Drugs of Abuse

Americans’ Views of the Seriousnessof Health Problems

(Top 10 of 36 Problems)

Americans’ Views of the Seriousnessof Health Problems

(Top 10 of 36 Problems)

65%

65%

68%

69%

71%

73%

74%

75%

78%

82%

StressStress

Alcohol abuseAlcohol abuse

SmokingSmoking

Child abuseChild abuse

ViolenceViolence

HIV/AIDSHIV/AIDS

Heart diseaseHeart disease

Drunk drivingDrunk driving

CancerCancer

Drug abuseDrug abuse

% s

ayin

g “v

ery

seri

ous

pro

ble

m”

% s

ayin

g “v

ery

seri

ous

pro

ble

m”

Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000

Drug abuseDrug abuse

SmokingSmoking

HIV/AIDSHIV/AIDS

Child abuseChild abuse

ViolenceViolence

StressStress

CancerCancer

Drunk drivingDrunk driving

Heart diseaseHeart disease

Alcohol abuseAlcohol abuse

Two Decades of NeurobiologicalResearch Have

Brought Us A New Understanding of Drug Abuse and Addiction, Their

Complexity and their Solutions

Two Decades of NeurobiologicalResearch Have

Brought Us A New Understanding of Drug Abuse and Addiction, Their

Complexity and their Solutions

We Know That DespiteTheir Many Differences, VirtuallyAll Abused Substances Enhance

Dopamine (neurotransmitter) Activity(particularly related to pleasure,

motor, and cognitive function

We Know That DespiteTheir Many Differences, VirtuallyAll Abused Substances Enhance

Dopamine (neurotransmitter) Activity(particularly related to pleasure,

motor, and cognitive function

For Example…For Example…

• Other pathways also involved!• Other pathways also involved!

Dopamine Pathways

Functions•reward (motivation)•pleasure,euphoria•motor function (fine tuning)•compulsion•perserveration•decision making

Serotonin Pathways

Functions•mood•memory processing•sleep•cognition

nucleusaccumbens

hippocampus

striatum

frontalcortex

substantianigra/VTA

raphe

Neuronal structure

(receiving)

(sending)

/serotonin/serotonin

Vmat

transporterstimulationstimulation

DA/5HT DA/5HT

How some drugs of abuse cause dopamine release:• opioids narcotics (activate opioid receptors)• nicotine (activate nicotine receptors)• marijuana (activate cannabinoid receptors)• caffeine• alcohol (activate GABA receptors; an inhibitory transmitter)

How some drugs of abuse cause dopamine release:• opioids narcotics (activate opioid receptors)• nicotine (activate nicotine receptors)• marijuana (activate cannabinoid receptors)• caffeine• alcohol (activate GABA receptors; an inhibitory transmitter)

Drug :• cocaine• ritalin

vesicle Neuronal terminal

• Release DA from vesicles and reverse transporter

Drug Types:• Amphetamines -methamphetamine -MDMA (Ecstasy)

Vmat

transporter

serotonin/serotonin/

DA/5HT DA/5HT

00100100200200300300400400500500600600700700800800900900

1000100011001100

00 11 22 33 44 5 hr5 hr

Time After AmphetamineTime After Amphetamine

% o

f B

as

al

Re

lea

se

% o

f B

as

al

Re

lea

se

DADADOPACDOPACHVAHVA

AccumbensAccumbens AMPHETAMINEAMPHETAMINE

00

100100

200200

300300

400400

00 11 22 33 44 5 hr5 hrTime After CocaineTime After Cocaine

% o

f B

as

al

Re

lea

se

% o

f B

as

al

Re

lea

se

DADADOPACDOPACHVAHVA

AccumbensAccumbensCOCAINECOCAINE

00

100100

150150

200200

250250

00 11 22 3 hr3 hr

Time After NicotineTime After Nicotine

% o

f B

as

al

Re

lea

se

% o

f B

as

al

Re

lea

se

AccumbensAccumbensCaudateCaudate

NICOTINENICOTINE

Source: Di Chiara and ImperatoSource: Di Chiara and Imperato

Effects of Drugs on Dopamine ReleaseEffects of Drugs on Dopamine ReleaseEffects of Drugs on Dopamine ReleaseEffects of Drugs on Dopamine Release

