Addiction: A Disease of Addiction: A Disease of the Brainthe Brain

Addiction: A Disease of Addiction: A Disease of the Brainthe Brain

Charles P. O’Brien, MD, PhDCharles P. O’Brien, MD, PhD

University of PennsylvaniaUniversity of Pennsylvania

Philadelphia VA Medical CenterPhiladelphia VA Medical Center

0

100,000

200,000

300,000

400,000

500,000

Tobacco Alcohol Cocaine Heroin

Annual Deaths USAAnnual Deaths USA

450,000

100,0002,0002,0005,0005,000

Is Addiction a Disease?Is Addiction a Disease?

• Volitional aspects at startVolitional aspects at start• Involuntary behavior in dependent Involuntary behavior in dependent

statestate• Chronic disease: relapses andChronic disease: relapses and

remissionsremissions• No cures, stable long term remissionNo cures, stable long term remission

with risk of relapsewith risk of relapse

What is Addiction/Dependence?What is Addiction/Dependence?What is Addiction/Dependence?What is Addiction/Dependence?

• Drug use “out of control”Drug use “out of control”• NOT necessarilyNOT necessarily

Daily useDaily use

ToleranceTolerance

Physiol. DependencePhysiol. Dependence

WithdrawalWithdrawal

UseUse Abuse Abuse Addiction AddictionUseUse Abuse Abuse Addiction Addiction

UseUse

UseUse

UseUse

UseUse

AbuseAbuse

AbuseAbuse AddictionAddiction

Which drug has the highest rate of Which drug has the highest rate of

addiction among those who try it?addiction among those who try it?

1.1. HeroinHeroin

2.2. CocaineCocaine

3.3. NicotineNicotine

4.4. AlcoholAlcohol

5.5. MarijuanaMarijuana

Risk of AddictionRisk of AddictionRisk of AddictionRisk of Addiction

Ever usedEver used Dependence Dependence RiskRisk

TobaccoTobacco 75.6% 75.6% 24.1% 24.1% 31.9% 31.9%CocaineCocaine 16.2 16.2 2.7 2.7 16.7 16.7HeroinHeroin 1.5 1.5 0.4 0.4 23.1 23.1AlcoholAlcohol 91.5 91.5 14.1 15.4 14.1 15.4CannabisCannabis 46.3 46.3 4.2 4.2 9.1 9.1

Anthony et al, 1994.Anthony et al, 1994.

DA increased in Nucleus AccumbensDA increased in Nucleus Accumbens

• NicotineNicotine

• AlcoholAlcohol• OpiatesOpiates• CocaineCocaine

0100200300400500600700800900

10001100

0 1 2 3 4 5 hrTime After Amphetamine

% o

f B

asa

l R

ele

as

e

DADOPACHVA

Accumbens AMPHETAMINEAMPHETAMINE

0

100

200

300

400

0 1 2 3 4 5 hrTime After Cocaine

% o

f B

asa

l R

ele

as

e

DADOPACHVA

AccumbensCOCAINECOCAINE

0

100

150

200

250

0 1 2 3 4 5hrTime After Morphine

% o

f B

asa

l R

ele

as

e Accumbens

0.51.02.510

Dose (mg/kg)

MORPHINEMORPHINE

0

100

150

200

250

0 1 2 3 hrTime After Nicotine

% o

f B

asa

l R

ele

as

e

AccumbensCaudate

NICOTINENICOTINE

Effects of Drugs on Dopamine LevelsEffects of Drugs on Dopamine Levels

Source: Di Chiara and Imperato

CA

PUT

NAc

BRAIN DOPAMINE SYSTEMBRAIN DOPAMINE SYSTEM

Striatum

VTA/SNVTA/SN

CG

PreF

OFC nucleusnucleusaccumbensaccumbens

Resultant of interacting variablesResultant of interacting variablesResultant of interacting variablesResultant of interacting variables

Agent (Drug)Agent (Drug)

