addiction: a disease of the brain
DESCRIPTION
Addiction: A Disease of the Brain. Charles P. O’Brien, MD, PhD University of Pennsylvania Philadelphia VA Medical Center. Annual Deaths USA. 450,000. 100,000. 5,000. 2,000. Is Addiction a Disease?. Volitional aspects at start Involuntary behavior in dependent state - PowerPoint PPT PresentationTRANSCRIPT
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
0.5
1
1.5
2
NeutralCocaine-Cues
Dis
tribu
tion
Volu
me
*
0
0.05
0.1
0.15
0.2
Cau
date
Puta
men
Vent
ral S
triat
um
Cer
ebel
lum
K1
0
0.5
1
1.5
2
NeutralCocaine-Cues
Dis
trib
utio
n V
olum
e *
0
0.05
0.1
0.15
0.2
Cau
date
Put
amen
Ven
tral
Str
iatu
m
Cer
ebel
lum
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?