100100

150150

200200

250250

00 11 22 33 4hr4hrTime After EthanolTime After Ethanol

% o

f B

as

al

Re

lea

se

% o

f B

as

al

Re

lea

se

0.250.250.50.5112.52.5

AccumbensAccumbens

00

Dose (g/kg ip)Dose (g/kg ip)

ETHANOLETHANOLETHANOLETHANOL

Much greaterActivity than anyOther drug of abuse -causes neurotoxicity

00

5050

100100

150150

200200

00 6060 120120 180180

Time (min)Time (min)

% o

f B

asal

DA

Ou

tpu

t%

of

Bas

al D

A O

utp

ut

NAc shellNAc shell

EmptyEmpty

BoxBox FeedingFeeding

Source: Di Chiara et al.Source: Di Chiara et al.

FOODFOOD

100100

150150

200200

DA

Co

nce

ntr

ati

on

(%

Bas

elin

e)D

A C

on

cen

tra

tio

n (

% B

asel

ine)

MountsMountsIntromissionsIntromissionsEjaculationsEjaculations

1515

00

55

1010

Co

pu

latio

n F

req

ue

nc

yC

op

ula

tion

Fre

qu

en

cy

SampleNumberSampleNumber

11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717

ScrScrScrScrBasBas Female 1 PresentFemale 1 Present

ScrScrFemale 2 PresentFemale 2 Present

ScrScr

Source: Fiorino and PhillipsSource: Fiorino and Phillips

SEXSEX

Natural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine Levels

Implication:Implication:

Elucidation of the mechanism of drug addiction will help to

understand other addictive andmotivational behaviors/disorders

Elucidation of the mechanism of drug addiction will help to

understand other addictive andmotivational behaviors/disorders

Addiction and tolerance can be synonymous

Pharmacodynamic mechanism of Tolerance

Induction of Tolerance to Morphine

OFCOFCSCC

NAccNAccVPVP

REWARDREWARD

PFCPFC

ACGACG

INHIBITORY CONTROL

INHIBITORY CONTROL

MOTIVATION/DRIVE

(saliency)

MOTIVATION/DRIVE

(saliency)

Brain Circuits Involved in Drug Addiction

Brain Circuits Involved in Drug Addiction

HippHipp

AmygAmyg MEMORY/LEARNING MEMORY/

LEARNING

Reward Pathways:Role of Opioids

HOW DOES ADDICTION OCCUR? HOW DOES ADDICTION OCCUR?

• Principles of Behavior Dynamics

Behavior Tracts Compete for ExpressionBehavior Tracts Compete for Expression

Expression is Determined by (i) Dominance of Tracts, (ii) Strength of Prefrontal Cortex to Select, (iii) Relevance or saliency (orbitofrontal cortex)

Expression is Determined by (i) Dominance of Tracts, (ii) Strength of Prefrontal Cortex to Select, (iii) Relevance or saliency (orbitofrontal cortex)

AA

BC

PrefrontalCortex CCbehavior

expressedbehaviorexpressed BBbehaviorexpressed

Activation of Dopamine reward pathway initiates a behavior track

Activation of Dopamine reward pathway initiates a behavior track

dopamine initiated

(Miller & Cohen, Annu. Rev. Neurosci. 24 [2001] 167)

Orbito-frontal cortex

• Principles of Behavior Dynamics

AAC

B

PrefrontalCortex

How does a behavior become an addiction?