HostHost

EnvironmentEnvironment

+

-

+

+

-

-

Outcomes:Outcomes:No useUse AbuseAddiction

AgentAgentAgentAgent

• AvailabilityAvailability• DoseDose• Price, PurityPrice, Purity

• Gateway hypothesis vs. RandomGateway hypothesis vs. Random cigarettes/marijuana most availablecigarettes/marijuana most available

• Crack as gateway drug in certain areasCrack as gateway drug in certain areas

HostHostHostHost

• Individual vulnerabilityIndividual vulnerability

HeredityHeredity• Rapidity of toleranceRapidity of tolerance• Metabolism (nicotine, alcohol) Metabolism (nicotine, alcohol) • Amount of rewardAmount of reward• Psychiatric Disorders,Psychiatric Disorders,

“ “self medication”self medication”

Inherited FactorsInherited FactorsInitial Drug ExposureInitial Drug Exposure

Inherited FactorsInherited FactorsInitial Drug ExposureInitial Drug Exposure

• Dose - Plasma levelDose - Plasma level• AbsorptionAbsorption• DispositionDisposition• Flushing ResponseFlushing Response• Perception of Pleasant EffectPerception of Pleasant Effect• Rapidity of Tolerance DevelopmentRapidity of Tolerance Development

EnvironmentEnvironmentEnvironmentEnvironment

• Role modelsRole models• Other reinforcersOther reinforcers• StressStress• BoredomBoredom• Peer pressurePeer pressure

ToleranceTolerance

InnateInnate

AcquiredAcquired

PharmacokineticPharmacokinetic

PharmacodynamicPharmacodynamic

Behavioral ToleranceBehavioral Tolerance

Conditioned ToleranceConditioned Tolerance

Cross ToleranceCross Tolerance

Useful in choosing detoxUseful in choosing detox

MedicationsMedications

heroin-methadoneheroin-methadone

alcohol-oxazepamalcohol-oxazepam

DependenceDependence

Withdrawal SyndromeWithdrawal Syndrome

(normal reactions, not necessarily(normal reactions, not necessarily

a sign of addiction)a sign of addiction)

Tolerance/WithdrawalTolerance/Withdrawal

• Neither necessary nor sufficientNeither necessary nor sufficient

• Patients with tolerance/withdrawalPatients with tolerance/withdrawal---no addiction---no addiction

• Patients with addiction--- noPatients with addiction--- no tolerance/withdrawaltolerance/withdrawal

SensitizationSensitization

Reverse of toleranceReverse of tolerance

Stimulants - increased effect withStimulants - increased effect with

repeatedrepeated, , spacedspaced dosing dosing

CompulsionCompulsionCompulsionCompulsion

• An irresistible impulse to act, An irresistible impulse to act,

regardless of the rationality of the regardless of the rationality of the

motivationmotivation

• A strong irrational impulse to carry out A strong irrational impulse to carry out

a given acta given act

ASI Problem Severity Profile of a ASI Problem Severity Profile of a Cocaine Dependent PhysicianCocaine Dependent Physician

ASI Problem Severity Profile of a ASI Problem Severity Profile of a Cocaine Dependent PhysicianCocaine Dependent Physician

Problem AreaProblem Area

0

10

20

30

40

50

60

70

80

Drug Med Emp Legal Fam Psych

Severity

ASI Problem Severity Profile of a ASI Problem Severity Profile of a Cocaine Dependent Teen MotherCocaine Dependent Teen MotherASI Problem Severity Profile of a ASI Problem Severity Profile of a Cocaine Dependent Teen MotherCocaine Dependent Teen Mother

Problem AreaProblem Area

0

10

20

30

40

50

60

70

80

Drug Med Emp Legal Fam Psych

Severity

““Pure” addicts are rarePure” addicts are rare““Pure” addicts are rarePure” addicts are rare

