganglia circuitsimplications for Parkinson diseaserdquoNeurology vol 69 no 3 pp306ndash309 2007

[117] F R Fusco A Martorana C Giampa et al ldquoImmunolocal-ization of CB1 receptor in rat striatal neurons A ConfocalMicroscopy Studyrdquo Synapse vol 53 no 3 pp 159ndash167 2004

[118] M Di Filippo B Picconi A Tozzi V Ghiglieri A Rossi and PCalabresi ldquoThe endocannabinoid system in Pakinsonrsquos diseaserdquoCurrent Pharmaceutical Design vol 14 no 23 pp 2337ndash23462008

[119] I Lastres-Becker M Cebeira M L De Ceballos et alldquoIncreased cannabinoid CB1 receptor binding and activationof GTP-binding proteins in the basal ganglia of patients withParkinsonrsquos syndrome and of MPTP-treated marmosetsrdquo Euro-pean Journal of Neuroscience vol 14 no 11 pp 1827ndash1832 2001

[120] I Lastres-Becker F Fezza M Cebeira et al ldquoChanges inendocannabinoid transmission in the basal ganglia in a ratmodel of Huntingtonrsquos diseaserdquo NeuroReport vol 12 no 10 pp2125ndash2129 2001

[121] T M Dawson and V L Dawson ldquoRare genetic mutations shedlight on the pathogenesis of Parkinson diseaserdquo The Journal ofClinical Investigation vol 111 no 2 pp 145ndash151 2003

[122] S Gonzalez M A Mena I Lastres-Becker et al ldquoCannabinoidCB1receptors in the basal ganglia and motor response to

activation or blockade of these receptors in parkin-null micerdquoBrain Research vol 1046 no 1-2 pp 195ndash206 2005

[123] R I Wilson and R A Nicoll ldquoEndocannabinoid signaling inthe brainrdquo Science vol 296 no 5568 pp 678ndash682 2002

[124] J P Meschler T J Conley and A C Howlett ldquoCannabinoidand dopamine interaction in rodent brain effects on locomotoractivityrdquo Pharmacology Biochemistry and Behavior vol 67 no3 pp 567ndash573 2000

[125] J P Meschler A C Howlett and B K Madras ldquoCannabinoidreceptor agonist and antagonist effects on motor functionin normal and 1-methyl-4-phenyl-1256-tetrahydropyridine(MPTP)-treated non-human primatesrdquo Psychopharmacologyvol 156 no 1 pp 79ndash85 2001

[126] L A Batista P H Gobira T G Viana D C Aguiar and FA Moreira ldquoInhibition of endocannabinoid neuronal uptakeand hydrolysis as strategies for developing anxiolytic drugsrdquoBehavioural Pharmacology vol 25 no 5-6 pp 425ndash433 2014

[127] E Mezey Z E Toth D N Cortright et al ldquoDistribution ofmRNA for vanilloid receptor subtype 1 (VR1) and VR1- likeimmunoreactivity in the central nervous system of the rat andhumanrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 97 no 7 pp 3655ndash3660 2000

[128] E Palazzo F Rossi and S Maione ldquoRole of TRPV1 receptorsin descending modulation of painrdquo Molecular and CellularEndocrinology vol 286 no 1-2 supplement 1 pp S79ndashS832008

[129] E de Lago R de Miguel I Lastres-Becker J A Ramos andJ Fernandez-Ruiz ldquoInvolvement of vanilloid-like receptors inthe effects of anandamide on motor behavior and nigrostriataldopaminergic activity in vivo and in vitro evidencerdquo BrainResearch vol 1007 no 1-2 pp 152ndash159 2004

[130] T dos Anjos-Garcia F Ullah L L Falconi-Sobrinho and NC Coimbra ldquoCB1 cannabinoid receptor-mediated anandamidesignalling reduces the defensive behaviour evoked throughGABAA receptor blockade in the dorsomedial division of theventromedial hypothalamusrdquo Neuropharmacology vol 113 pp156ndash166 2016


[131] E Lizanecz Z Bagi E T Pasztor et al ldquoPhosphorylation-dependent desensitization by anandamide of vanilloid receptor-1 (TRPV1) function in rat skeletal muscle arterioles and inChinese hamster ovary cells expressing TRPV1rdquo MolecularPharmacology vol 69 no 3 pp 1015ndash1023 2006

[132] A V Kravitz B S Freeze P R L Parker et al ldquoRegulation ofparkinsonian motor behaviours by optogenetic control of basalganglia circuitryrdquo Nature vol 466 no 7306 pp 622ndash626 2010

[133] A C Kreitzer and R C Malenka ldquoEndocannabinoid-mediatedrescue of striatal LTD and motor deficits in Parkinsonrsquos diseasemodelsrdquo Nature vol 445 no 7128 pp 643ndash647 2007

[134] O Sagredo M R Pazos V Satta J A Ramos R GPertwee and J Fernandez-Ruiz ldquoNeuroprotective effects ofphytocannabinoid-based medicines in experimental models ofHuntingtonrsquos diseaserdquo Journal of Neuroscience Research vol 89no 9 pp 1509ndash1518 2011

[135] D E Moss S B McMaster and J Rogers ldquoTetrahydrocannabi-nol potentiates reserpine-induced hypokinesiardquo PharmacologyBiochemistry and Behavior vol 15 no 5 pp 779ndash783 1981

[136] M Van Der Stelt S H Fox M Hill et al ldquoA role for endo-cannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primatemodels of Parkinsonrsquos diseaserdquo FASEB Journal vol 19 no 9 pp1140ndash1142 2005

[137] T Bisogno F Berrendero G Ambrosino et al ldquoBrain region-al distribution of endocannabinoids implications for theirbiosynthesis and biological functionrdquo Biochemical and Biophys-ical Research Communications vol 256 no 2 pp 377ndash380 1999

[138] M C Sanudo-Pena K Tsou and J M Walker ldquoMotor actionsof cannabinoids in the basal ganglia output nucleirdquo Life Sciencesvol 65 no 6-7 pp 703ndash713 1999

[139] I Lastres-Becker H H Hansen F Berrendero et al ldquoAllevia-tion ofmotor hyperactivity andneurochemical deficits by endo-cannabinoid uptake inhibition in a rat model of Huntingtonrsquosdiseaserdquo Synapse vol 44 no 1 pp 23ndash35 2002

[140] M Glass M Dragunow and R L Faull ldquoThe pattern of neu-rodegeneration in Huntingtonrsquos disease a comparative studyof cannabinoid dopamine adenosine and GABA

119860receptor

alterations in the human basal ganglia in Huntingtonrsquos diseaserdquoNeuroscience vol 97 no 3 pp 505ndash519 2000