BBB BAddictionbehaviorexpressed

dopamine

Orbito-frontal cortex

Prolonged Drug Use Prolonged Drug Use ChangesChangesthe Brain and the Brain and

In FundamentalIn Fundamentaland Long-Lasting Waysand Long-Lasting Ways

Prolonged Drug Use Prolonged Drug Use ChangesChangesthe Brain and the Brain and

In FundamentalIn Fundamentaland Long-Lasting Waysand Long-Lasting Ways

We Have Generated A Lot of Evidence Showing That… We Have Generated A Lot of Evidence Showing That…

We Have Evidence That These Changes Can Be Both

Structural and Functional

We Have Evidence That These Changes Can Be Both

Structural and Functional

AND…AND…

Positron Emission TomographyPositron Emission Tomography

BRAIN IMAGINGBRAIN IMAGING

Magnetic Resonance ImagingMagnetic Resonance Imaging

control cocaine abuser

Decreases in Metabolism in Orbito Frontal Cortex (OFC)

Decreases in Metabolism in Orbito Frontal Cortex (OFC)

Volkow et al. Am. J. Psychiatry 148, 621Volkow et al. Am. J. Psychiatry 148, 621

Source: McCann U.D. et al., The Journal of Neuroscience, 18(20), pp. 8417-8422, October 15, 1998.Source: McCann U.D. et al., The Journal of Neuroscience, 18(20), pp. 8417-8422, October 15, 1998.

METH Suppresses Expression of DAT

(note: duration of use/3-20 yrs; abstinent/ 1-4 yrs)

Comparison Subject METH AbuserComparison Subject METH Abuser

Dopamine Transporter Loss AfterHeavy Methamphetamine Use

(PET analysis)

Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001. Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001.

Dependence of Verbal Memory on Striatal Dependence of Verbal Memory on Striatal DATDAT

Dependence of Verbal Memory on Striatal Dependence of Verbal Memory on Striatal DATDAT

R = 0.70R = 0.70p < 0.005p < 0.005R = 0.70R = 0.70p < 0.005p < 0.005

R = 0.64R = 0.64p < 0.01p < 0.01R = 0.64R = 0.64p < 0.01p < 0.01

Interference recallInterference recallInterference recallInterference recall Delayed recallDelayed recallDelayed recallDelayed recall

Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001. Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001.

Compromises Cognitive FunctionsCompromises Cognitive Functions

MOTOR FUNCTIONMOTOR FUNCTION

• Slowed gait• Slowed gait

•Impaired balance•Impaired balance

• Impairment correlates with damage to dopamine system• Impairment correlates with damage to dopamine system

Implication:Implication:

Brain changes resulting from prolonged use of psychostimulants,

such as methamphetamine may be reflected in compromised cognitive and motor functioning

Brain changes resulting from prolonged use of psychostimulants,

such as methamphetamine may be reflected in compromised cognitive and motor functioning

Is There Recovery?Is There Recovery?

• Good News: After 2 years some of the dopamine deficits are recovering

• Good News: After 2 years some of the dopamine deficits are recovering

• Bad News: Functional deficits persist• Bad News: Functional deficits persist

• What does this mean???• What does this mean???

Reward System in AddictionReward System in Addiction

CocaineCocaine

FoodFood

Ac t

i vit

y o

f R

e war

d S

yst e

m

METHMETH

AlcoholAlcohol

Ability to Experience Rewards Is DamagedAbility to Experience Rewards Is Damaged

con

trol

s

trea

ted

More

Less

Get Rewired by Drug UseGet Rewired by Drug Use

Their Brains…Their Brains…

INHERITED FACTORS(genetic vulnerability-not inevitability)

INHERITED FACTORS(genetic vulnerability-not inevitability)

• Common strategy to investigate are Twin Studies• Common strategy to investigate are Twin Studies

In General: Inheritability for Drug Abuse Ranges From 40-60%In General: Inheritability for Drug Abuse Ranges From 40-60%

• Some Variability Between Drugs• Some Variability Between Drugs

• Some Gender Variability• Some Gender Variability

17172222

r-SA

r-candidate

r-SA

r-candidate

55 66 3 samples, > 2 labs4 samples, > 3 labs

>2 samples, >2 labs

3 samples, > 2 labs4 samples, > 3 labs

>2 samples, >2 labs

Chromosomal Locations for Substance Abuse Vulnerability Loci Chromosomal Locations for Substance Abuse Vulnerability Loci

Uhl et al Tr Genetics, updated June 03Uhl et al Tr Genetics, updated June 03

Complex geneticsComplex genetics

Complex phenotypes (expressions)Complex phenotypes (expressions)

(Relation to Risk Factors?)(Relation to Risk Factors?)