• most have additional problemsmost have additional problems

• treatment depends on additional treatment depends on additional

problemsproblems

• high treatment success rate for “pure” high treatment success rate for “pure”

addictsaddicts

Plasma Nicotine LevelsPlasma Nicotine LevelsPlasma Nicotine LevelsPlasma Nicotine Levels

0

10

20

30

40

50

0 1 2 3 4 5 6

ArterialVenous

Time after smoking Cigarette (minutes)Time after smoking Cigarette (minutes)

Mea

n P

lasm

a M

ean

Pla

sma

Nic

oti

ne

Nic

oti

ne

Lev

els

(mg

/ml)

Lev

els

(mg

/ml)

Factors Leading to RelapseFactors Leading to RelapseFactors Leading to RelapseFactors Leading to Relapse

• Psychiatric problemsPsychiatric problems- Depression- Depression- Anxiety- Anxiety

• Social ProblemsSocial Problems- Unemployment- Unemployment- Family problems- Family problems- Peer influence- Peer influence

• Protracted AbstinenceProtracted Abstinence• Conditioned ResponsesConditioned Responses

1500

2000

2500

650

670

690

3

3.5

4

10

15

20

0

10

20

30

0

10

20

30

0

100

200

300

36

36.5

37

37.5

60

65

70

75

60

80

100

120

0 5 10 15 20 25 30

Weeks 0 5 10 15 20 25 30

Weeks

Systolic and

Diastolic Blood Pressure

Pulse Rate

Body Temperature

Daily Dose Level

Caloric Intake

Body Weight

Pupillary Diameter

Respiratory Rate

Abstinence Scores

BEATS / MIN.

mmHg

oC

mg / DAY

Calories

k gmm

BREATHS / MIN.

POINTS

Conditioned ResponsesConditioned ResponsesConditioned ResponsesConditioned Responses

• Thousands of pairings of environmental Thousands of pairings of environmental cues with drug effectscues with drug effects

• Cellular level: changes in gene transcriptionCellular level: changes in gene transcription

• Persist long after last use of drugPersist long after last use of drug

Cue induced cravingCue induced cravingCue induced cravingCue induced craving

• 25 years after last dose of 25 years after last dose of

nicotinenicotine• Not just recall of feelingNot just recall of feeling• Compulsion, difficult to resistCompulsion, difficult to resist

Amygdala Nature Video Cocaine Video

Anterior Cingulate1.5

0

.5

1.0

2.0

2.5

Cocaine Pt. 30023Pt. 30023

Childress ‘97

Pt. Op_1.1

Nature Video Opiate Video

Anterior Cingulate1.5

0

.5

1.0

2.0

2.5

Orbitofrontal

Opiate Patient 01

Pt. SX_4

Amygdala Nature Video Sexual Video

Anterior Cingulate

t

00.511.52NeutralCocaine-CuesDistribution Volume*00.050.10.150.2Caudate Putamen Ventral Striatum CerebellumK1

0

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1

1.5

2

NeutralCocaine-Cues

Dis

tribu

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Volu

me

*

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0.1

0.15

0.2

Cau

date

Puta

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Cer

ebel

lum

K1

0

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1

1.5

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NeutralCocaine-Cues

Dis

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0

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0.1

0.15

0.2

Cau

date

Put

amen

Ven

tral

Str

iatu

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K1

Conditioned drug effectsConditioned drug effectsConditioned drug effectsConditioned drug effectsCravingCraving

Autonomic (HR, Skin Temp, GSR)Autonomic (HR, Skin Temp, GSR)

Regional CBFRegional CBF

Regional Brain MetabolismRegional Brain Metabolism

Neurotransmitter release (DA)Neurotransmitter release (DA)

Immediate early genes (c Fos)Immediate early genes (c Fos)

DiscussionDiscussionDiscussionDiscussion

• If addiction is a brain disease, where is the If addiction is a brain disease, where is the lesion?lesion?

• How can you compare drug taking which is How can you compare drug taking which is voluntary behavior to diabetes which is voluntary behavior to diabetes which is completely involuntary?completely involuntary?