[141] K Van Laere C Casteels S Lunskens et al ldquoRegional changesin type 1 cannabinoid receptor availability in Parkinsonrsquos diseasein vivordquo Neurobiology of Aging vol 33 no 3 pp 620e1ndash620e82012

[142] EM Romero B Fernandez O Sagredo et al ldquoAntinociceptivebehavioural and neuroendocrine effects of CP 55940 in youngratsrdquo Developmental Brain Research vol 136 no 2 pp 85ndash922002

[143] L E Long R Chesworth X-F Huang I S McGregor J CArnold and T Karl ldquoA behavioural comparison of acute andchronic 9- tetrahydrocannabinol and cannabidiol in C57BL6JArcmicerdquo International Journal of Neuropsychopharmacologyvol 13 no 7 pp 861ndash876 2010

[144] W R Prescott L H Gold and B R Martin ldquoEvidence for sep-arate neuronal mechanisms for the discriminative stimulus andcatalepsy induced by Δ9-THC in the ratrdquo Psychopharmacologyvol 107 no 1 pp 117ndash124 1992

[145] J N Crawley R L Corwin J K Robinson C C FelderW A Devane and J Axelrod ldquoAnandamide an endogenousligand of the cannabinoid receptor induces hypomotility andhypothermia in vivo in rodentsrdquo Pharmacology Biochemistryand Behavior vol 46 no 4 pp 967ndash972 1993

[146] J Romero R de Miguel E Garcıa-Palomero J J Fernandez-Ruiz and J A Ramos ldquoTime-course of the effects of anan-damide the putative endogenous cannabinoid receptor ligandon extrapyramidal functionrdquo Brain Research vol 694 no 1-2pp 223ndash232 1995

[147] J Romero L Garcia M Cebeira D Zadrozny J J Fernandez-Ruiz and J A Ramos ldquoThe endogenous cannabinoid receptorligand anandamide inhibits themotor behavior role of nigros-triatal dopaminergic neuronsrdquo Life Sciences vol 56 no 23-24pp 2033ndash2040 1995

[148] L A Anderson J J Anderson T N Chase and J R WaltersldquoThe cannabinoid agonists WIN 55212-2 and CP 55940 atten-uate rotational behavior induced by a dopamine D1 but not aD2 agonist in rats with unilateral lesions of the nigrostriatalpathwayrdquo Brain Research vol 691 no 1-2 pp 106ndash114 1995

[149] J Fernandez-Ruiz I Lastres-Becker A Cabranes S Gonzalezand J A Ramos ldquoEndocannabinoids and basal ganglia func-tionalityrdquo Prostaglandins Leukotrienes and Essential Fatty Acidsvol 66 no 2-3 pp 257ndash267 2002

[150] M Herkenham A B Lynn M Ross Johnson L S Melvin BR De Costa and K C Rice ldquoCharacterization and localizationof cannabinoid receptors in rat brain a quantitative in vitroautoradiographic studyrdquo Journal of Neuroscience vol 11 no 2pp 563ndash583 1991

[151] A G Hohmann and M Herkenham ldquoLocalization of cannabi-noid CB1 receptor mRNA in neuronal subpopulations of ratstriatum a double-label in situ hybridization studyrdquo Synapsevol 37 no 1 pp 71ndash80 2000

[152] J Romero I Lastres-Becker R de Miguel F Berrendero J ARamos and J Fernandez-Ruiz ldquoThe endogenous cannabinoidsystem and the basal ganglia biochemical pharmacologicaland therapeutic aspectsrdquo Pharmacology and Therapeutics vol95 no 2 pp 137ndash152 2002

[153] P Gubellini B PicconiM Bari et al ldquoExperimental parkinson-ism alters endocannabinoid degradation implications for stri-atal glutamatergic transmissionrdquo The Journal of Neurosciencevol 22 no 16 pp 6900ndash6907 2002

[154] Y Gilgun-Sherki E Melamed R Mechoulam and D OffenldquoThe CB1 cannabinoid receptor agonist HU-210 reduceslevodopa-induced rotations in 6-hydroxydopamine-lesionedratsrdquo Pharmacology and Toxicology vol 93 no 2 pp 66ndash702003

[155] D T Malone and D A Taylor ldquoModulation by fluoxetine ofstriatal dopamine release following Δ9-tetrahydrocannabinola microdialysis study in conscious ratsrdquo British Journal ofPharmacology vol 128 no 1 pp 21ndash26 1999

[156] G Tanda F E Pontieri and G Di Chiara ldquoCannabinoid andheroin activation of mesolimbic dopamine transmission by acommon 1205831 opioid receptor mechanismrdquo Science vol 276 no5321 pp 2048ndash2050 1997

[157] R G Pertwee A Thomas L A Stevenson et al ldquoThe psy-choactive plant cannabinoid Δ 9- tetrahydrocannabinol isantagonized byΔ 8- and Δ 9-tetrahydrocannabivarin in mice invivordquo British Journal of Pharmacology vol 150 no 5 pp 586ndash594 2007

[158] A Richter andW Loscher ldquo(+)-WIN 55212-2 a novel cannabi-noid receptor agonist exerts antidystonic effects in mutantdystonic hamstersrdquo European Journal of Pharmacology vol 264no 3 pp 371ndash377 1994

[159] Y P Maneuf A R Crossman and J M Brotchie ldquoThecannabinoid receptor agonist WIN 55212-2 reduces D

2 but

not D1 dopamine receptor-mediated alleviation of akinesia


in the reserpine-treated rat model of Parkinsonrsquos diseaserdquoExperimental Neurology vol 148 no 1 pp 265ndash270 1997

[160] G Segovia FMora A R Crossman and JM Brotchie ldquoEffectsof CB1 cannabinoid receptor modulating compounds on thehyperkinesia induced by high-dose levodopa in the reserpine-treated rat model of Parkinsonrsquos diseaserdquo Movement Disordersvol 18 no 2 pp 138ndash149 2003

[161] M G Morgese T Cassano V Cuomo and A Giuffrida ldquoAnti-dyskinetic effects of cannabinoids in a rat model of Parkinsonrsquosdisease role of CB

1and TRPV1 receptorsrdquo Experimental Neu-

rology vol 208 no 1 pp 110ndash119 2007[162] M G Morgese T Cassano S Gaetani et al ldquoNeurochemical

changes in the striatum of dyskinetic rats after administrationof the cannabinoid agonistWIN55212-2rdquoNeurochemistry Inter-national vol 54 no 1 pp 56ndash64 2009

[163] B Ferrer N Asbrock S Kathuria D Piomelli and A GiuffridaldquoEffects of levodopa on endocannabinoid levels in rat basalganglia implications for the treatment of levodopa-induceddyskinesiasrdquo European Journal of Neuroscience vol 18 no 6 pp1607ndash1614 2003