VULNERABILITY to What?VULNERABILITY to What?Starting Drug Use?

Liking Drugs More?

Continuing Drug Use?

Becoming Addicted?

Specific to A Particular Drug?

Starting Drug Use?

Liking Drugs More?

Continuing Drug Use?

Becoming Addicted?

Specific to A Particular Drug?

For Example-Contribution of Genetic Factors to:

Nicotine-Nicotine-

•Liability to initiate=56%•Liability to initiate=56%• Transition to dependence=70%• Transition to dependence=70%

• Smoking persistence= >50%• Smoking persistence= >50%

(Lerman & Berrettine, Amer. J. Med. Gen. 54 (2003) 48)(Lerman & Berrettine, Amer. J. Med. Gen. 54 (2003) 48)

Genetics May Influence HowNeurobiology Interacts With Environment

Genetics May Influence HowNeurobiology Interacts With Environment

GeneticsGeneticsGeneticsGenetics

EnvironmentEnvironmentEnvironmentEnvironment

Gene/Gene/EnvironmentEnvironmentInteractionInteraction

Gene/Gene/EnvironmentEnvironmentInteractionInteraction

PET Images:PET Images:Dopamine Receptor DensityDopamine Receptor Density

PET Images:PET Images:Dopamine Receptor DensityDopamine Receptor Density

MoreMore likelylikelyto self-to self-administeradministerCocaineCocaine

MoreMore likelylikelyto self-to self-administeradministerCocaineCocaine

Addictive Disorders Often Co-Exist with Addictive Disorders Often Co-Exist with or Predispose to Mental Disordersor Predispose to Mental Disorders

DSM IV Manual: Devotes ~ 100 pages to describing addiction and dependence disorders

DSM IV Manual: Devotes ~ 100 pages to describing addiction and dependence disorders

Discusses substance abuse as a confound to diagnosis and Tx Discusses substance abuse as a confound to diagnosis and Tx

National ComorbidityNational ComorbiditySurvey (NCS)Survey (NCS)

Nearly half of individuals with a past yearNearly half of individuals with a past yearsubstance use disorder also had a mentalsubstance use disorder also had a mentaldisorderdisorder

Mental disorders found to be most prevalentMental disorders found to be most prevalentincluded affective disorders, anxiety disorders,included affective disorders, anxiety disorders,personality disorders, and psychotic disorderspersonality disorders, and psychotic disorders

Nearly half of individuals with a past yearNearly half of individuals with a past yearsubstance use disorder also had a mentalsubstance use disorder also had a mentaldisorderdisorder

Mental disorders found to be most prevalentMental disorders found to be most prevalentincluded affective disorders, anxiety disorders,included affective disorders, anxiety disorders,personality disorders, and psychotic disorderspersonality disorders, and psychotic disorders

(Note: can we have parity for mental health with- out considering drug abuse?)(Note: can we have parity for mental health with- out considering drug abuse?)

Common Underlying NeurobiologicalFactors Can Be:

Common Underlying NeurobiologicalFactors Can Be:

Structural/anatomical (same regions and pathways)Structural/anatomical (same regions and pathways)

Neurochemical (imbalance of neurotransmitters)Neurochemical (imbalance of neurotransmitters)

Genetic (inherited factors that compromise function) Genetic (inherited factors that compromise function)

Because of this overlap, drugs of abusecan cause symptoms that mimic

most forms of mental illness

Because of this overlap, drugs of abusecan cause symptoms that mimic

most forms of mental illness

Drug DisorderCocaine and MethamphetamineCocaine and Methamphetamine Schizophrenia, paranoia,

anhedonia, compulsivebehavior

Schizophrenia, paranoia,anhedonia, compulsivebehavior

StimulantsStimulants Anxiety, panic attacks, mania and sleep disordersAnxiety, panic attacks, mania and sleep disorders

LSD, Ecstasy & psychedelicsLSD, Ecstasy & psychedelics Delusions and hallucinationsDelusions and hallucinations

Alcohol, sedatives, sleepaids & narcoticsAlcohol, sedatives, sleepaids & narcotics