[164] R Gonzalez-Aparicio and R Moratalla ldquoOleoylethanolamidereduces L-DOPA-induced dyskinesia via TRPV1 receptor in amouse model of Parkinsonrsquos diseaserdquo Neurobiology of Diseasevol 62 pp 416ndash425 2014

[165] S H Fox B Henry M Hill A Crossman and J M BrotchieldquoStimulation of Cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primatemodel of Parkinsonrsquos diseaserdquo Movement Disorders vol 17 no6 pp 1180ndash1187 2002

[166] S H Fox M Kellett A P Moore A R Crossman and J MBrotchie ldquoRandomised double-blind placebo-controlled trialto assess the potential of cannabinoid receptor stimulation inthe treatment of dystoniardquo Movement Disorders vol 17 no 1pp 145ndash149 2002

[167] M Solinas Z Justinova S R Goldberg and G TandaldquoAnandamide administration alone and after inhibition of fattyacid amide hydrolase (FAAH) increases dopamine levels in thenucleus accumbens shell in ratsrdquo Journal of Neurochemistry vol98 no 2 pp 408ndash419 2006

[168] P M Zygmunt J Petersson D A Andersson et al ldquoVanilloidreceptors on sensory nerves mediate the vasodilator action ofanandamiderdquo Nature vol 400 no 6743 pp 452ndash457 1999

[169] D Smart M J Gunthorpe J C Jerman et al ldquoThe endogenouslipid anandamide is a full agonist at the human vanilloidreceptor (hVR1)rdquo British Journal of Pharmacology vol 129 no2 pp 227ndash230 2000

[170] V Di Marzo I Lastres-Becker T Bisogno et al ldquoHypoloco-motor effects in rats of capsaicin and two long chain capsaicinhomologuesrdquo European Journal of Pharmacology vol 420 no2-3 pp 123ndash131 2001

[171] S Marinelli V Di Marzo N Berretta et al ldquoPresynaptic facil-itation of glutamatergic synapses to dopaminergic neurons ofthe rat substantia nigra by endogenous stimulation of vanilloidreceptorsrdquoThe Journal of Neuroscience vol 23 no 8 pp 3136ndash3144 2003

[172] P B Smith D R Compton S P Welch R K Razdan RMechoulam and B R Martin ldquoThe pharmacological activityof anandamide a putative endogenous cannabinoid in micerdquoJournal of Pharmacology and Experimental Therapeutics vol270 no 1 pp 219ndash227 1994

[173] E Fride and R Mechoulam ldquoPharmacological activity of thecannabinoid receptor agonist anandamide a brain constituentrdquo

European Journal of Pharmacology vol 231 no 2 pp 313ndash3141993

[174] E De Lago J Fernandez-Ruiz S Ortega-Gutierrez A VisoM L Lopez-Rodrıguez and J A Ramos ldquoUCM707 a potentand selective inhibitor of endocannabinoid uptake potentiateshypokinetic and antinociceptive effects of anandamiderdquo Euro-pean Journal of Pharmacology vol 449 no 1-2 pp 99ndash103 2002

[175] N Ueda R A Puffenbarger S Yamamoto and D G DeutschldquoThe fatty acid amide hydrolase (FAAH)rdquoChemistry andPhysicsof Lipids vol 108 no 1-2 pp 107ndash121 2000

[176] M Maccarrone ldquoFatty acid amide hydrolase a potential tar-get for next generation therapeuticsrdquo Current PharmaceuticalDesign vol 12 no 6 pp 759ndash772 2006

[177] V DiMarzo andMMaccarrone ldquoFAAH and anandamide is 2-AG really the odd one outrdquo Trends in Pharmacological Sciencesvol 29 no 5 pp 229ndash233 2008

[178] T H Johnston P Huot S H Fox et al ldquoFatty Acid AmideHydrolase (FAAH) inhibition reduces L-34- dihydroxyphenyl-alanine-induced hyperactivity in the 1-methyl-4-phenyl-1236-tetrahydropyridine-lesioned non-human primate model ofParkinsonrsquos diseaserdquo Journal of Pharmacology and ExperimentalTherapeutics vol 336 no 2 pp 423ndash430 2011

[179] M Celorrio D Fernandez-Suareza E Rojo-Bustamantea etal ldquoFatty acid amide hydrolase inhibition for the symptomaticrelief of Parkinsonrsquos diseaserdquoBrain Behavior and Immunity vol57 pp 94ndash105 2016

[180] M Hodaie J S Neimat and A M Lozano ldquoThe dopaminergicnigrostriatal system and Parkinsonrsquos disease molecular eventsin development disease and cell death and new therapeuticstrategiesrdquo Neurosurgery vol 60 no 1 pp 17ndash28 2007

[181] A Sayd M Anton F Alen et al ldquoSystemic administrationof oleoylethanolamide protects from neuroinflammation andanhedonia induced by LPS in ratsrdquo International Journal ofNeuropsychopharmacology vol 18 no 6 pp 1ndash14 2015

[182] I Lastres-Becker F Molina-Holgado J A Ramos RMechoulam and J Fernandez-Ruiz ldquoCannabinoids provideneuroprotection against 6-hydroxydopamine toxicity in vivoand in vitro relevance to Parkinsonrsquos diseaserdquo Neurobiology ofDisease vol 19 no 1-2 pp 96ndash107 2005

[183] S V More H Kumar I S Kim S-Y Song and D-K ChoildquoCellular andmolecularmediators of neuroinflammation in thepathogenesis of Parkinsonrsquos diseaserdquoMediators of Inflammationvol 2013 Article ID 952375 12 pages 2013

[184] MGarcıa-Arencibia L Ferraro S Tanganelli and J Fernandez-Ruiz ldquoEnhanced striatal glutamate release after the adminis-tration of rimonabant to 6-hydroxydopamine-lesioned ratsrdquoNeuroscience Letters vol 438 no 1 pp 10ndash13 2008

[185] P Huang L-Y Liu-Chen E M Unterwald and A CowanldquoHyperlocomotion and paw tremors are two highly quantifi-able signs of SR141716-precipitated withdrawal from delta9-tetrahydrocannabinol in C57BL6 micerdquo Neuroscience Lettersvol 465 no 1 pp 66ndash70 2009

[186] S Gonzalez C Scorticati M Garcıa-Arencibia R de MiguelJ A Ramos and J Fernandez-Ruiz ldquoEffects of rimonabant aselective cannabinoid CB1 receptor antagonist in a rat modelof Parkinsonrsquos diseaserdquo Brain Research vol 1073-1074 no 1 pp209ndash219 2006

[187] E Fernandez-Espejo I Caraballo F R de Fonseca et alldquoCannabinoid CB1 antagonists possess antiparkinsonian effi-cacy only in rats with very severe nigral lesion in experimentalparkinsonismrdquo Neurobiology of Disease vol 18 no 3 pp 591ndash601 2005


[188] F El Banoua I Caraballo J A Flores B Galan-RodriguezandE Fernandez-Espejo ldquoEffects on turning ofmicroinjectionsinto basal ganglia of D1 and D2 dopamine receptors agonistsand the cannabinoid CB1 antagonist SR141716A in a rat Parkin-sonrsquos modelrdquoNeurobiology of Disease vol 16 no 2 pp 377ndash3852004

[189] X Cao L Liang J R Hadcock et al ldquoBlockade of cannabinoidtype 1 receptors augments the antiparkinsonian action oflevodopa without affecting dyskinesias in 1-methyl-4-phenyl-1236- tetrahydropyridine-treated rhesus monkeysrdquo Journal ofPharmacology and ExperimentalTherapeutics vol 323 no 1 pp318ndash326 2007

[190] S M Papa ldquoThe cannabinoid system in Parkinsonrsquos diseasemultiple targets to motor effectsrdquo Experimental Neurology vol211 no 2 pp 334ndash338 2008

[191] M Garcıa-Arencibia S Gonzalez E de Lago J A Ramos RMechoulam and J Fernandez-Ruiz ldquoEvaluation of the neuro-protective effect of cannabinoids in a rat model of Parkinsonrsquosdisease importance of antioxidant and cannabinoid receptor-independent propertiesrdquoBrainResearch vol 1134 no 1 pp 162ndash170 2007

[192] J Fernandez-Ruiz M Moreno-Martet C Rodrıguez-Cuetoet al ldquoProspects for cannabinoid therapies in basal gangliadisordersrdquo British Journal of Pharmacology vol 163 no 7 pp1365ndash1378 2011

[193] W Gowers A Manual of Diseases of the Nervous System PBlakistonrsquos Son amp Co Philadelphia Pa USA 1888

[194] K R Muller-Vahl ldquoTreatment of Tourette syndrome withcannabinoidsrdquo Behavioural Neurology vol 27 no 1 pp 119ndash1242013

[195] K R Muller-Vahl U Schneider H Prevedel et al ldquoΔ9-tetrahydrocannabinol (THC) is effective in the treatment of ticsin Tourette syndrome a 6-week randomized trialrdquo Journal ofClinical Psychiatry vol 64 no 4 pp 459ndash465 2003

[196] K R Muller-Vahl U Schneider A Koblenz et al ldquoTreatmentof Tourettersquos syndrome with Δ9-tetrahydrocannabinol (THC) arandomized crossover trialrdquo Pharmacopsychiatry vol 35 no 2pp 57ndash61 2002

[197] K R Muller-Vahl H Kolbe U Schneider and H M EmrichldquoCannabis in movement disordersrdquo Forschende Komplemen-tarmedizin vol 6 no 3 pp 23ndash27 1999

[198] K R Muller-Vahl U Schneider and H M Emrich ldquoNabiloneincreases choreatic movements in Huntingtonrsquos diseaserdquoMove-ment Disorders vol 14 no 6 pp 1038ndash1040 1999

[199] K R Muller-Vahl H Kolbe U Schneider and H M EmrichldquoCannabinoids possible role in patho-physiology and therapyof Gilles de la Tourette syndromerdquoActa Psychiatrica Scandinav-ica vol 98 no 6 pp 502ndash506 1998

[200] P Consroe R Sandyk and S R Snider ldquoOpen label evaluationof cannabidiol in dystonic movement disordersrdquo InternationalJournal of Neuroscience vol 30 no 4 pp 277ndash282 1986

[201] R Sandyk S R Snider P Consroe and S M Elias ldquoCannabid-iol in dystonic movement disordersrdquo Psychiatry Research vol18 no 3 p 291 1986

[202] K Venderova E Ruzicka V Vorisek and P Visnovsky ldquoSurveyon cannabis use in Parkinsonrsquos disease subjective improvementof motor symptomsrdquo Movement Disorders vol 19 no 9 pp1102ndash1106 2004

[203] I Lotan T Treves Y Roditi and R Djaldetti ldquoMedicalmarijuana (cannabis) treatment for motor and non-motorsymptoms in Parkinsonrsquos disease An open-label observationalstudyrdquoMovement Disorders vol 28 no 1 p 448 2013

[204] J P Frankel A Hughes A A J Lees and G M SternldquoMarijuana for parkinsonian tremorrdquo Journal of NeurologyNeurosurgery amp Psychiatry vol 53 no 5 p 436 1990

[205] C B Carroll P G Bain L Teare X Liu C Joint andCWroathldquoCannabis for dyskinesia in Parkinson disease a randomizeddouble-blind crossover studyrdquoNeurology vol 63 pp 1245ndash12502004

[206] S R Snider and P Consroe ldquoBeneficial and adverse effectsof cannabidiol in a Parkinson patient with sinemet-induceddystonic dyskinesiardquo Neurology vol 35 article 201 1985

[207] K A Sieradzan S H Fox J Dick and J M Brotchie ldquoTheeffects of the cannabinoid receptor agonist nabilone onL-DOPAinduced dyskinesia in patients with idiopathic ParkinsonrsquosdiseaserdquoMovement Disorders vol 13 supplement 2 p 29 1998

[208] K A Sieradzan S H FoxM Hill J P R Dick A R Crossmanand J M Brotchie ldquoCannabinoids reduce levodopa-induceddyskinesia in Parkinsonrsquos disease A Pilot StudyrdquoNeurology vol57 no 11 pp 2108ndash2111 2001

[209] P Consroe ldquoBrain cannabinoid systems as targets for thetherapy of neurological disordersrdquoNeurobiology of Disease vol5 no 6 pp 534ndash551 1998

[210] V Mesnage J L Houeto A M Bonnet et al ldquoNeurokininB neurotensin and cannabinoid receptor antagonists andParkinson diseaserdquo Clinical Neuropharmacology vol 27 no 3pp 108ndash110 2004

[211] B S Koppel J C M Brust T Fife et al ldquoSystematic reviewefficacy and safety of medical marijuana in selected neurologicdisorders report of the Guideline Development Subcommitteeof the American Academy of NeurologyrdquoNeurology vol 82 no17 pp 1556ndash1563 2014

[212] A Chatterjee A Almahrezi MWare andM A Fitzcharles ldquoAdramatic response to inhaled cannabis in a woman with centralthalamic pain and dystoniardquo Journal of Pain and SymptomManagement vol 24 no 1 pp 4ndash6 2002

[213] C D Marsden ldquoTreatment of torsion dystoniardquo in Disorders ofMovement Current Status of Modern Therapy A Barbeau Edvol 8 pp 81ndash104 Lippincott Williams ampWilkins PhiladelphiaPa USA 1981

[214] MCUribe Roca FMicheli andRViotti ldquoCannabis sativa anddystonia secondary to Wilsonrsquos diseaserdquo Movement Disordersvol 20 no 1 pp 113ndash115 2005