Depression and mood disturbancesDepression and mood disturbances

PCP & KetaminePCP & Ketamine Antisocial behaviorAntisocial behavior

Some drugs of abuse have a mechanism of action similar to

that of drugs used as psychotherapeutic agents

Some drugs of abuse have a mechanism of action similar to

that of drugs used as psychotherapeutic agents

Significance: rationale for

self-administrationSignificance: rationale for

self-administration

Serotonin/dopamine synaptic terminal

Synaptic vesicle

Postsynaptictarget

Activate transmitter receptors

Causes an effectCauses an effect

transporterProzac,Ritalin, &Cocaineblock

Mechanism of actionof amphetamine andcocaine

Chronic use of some of these drugs ofabuse may alter the way the brain

functions, making persons particularlysusceptible to mental illness

Chronic use of some of these drugs ofabuse may alter the way the brain

functions, making persons particularlysusceptible to mental illness

Double

People With Comorbid Mental and Addictive DisordersHave a Brain Disease

People With Comorbid Mental and Addictive DisordersHave a Brain DiseaseDoubleDouble

MentalDisorder

MentalDisorder

AddictiveDisorder

AddictiveDisorder

ComorbidDisordersComorbidDisorders

Role of Stress and TraumaRole of Stress and Trauma

The Stress Hormone CycleThe Stress Hormone Cycle

HypothalamusHypothalamus

PituitaryGland

PituitaryGland

AdrenalGlands

AdrenalGlands

KidneysKidneys

CRFCRF

ACTHACTHCORTISOLCORTISOL

Stress ResponsesStress ResponsesStress ResponsesStress ResponsesStress ResponsesStress ResponsesStress ResponsesStress Responses

CRF:Corticotropin ReleasingFactor

CRF:Corticotropin ReleasingFactor

DRUG USEDRUG USE(Self-Medication)(Self-Medication)DRUG USEDRUG USE

(Self-Medication)(Self-Medication)

STRESSSTRESSSTRESSSTRESS

CRFCRFCRFCRF

AnxietyAnxietyAnxietyAnxiety

CRFCRFCRFCRF

AnxietyAnxietyAnxietyAnxiety

What Role Does Stress Play In Initiating Drug Use?

What Role Does Stress Play In Initiating Drug Use?

ProlongedProlongedDRUGDRUGUSEUSE

ProlongedProlongedDRUGDRUGUSEUSE

AbstinenceAbstinenceAbstinenceAbstinence

RELAPSERELAPSERELAPSERELAPSE

CRFCRFCRFCRF

AnxietyAnxietyAnxietyAnxiety

What Happens When A Person Stops Taking A Drug?

What Happens When A Person Stops Taking A Drug?

Stress Reliably Reinstates Drug Seeking in RatsStress Reliably Reinstates Drug Seeking in Rats

SalineSaline NicotineNicotine

Nicotine-trained ratsNicotine-trained rats

FootshockFootshock

SalineSaline CocaineCocaine FootshockFootshock WaterWater AlcoholAlcohol FootshockFootshock

Cocaine-trained ratsCocaine-trained rats Alcohol-trained ratsAlcohol-trained rats

00

2020

40406060

8080100100

Res

pon

ses

Res

pon

ses Inactive LeverInactive Lever

Active LeverActive Lever

SalineSaline HeroinHeroin FootshockFootshock

Heroin-trained ratsHeroin-trained rats

**

*

*

* **

*

00

2020

40406060

8080100100

Res

pon

ses

Res

pon

ses

From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996

CRF1 Receptor Antagonist AttenuatesStress-Induced Reinstatement

of Drug Seeking

CRF1 Receptor Antagonist AttenuatesStress-Induced Reinstatement

of Drug SeekingAlcohol-trained ratsAlcohol-trained rats

From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000

CP-154,526 Dose (mg/kg, SC)CP-154,526 Dose (mg/kg, SC)

Intermittent Footshock Intermittent Footshock No stressNo stress

Heroin-trained ratsHeroin-trained rats Cocaine-trained ratsCocaine-trained rats

00 1515

*

3030

*

00

1515

3030

4545

6060

Res

pon

ses

(3 h

r)R

esp

onse

s (3

hr)