[215] S R Snider and P Consroe ldquoTreatment of Meigersquos syndromewith cannabidiolrdquo Neurology vol 34 article 147 1984

[216] R Lorenz ldquoOn the application of cannabis in paediatrics andepileptologyrdquo Neuroendocrinology Letters vol 25 no 1-2 pp40ndash44 2004

[217] A Curtis I Mitchell S Patel N Ives and H RickardsldquoA pilot study using nabilone for symptomatic treatment inHuntingtonrsquos diseaserdquo Movement Disorders vol 24 no 15 pp2254ndash2259 2009

[218] M J Armstrong and JMMiyasaki ldquoEvidence-based guidelinepharmacologic treatment of chorea in Huntington diseasereport of the guideline development subcommittee of theAmerican Academy of NeurologyrdquoNeurology vol 79 no 6 pp597ndash603 2012

[219] R Sandyk P Consroe L Stern S R Snider and D BliklenldquoPreliminary trial of cannabidiol in Huntingtonrsquos diseaserdquo inMarijuana An International Research Report G Chesher PConsroe and R Musty Eds Australian Government Publish-ing Service Canberra Australia 1988


[220] P Consroe J Laguna J Allender et al ldquoControlled clinicaltrial of cannabidiol in Huntingtonrsquos diseaserdquo PharmacologyBiochemistry and Behavior vol 40 no 3 pp 701ndash708 1991

[221] N M Kogan and R Mechoulam ldquoCannabinoids in health anddiseaserdquoDialogues inClinicalNeuroscience vol 9 no 4 pp 413ndash430 2007

[222] R Sandyk and G Awerbuch ldquoMarijuana and tourettersquos syn-dromerdquo Journal of Clinical Psychopharmacology vol 8 no 6 pp444ndash445 1988

[223] M Hemming and P M Yellowlees ldquoEffective treatment ofTourettersquos syndrome with marijuanardquo Journal of Psychopharma-cology vol 7 no 4 pp 389ndash391 1993

[224] A Hasan A Rothenberger A Munchau T Wobrock P Falkaiand V Roessner ldquoOral Δ9-tetrahydrocannabinol improvedrefractory Gilles de la Tourette syndrome in an adolescent byincreasing intracortical inhibition a case reportrdquo Journal ofClinical Psychopharmacology vol 30 no 2 pp 190ndash192 2010

[225] A Brunnauer F M Segmiller T Volkamer G Laux N Mullerand S Dehning ldquoCannabinoids improve driving ability in aTourettersquos patientrdquo Psychiatry Research vol 190 no 2-3 p 3822011

[226] G Berding K Muller-Vahl U Schneider et al ldquo[123I]AM281single-photon emission computed tomography imaging ofcentral cannabinoid CB1 receptors before and after Δ9-tetrahydrocannabinol therapy and whole-body scanning forassessment of radiation dose in Tourette patientsrdquo BiologicalPsychiatry vol 55 no 9 pp 904ndash915 2004

[227] J Sevcık and K Masek ldquoPotential role of cannabinoids inParkinsonrsquos diseaserdquoDrugs and Aging vol 16 no 6 pp 391ndash3952000

[228] H Pan P Mukhopadhyay M Rajesh et al ldquoCannabidiol atten-uates cisplatin-Lnduced nephrotoxicity by decreasing oxida-tivenitrosative stress inflammation and cell deathrdquo Journal ofPharmacology andExperimentalTherapeutics vol 328 no 3 pp708ndash714 2009

[229] M S Hernandes C C Cafe-Mendes and L R G BrittoldquoNADPH oxidase and the degeneration of dopaminergic neu-rons in Parkinsonian micerdquo Oxidative Medicine and CellularLongevity vol 2013 Article ID 157857 13 pages 2013

[230] E Hebert-Chatelain L Reguero N Puente et al ldquoCannabinoidcontrol of brain bioenergetics exploring the subcellular local-ization of the CB1 receptorrdquoMolecular Metabolism vol 3 no 4pp 495ndash504 2014

[231] S Yamaori J Ebisawa Y Okushima I Yamamoto and KWatanabe ldquoPotent inhibition of human cytochrome P450 3Aisoforms by cannabidiol role of phenolic hydroxyl groups in theresorcinol moietyrdquo Life Sciences vol 88 no 15-16 pp 730ndash7362011

[232] A J Hampson M Grimaldi J Axelrod and D WinkldquoCannabidiol and (minus)Δ9-tetrahydrocannabinol are neuropro-tective antioxidantsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 14 pp 8268ndash8273 1998

[233] G Benard F Massa N Puente et al ldquoMitochondrial CB1receptors regulate neuronal energy metabolismrdquo Nature Neu-roscience vol 15 no 4 pp 558ndash564 2012

[234] S Amor F Puentes D Baker and P Van Der Valk ldquoInflamma-tion in neurodegenerative diseasesrdquo Immunology vol 129 no 2pp 154ndash169 2010

[235] S Amor L AN Peferoen D Y S Vogel et al ldquoInflammation inneurodegenerative diseasesmdashan updaterdquo Immunology vol 142no 2 pp 151ndash166 2014

[236] L F Clark and T Kodadek ldquoThe immune system and neu-roinflammation as potential sources of blood-based biomarkersfor Alzheimerrsquos disease Parkinsonrsquos disease and huntingtonrsquosdiseaserdquo ACS Chemical Neuroscience vol 7 no 5 pp 520ndash5272016

[237] M A Mena and J Garcıa De Yebenes ldquoGlial cells as players inparkinsonism the lsquogoodrsquo the lsquobadrsquo and the lsquomysteriousrsquo gliardquoNeuroscientist vol 14 no 6 pp 544ndash560 2008

[238] P L McGeer and E G McGeer ldquoGlial reactions in ParkinsonrsquosdiseaserdquoMovement Disorders vol 23 no 4 pp 474ndash483 2008

[239] N Stella ldquoCannabinoid and cannabinoid-like receptors inmicroglia astrocytes and astrocytomasrdquoGlia vol 58 no 9 pp1017ndash1030 2010

[240] A Klegeris C J Bissonnette and P L McGeer ldquoReduction ofhuman monocytic cell neurotoxicity and cytokine secretion byligands of the cannabinoid-type CB2 receptorrdquo British Journalof Pharmacology vol 139 no 4 pp 775ndash786 2003

[241] G Esposito C Scuderi C Savani et al ldquoCannabidiol in vivoblunts 120573-amyloid induced neuroinflammation by suppressingIL-1120573 and iNOS expressionrdquo British Journal of Pharmacologyvol 151 no 8 pp 1272ndash1279 2007

[242] B Watzl P Scuderi and R R Watson ldquoInfluence of marijuanacomponents (THC and CBD) on human mononuclear cellcytokine secretion in vitrordquo Advances in Experimental Medicineand Biology vol 288 pp 63ndash70 1991

[243] M D Srivastava B I S Srivastava and B Brouhard ldquoΔ9Tetrahydrocannabinol and cannabidiol alter cytokine produc-tion by human immune cellsrdquo Immunopharmacology vol 40no 3 pp 179ndash185 1998

[244] A M Malfait R Gallily P F Sumariwalla et al ldquoThe nonpsy-choactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 97 no 17 pp 9561ndash9566 2000

[245] R Mechoulam L A Parker and R Gallily ldquoCannabidiol anoverview of some pharmacological aspectsrdquo Journal of ClinicalPharmacology vol 42 no 11 pp 11Sndash19S 2002

[246] R Mechoulam M Peters E Murillo-Rodriguez and L OHanus ldquoCannabidiolmdashrecent advancesrdquo Chemistry and Biodi-versity vol 4 no 8 pp 1678ndash1692 2007

[247] B Costa M Colleoni S Conti et al ldquoOral anti-inflammatoryactivity of cannabidiol a non-psychoactive constituent ofcannabis in acute carrageenan-induced inflammation in therat pawrdquo Naunyn-Schmiedebergrsquos Archives of Pharmacology vol369 no 3 pp 294ndash299 2004

[248] B Costa A E Trovato F Comelli G Giagnoni and MColleoni ldquoThe non-psychoactive cannabis constituent can-nabidiol is an orally effective therapeutic agent in rat chronicinflammatory and neuropathic painrdquo European Journal of Phar-macology vol 556 no 1ndash3 pp 75ndash83 2007

[249] F Assaf M Fishbein M Gafni O Keren and Y Sarne ldquoPre-and post-conditioning treatment with an ultra-low dose ofΔ9-tetrahydrocannabinol (THC) protects against pentylenete-trazole (PTZ)-induced cognitive damagerdquo Behavioural BrainResearch vol 220 no 1 pp 194ndash201 2011

[250] P E Szmitko and S Verma ldquoDoes cannabis hold the keyto treating cardiometabolic diseaserdquo Nature Clinical PracticeCardiovascular Medicine vol 3 no 3 pp 116ndash117 2006

[251] M Fishbein-Kaminietsky M Gafni and Y Sarne ldquoUltralowdoses of cannabinoid drugs protect the mouse brain frominflammation-induced cognitive damagerdquo Journal of Neuro-science Research vol 92 no 12 pp 1669ndash1677 2014


[252] O Sagredo M Garcıa-Arencibia E de Lago S Finetti ADecio and J Fernandez-Ruiz ldquoCannabinoids and neuroprotec-tion in basal ganglia disordersrdquoMolecular Neurobiology vol 36no 1 pp 82ndash91 2007

[253] D A Price A A Martinez A Seillier et al ldquoWIN55212-2 acannabinoid receptor agonist protects against nigrostriatal cellloss in the 1-methyl-4-phenyl-1236-tetrahydropyridinemousemodel of Parkinsonrsquos diseaserdquo European Journal of Neurosciencevol 29 no 11 pp 2177ndash2186 2009

[254] J Martınez-Orgado D Fernandez-Lopez I Lizasoain and JRomero ldquoThe seek of neuroprotection introducing cannabi-noidsrdquo Recent Patents on CNS Drug Discovery vol 2 no 2 pp131ndash139 2007

[255] J Romero and J Martınez-Orgado ldquoCannabinoids and neu-rodegenerative diseasesrdquo CNS and Neurological DisordersmdashDrug Targets vol 8 no 6 pp 440ndash450 2009

[256] M F Beal ldquoExcitotoxicity andnitric oxide in Parkinsonrsquos diseasepathogenesisrdquoAnnals of Neurology vol 44 no 3 pp S110ndashS1141998

[257] S Valdeolivas V Satta R G Pertwee J Fernandez-Ruiz andO Sagredo ldquoSativex-like combination of phytocannabinoidsis neuroprotective in malonate-lesioned rats an inflammatorymodel of Huntingtonrsquos disease role of CB1 and CB2 receptorsrdquoACS Chemical Neuroscience vol 3 no 5 pp 400ndash406 2012

[258] M Zeissler C Hanemann J Zajicek and C Carroll ldquoFAAHinhibition is protective in a cell culture model of Parkinsonrsquosdiseaserdquo Journal of Neurology Neurosurgery amp Psychiatry vol83 supplement 2 p A15 2012

[259] M Sophie and B Ford ldquoManagement of pain in Parkinsonrsquosdiseaserdquo CNS Drugs vol 26 no 11 pp 937ndash948 2012

[260] E G Silva M A Viana and E M Quagliato ldquoDiagnosticof parkinsonian syndrome in a Brazilian movement disordersclinicrdquo Revista Neurociencias vol 13 no 4 pp 173ndash177 2005

[261] M Tinazzi C Del Vesco E Fincati et al ldquoPain and motorcomplications in Parkinsonrsquos diseaserdquo Journal of NeurologyNeurosurgery and Psychiatry vol 77 no 7 pp 822ndash825 2006

[262] J I Sage ldquoPain in Parkinsonrsquos diseaserdquo Current TreatmentOptions in Neurology vol 6 no 3 pp 191ndash200 2004

[263] R H Dworkin E M Nagasako B S Galer R D Hetzel and JT Farrar ldquoAssessment of pain and pain-related quality of life inclinical trialsrdquo in Handbook of Pain Assessment D C Turk andR Melzack Eds pp 519ndash548 Guilford New York NY USA2nd edition 2001

[264] R H Dworkin M Backonja M C Rowbotham et al ldquoAdvan-ces in neuropathic pain diagnosis mechanisms and treatmentrecommendationsrdquo Archives of Neurology vol 60 no 11 pp1524ndash1534 2003

[265] R H Dworkin A E Corbin J P Young Jr et al ldquoPregabalin forthe treatment of postherpetic neuralgia a randomized placebo-controlled trialrdquo Neurology vol 60 no 8 pp 1274ndash1283 2003

[266] L Greenbaum I Tegeder Y Barhum E Melamed Y Roditiand R Djaldetti ldquoContribution of genetic variants to painsusceptibility in Parkinson diseaserdquo European Journal of Painvol 16 no 9 pp 1243ndash1250 2012

[267] A Calignano G La Rana A Giuffrida and D Piomelli ldquoCon-trol of pain initiation by endogenous cannabinoidsrdquoNature vol394 no 6690 pp 277ndash281 1998

[268] R J Ellis W Toperoff F Vaida et al ldquoSmoked medicinalcannabis for neuropathic pain in HIV a randomized crossoverclinical trialrdquoNeuropsychopharmacology vol 34 no 3 pp 672ndash680 2009