*

*

00 1515 3030

*

00

1515

3030

4545

6060

Res

pon

ses

(1 h

r)R

esp

onse

s (1

hr)

00 1515 3030

Objectives of Intervention:

• Rearrange dominance of behavior tracks• Rearrange dominance of behavior tracks contingency management (vouchers) contingency management (vouchers)

motivational enhancement motivational enhancement

therapeutic communities therapeutic communities

• Principles of Behavior Dynamics

AA

BC

PrefrontalCortex CCbehavior

expressedbehaviorexpressed BBbehaviorexpressed

dopamine initiated

Orbito-frontal cortex

• Strengthen prefrontal cortex influence (change thinking process)• Strengthen prefrontal cortex influence (change thinking process)

cognitive and cognitive behavioral tx (unlearn old habits-suppress; learn new skills)

cognitive and cognitive behavioral tx (unlearn old habits-suppress; learn new skills) assertiveness training (suppress and express)

assertiveness training (suppress and express)

• Principles of Behavior Dynamics

AA

BC

PrefrontalCortex CCbehavior

expressedbehaviorexpressed BBbehaviorexpressed

dopamine initiated

Orbito-frontal cortex

•Alter function of orbitofrontal (saliency) cortex•Alter function of orbitofrontal (saliency) cortex

motivational therapy motivational therapy

family therapies family therapies

• Principles of Behavior Dynamics

AA

BC

PrefrontalCortex CCbehavior

expressedbehaviorexpressed BBbehaviorexpressed

dopamine initiated

Orbito-frontal cortex

• Recovery of function (frontal and obito- frontal cortex)• Recovery of function (frontal and obito- frontal cortex)

all treatments that keep brain away from drugs for extended time

all treatments that keep brain away from drugs for extended time

• Principles of Behavior Dynamics

AA

BC

PrefrontalCortex CCbehavior

expressedbehaviorexpressed BBbehaviorexpressed

dopamine initiated

Orbito-frontal cortex

• Alleviate underlying psychiatric disorder• Alleviate underlying psychiatric disorder

administer: Antidepressants for depression

Ritalin for ADHD

Sedatives for anxiety

administer: Antidepressants for depression

Ritalin for ADHD

Sedatives for anxiety

Targets of MedicationTargets of Medication

• Methadone, LAAM and Buprenorphine• Methadone, LAAM and Buprenorphine

Activate opioid receptorsActivate opioid receptors

• Nicotine gum/patch• Nicotine gum/patch

Activate nicotinic receptorsActivate nicotinic receptors

• Naloxone• NaloxoneBlock opioid receptorsBlock opioid receptors

Vmat

transporterstimulationstimulation

DA DA

How some drugs of abuse cause dopamine release:• opioids narcotics (activate opioid receptors)• nicotine (activate nicotine receptors)

How some drugs of abuse cause dopamine release:• opioids narcotics (activate opioid receptors)• nicotine (activate nicotine receptors)

vesicle Neuronal terminal

• Psychostimulants• PsychostimulantsEnhancing GABA-ergic inhibition (baclofen-muscle relaxant; anti-seizure- Tiagabine)

Enhancing GABA-ergic inhibition (baclofen-muscle relaxant; anti-seizure- Tiagabine)

Cannabinoid antagonist (rimonabant)Cannabinoid antagonist (rimonabant)

• Principles of Behavior Dynamics

AA

BC

PrefrontalCortex CCbehavior

expressedbehaviorexpressed BBbehaviorexpressed

dopamine initiated

Orbito-frontal cortex

GABA and cannabinoidsystems critical forfunction

GABA and cannabinoidsystems critical forfunction

• Relieve stress-related drug abuse• Relieve stress-related drug abuse

CRF antagonistCRF antagonist

ProlongedProlongedDRUGDRUGUSEUSE

ProlongedProlongedDRUGDRUGUSEUSE

AbstinenceAbstinenceAbstinenceAbstinence

RELAPSERELAPSERELAPSERELAPSE

CRFCRFCRFCRF

AnxietyAnxietyAnxietyAnxiety

No cure