[269] B Wilsey T Marcotte A Tsodikov et al ldquoA randomizedplacebo-controlled crossover trial of cannabis cigarettes inneuropathic painrdquo Journal of Pain vol 9 no 6 pp 506ndash5212008

[270] D I Abrams C A Jay S B Shade et al ldquoCannabis in painfulHIV-associated sensory neuropathy a randomized placebo-controlled trialrdquo Neurology vol 68 no 7 pp 515ndash521 2007

[271] J S Berman C Symonds and R Birch ldquoEfficacy of twocannabis based medicinal extracts for relief of central neuro-pathic pain from brachial plexus avulsion results of a ran-domised controlled trialrdquo Pain vol 112 no 3 pp 299ndash3062004

[272] K B Svendsen T S Jensen and F W Bach ldquoDoes the cannabi-noid dronabinol reduce central pain in multiple sclerosisRandomised double blind placebo controlled crossover trialrdquoBritish Medical Journal vol 329 no 7460 pp 253ndash257 2004

[273] D J Rog T J Nurmikko T Friede and C A Young ldquoRandom-ized controlled trial of cannabis-basedmedicine in central paininmultiple sclerosisrdquoNeurology vol 65 no 6 pp 812ndash819 2005

[274] T J Nurmikko M G Serpell B Hoggart P J Toomey B JMorlion andDHaines ldquoSativex successfully treats neuropathicpain characterised by allodynia a randomised double-blindplacebo-controlled clinical trialrdquo Pain vol 133 no 1ndash3 pp 210ndash220 2007

[275] K P Hill ldquoMedical marijuana for treatment of chronic pain andother medical and psychiatric problems a clinical reviewrdquo TheJournal of the AmericanMedical Association vol 313 no 24 pp2474ndash2483 2015

[276] M E Lynch and F Campbell ldquoCannabinoids for treatment ofchronic non-cancer pain a systematic review of randomizedtrialsrdquo British Journal of Clinical Pharmacology vol 72 no 5pp 735ndash744 2011

[277] M I Martın Fontelles and C Goicoechea Garcıa ldquoRole ofcannabinoids in the management of neuropathic painrdquo CNSDrugs vol 22 no 8 pp 645ndash653 2008

[278] M Iskedjian B Bereza A Gordon C Piwko and T REinarson ldquoMeta-analysis of cannabis based treatments for neu-ropathic and multiple sclerosis-related painrdquo Current MedicalResearch and Opinion vol 23 no 1 pp 17ndash24 2007

[279] S Corey ldquoRecent developments in the therapeutic potential ofcannabinoidsrdquo Puerto Rico Health Sciences Journal vol 24 no1 pp 19ndash26 2005

[280] P F Smith ldquoCannabinoids in the treatment of pain and spas-ticity in multiple sclerosisrdquo Current Opinion in InvestigationalDrugs vol 3 no 6 pp 859ndash864 2002

[281] F A Campbell M R Tramer D Carroll D J M Reynolds RAMoore andH JMcQuay ldquoAre cannabinoids an effective andsafe treatment option in the management of pain A qualitativesystematic reviewrdquo British Medical Journal vol 323 no 7303pp 13ndash16 2001

[282] W J G Hoogendijk I E C Sommer G Tissingh D J HDeeg and E CWolters ldquoDepression in Parkinsonrsquos disease theimpact of symptom overlap on prevalencerdquo Psychosomatics vol39 no 5 pp 416ndash421 1998

[283] M Yamamoto ldquoDepression in Parkinsonrsquos disease its preva-lence diagnosis and neurochemical backgroundrdquo Journal ofNeurology vol 248 no 3 pp III5ndash11 2001

[284] J S A M Reijnders U Ehrt W E J Weber D Aarsland andA F G Leentjens ldquoA systematic review of prevalence studies ofdepression in Parkinsonrsquos diseaserdquoMovement Disorders vol 23no 2 pp 183ndash189 2008


[285] A Schrag A Hovris D Morley N Quinn and M JahanshahildquoCaregiver-burden in parkinsonrsquos disease is closely associatedwith psychiatric symptoms falls and disabilityrdquo Parkinsonismamp Related Disorders vol 12 no 1 pp 35ndash41 2006

[286] A Schrag ldquoQuality of life and depression in Parkinsonrsquosdiseaserdquo Journal of the Neurological Sciences vol 248 no 1-2pp 151ndash157 2006

[287] H Reichmann C Schneider and M Lohle ldquoNon-motor fea-tures of Parkinsonrsquos disease depression and dementiardquo Parkin-sonism and Related Disorders vol 15 no 3 pp S87ndashS92 2009

[288] B B Gorzalka and M N Hill ldquoPutative role of endocannabi-noid signaling in the etiology of depression and actions ofantidepressantsrdquo Progress in Neuro-Psychopharmacology andBiological Psychiatry vol 35 no 7 pp 1575ndash1585 2011

[289] M Navarro E Hernandez R M Munoz et al ldquoAcute adminis-tration of the CB1 cannabinoid receptor antagonist SR 141716Ainduces anxiety-like responses in the ratrdquo NeuroReport vol 8no 2 pp 491ndash496 1997

[290] F A Moreira and B Lutz ldquoThe endocannabinoid systememotion learning and addictionrdquo Addiction Biology vol 13 no2 pp 196ndash212 2008

[291] F AMoreira and J A S Crippa ldquoThe psychiatric side-effects ofrimonabantrdquo Revista Brasileira de Psiquiatria vol 31 no 2 pp145ndash153 2009

[292] F J Barrero I Ampuero B Morales et al ldquoDepression inParkinsonrsquos disease is related to a genetic polymorphism ofthe cannabinoid receptor gene (CNR1)rdquoThePharmacogenomicsJournal vol 5 no 2 pp 135ndash141 2005

[293] F R Bambico P R Hattan J P Garant and G Gobbi ldquoEffectof delta-9-tetrahydrocannabinol on behavioral despair and onpre- and postsynaptic serotonergic transmissionrdquo Progress inNeuro-Psychopharmacology amp Biological Psychiatry vol 38 no1 pp 88ndash96 2012

[294] G Gobbi F R Bambico RMangieri et al ldquoAntidepressant-likeactivity and modulation of brain monoaminergic transmissionby blockade of anandamide hydrolysisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 102 no 51 pp 18620ndash18625 2005

[295] T F Denson and M Earleywine ldquoDecreased depression inmarijuana usersrdquoAddictive Behaviors vol 31 no 4 pp 738ndash7422006

[296] L Degenhardt W Hall and M Lynskey ldquoExploring the associ-ation between cannabis use and depressionrdquo Addiction vol 98no 11 pp 1493ndash1504 2003

[297] B Porter R MacFarlane and R Walker ldquoThe frequency andnature of sleep disorders in a community-based population ofpatients with Parkinsonrsquos diseaserdquo European Journal of Neurol-ogy vol 15 no 1 pp 46ndash50 2008

[298] A Videnovic and D Golombek ldquoCircadian and sleep disordersin Parkinsonrsquos diseaserdquo Experimental Neurology vol 243 pp45ndash56 2013

[299] L M Trotti and D L Bliwise ldquoTreatment of the sleep disordersassociated with Parkinsonrsquos diseaserdquo Neurotherapeutics vol 11no 1 pp 68ndash77 2014

[300] M Stacy ldquoSleep disorders in Parkinsonrsquos disease epidemiologyand managementrdquoDrugs and Aging vol 19 no 10 pp 733ndash7392002

[301] E B Russo G W Guy and P J Robson ldquoCannabis painand sleep lessons from therapeutic clinical trials of sativex acannabis-based medicinerdquo Chemistry amp Biodiversity vol 4 no8 pp 1729ndash1743 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


treatment of spasticity due to multiple sclerosis in a numberof countries outside the United States Nabiximols is anextract of Cannabis sativa L that consists of mainly THC andCBD [10 11]

Although recent studies have provided strong evidencefor the therapeutic benefit of medical marijuana [12ndash16]increasing access to cannabis andor cannabinoids can resultin side effects such as addiction respiratory illness anddecline in cognitive processing Cannabis use has beenindicated as a potential cause aggravator or masker of majorpsychiatric symptoms including psychotic depressive andanxiety disorders particularly in young people [17ndash19] Othernegative effects include working memory deficits reducedattention and processing speed anhedonia abnormal socialbehavior and susceptibility to mood and anxiety disor-ders [20 21] While adult users seem comparatively resis-tant to cannabis-induced behavioral and brain morphologicchanges the individuals who start using cannabis duringtheir early teens can have more severe and more long-lastingeffects [22]

The target of medical marijuana and its constituentsis the endocannabinoid system which is involved in themodulation of a number of physiological functions Theendocannabinoid system includes the endocannabinoids thecannabinoid receptors and the enzymes involved in thebiosynthesis and inactivation of the endocannabinoids [23]The cannabinoid receptors aremainly expressed in the centralnervous system and the immune system but they have alsobeen identified in a number of other parts of the body includ-ing the cardiovascular system the peripheral nervous systemthe reproductive system and the gastrointestinal tract Dueto its wide distribution and effects on a range of biologicalprocess the cannabinoid system has become an attractivetarget for the development of drugs that can potentially beused for the treatment of a number of pathological conditionsincluding mood disorders and movement disorders such asPD [24] Components of the endocannabinoid system areabundant in the striatum and other parts of the basal gangliaand play a crucial role in modulating dopamine activity andmotor functions [25ndash27]

Parkinsonrsquos disease (PD) is the second most commonneurodegenerative disorder following Alzheimerrsquos diseaseand the 14th leading cause of death in all age groups inthe United States [28] The prevalence of PD increases withage and is shown to be higher in males than females insome age groups [29] The number of people with PD isprojected at approximately 9 million by 2030 in the 15 mostpopulous countries in the world [30 31] NeurologicallyPD is characterized by the destruction of dopaminergiccells in the pars compacta region of the substantia nigrain the midbrain resulting in dopamine deficiency in thenerve terminals of the striatum in the forebrain [32] Thesechanges cause impairments not just to the motor systembut also to the cognitive and neuropsychological systems[33] The nigrostriatal pathway is one of the dopaminepathways in the brain that regulates movement The exactcause for the loss of neuronal cells is unknown and the triggerof dopaminergic degeneration seems to be multifactorialincluding environmental factors and genetic susceptibilities

[34ndash36] Clinically PD is characterized by resting tremormuscle rigidity bradykinesia and postural instability [3234 37 38] and it is also associated with a number ofnonmotor symptoms including depression anxiety consti-pation orthostatic hypotension fatigue and sleep disordersas well as in advanced disease dementia [39ndash44] Althoughdopamine deficiency accounts for themajormotor symptomsof the disease loss of noradrenergic and serotoninergic nerveterminals in the limbic system may account for several of thenonmotor features seen in Parkinsonrsquos disease [45 46]

Current therapy involves treatment of motor symptomsof PD through replacement of dopamine deficiency [47]This includes (1) enhancement of the synthesis of braindopamine by administration of levodopa a dopamine pre-cursor (2) direct stimulation of dopamine receptors (3)decreasing dopamine catabolism and (4) stimulation ofdopamine release and inhibition of dopamine reuptake frompresynaptic sites Another therapy involves restoring thenormal balance of cholinergic and dopaminergic actions onthe basal ganglia using anticholinergic drugs [47ndash49]

However these drugs treat only motor symptoms ofParkinsonrsquos disease and are associated with a number ofadverse effects Long-term use of levodopa the mainstaytherapy for PD is associated with motor fluctuations [50]and levodopa-induced dyskinesia [51ndash53] The monoamineoxidase B (MAO-B) inhibitors (selegiline and rasagiline) aswell as inhibitors of catechol-o-methyltransferase COMT(tolcapone and entacapone) are used mostly to reduce themotor fluctuations associated with levodopa therapy dueto their levodopa-sparing effect [54ndash59] Several dopamineagonists including pramipexole ropinirole rotigotine andapomorphine are used as monotherapy in early stage ofParkinson disease or as adjunctive therapy with levodopain patients with advanced PD in order to reduce motorfluctuations [56 60ndash64] In addition to their limited efficacyon motor symptoms and their adverse effects drugs that arecurrently used for the treatment of PD do not have an effecton disease progressionTherefore there is an urgent need forthe development of safer drugs that treat both the motor andnonmotor symptoms of PD as well as drugs that slow theprogression of the disease

Medical marijuana has been demonstrated to improvemotor symptoms including tremor rigidity and bradykinesiaas well as nonmotor symptoms such as pain and sleepdisorders of PD in observational studies [65] Survey ofPD patients in Colorado USA also indicated the beneficialeffects of marijuana in alleviating nonmotor symptoms ofPD [66] Cannabidiol (CBD) one of the major constituentsof marijuana has been shown to be effective in the treat-ment of psychosis and sleep disorders in PD patients [67ndash69] Another phytocannabinoid Δ9-tetrahydrocannabivarin(Δ9-THCV THCV) was studied in animal disease modelof PD and found to have neuroprotective and symptom-relieving effects [70] Therefore marijuana may provide analternative or add-on therapy for Parkinsonrsquos disease Inaddition Parkinsonrsquos disease has been listed as one of thedisease conditions for which medical marijuana is allowed inConnecticut Illinois Massachusetts New Hampshire New














































3) from



















5 Summary




Competing Interests


References






















































































































































119860receptor





















2 but






























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























































3) from



















5 Summary




Competing Interests


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