Implications for Policy The Science of Addiction: Implications for Policy Wilson M. Compton, MD, MPE Director, Division of Epidemiology, Services, and

The Science of Addiction:Implications for Policy

Wilson M. Compton, MD, MPEDirector, Division of Epidemiology, Services, and

Prevention ResearchNational Institute on Drug Abuse

USA

AddictionAddiction

DRUG/ALCOHOLDRUG/ALCOHOL

Brain MechanismsBrain Mechanisms

BiologyGenes/Development

BiologyGenes/Development

EnvironmentEnvironment

Addictions are common, developmental brain diseases expressed as compulsive behavior through continued use of a drug despite negative consequences: Onset

depends on many intrinsic and extrinsic factors.

• Addictions are brain diseases• Human development is key• Treatment can be based on neuroscience advances

• Policies need to account for the nature of addictive disorders



Healthy Heart

Diseased Heart

Decreased Heart Metabolism in Heart Disease

ADDICTION IS A DISEASE OF THE BRAINas other diseases it affects the tissue function

Control Cocaine Abuser

Decreased Brain Metabolism in Drug Abuse

Sources: From the laboratories of Drs. N. Volkow and H. Schelbert

High

Low



Addiction Is Development

al

5 10

15

20

25

30

35

40

45

50

55

60

0.000

0.002

0.004

0.006

0.008

0.010

0.012

DSM-IV Abuse

DSM-IV Dependence

Age

Haz

ard

Rat

e

Age of Onset of Drug Abuse and Dependence Source: Compton, et al. Archives of General Psychiatry 2007. NESARC Study.

8

IndividuallyHoused

Morgan, D. et al. Nature Neuroscience, 2002.

**

S.003.01 .03 .1

0

10

20

30

40

50

Rein

forc

ers

(p

er

sessio

n)

Cocaine (mg/kg/injection)

DominantSubordinate

Becomes SubordinateStress remains

GroupHoused

Becomes DominantNo longer stressed

Social Setting Can Change NeurobiologySocial Setting Can Change Neurobiology

Effects of a Social Stressor on Brain Dopamine D2 Receptors and

Propensity to Administer Drugs

Effects of a Social Stressor on Brain Dopamine D2 Receptors and

Propensity to Administer Drugs

0

2

4

6

8

10

0 1 2 3 4 5

Od

ds r

ati

o

ACE Score

Ever Addicted

Adverse Childhood Experiences

(ACE) and Illicit Drug Use (n = 8603)

SR Dube, et al. PEDIATRICS 111: 564-572, 2003

1.0

Children with deprivation (n=17) vs controls (n=15) had decreased connectivity in uncinate fasciculus (connects amygdala with frontal cortex), proportional to time in orphanage. This could facilitate heightened emotional reactivity and impaired cognitive control.

Social Neglect During Early Childhood Decreases Brain Connectivity

Govindan et al., Cereb Cortex 2009

r = -0.604, p=.01

Children with low self-control had poorer health, more wealth problems, more single-parent child rearing, and more criminal convictions and drug use than those with high self-control

A gradient of childhood self-control predicts health, wealth, and public safety (Dunedin Study;

1000+ children)Health Wealth Criminal behavior

Moffitt et al., PNAS 2011

Since self-control can be improved by interventions early childhood intervention that enhances self-control is likely to bring a greater

return on investment than harm reduction programs targeting adolescents alone.

Nurse Home Visiting during pregnancy and the first two years of life

has an impact on substance use, mental health and academic achievement at 12 years of age

Arch Pediatr Adoles Med, 164(5) 412-418, 2010

Percent of Children Who Used Tobacco, Alcohol, or Marijuana (Last 30 Days)

Child Age 12

Percent of Children with Internalizing Problems (Borderline or Clinical)

Child Age 12

0

1

2

3

4

5

6

Nurse Comparison

0

1

2

3

4

5

6

Nurse Comparison

PIAT Scores - Reading & Math – Age 12(Born to Low-Resource Mothers)

80

85

90

Nurse Comparison

Percent of Mothers with Role Impairment due to Alcohol or Drug Use – Child Age 12

0

1

2

3

Nurse Comparison



Addiction Reward & well-being

Motivation

Movement

Dopamine

But Dopamine is only Part of the Story

• Other neurotransmitter systems are also implicated–Serotonin–Regulates mood, sleep, etc.

–Glutamate–Regulates learning and memory, etc.

–And Others

These and other brain neurochemicals and electrical signals are responsible for your ability to think, move, feel, and behave.

Key Question:

OFCOFCSCCSCC

MOTIVATION/DRIVE

MOTIVATION/DRIVE

HippHipp

Amyg

Amyg MEMORY/

LEARNING MEMORY/

LEARNING

Circuits Involved In Drug Abuse and Addiction

Circuits Involved In Drug Abuse and Addiction

NAcc

NAcc VPVP

REWARDREWARD

PFCPFC

ACGACG

EXECUTIVEFUNCTION/ INHIBITORY

CONTROL

EXECUTIVEFUNCTION/ INHIBITORY

CONTROL

NAcc

NAcc VPVP

REWARD

1. Reward Circuit

Drugs of Abuse EngageSystems in the Motivation Pathwaysof the Brain

Di Chiara et al., Neuroscience, 1999.,Fiorino and Phillips, J. Neuroscience, 1997.

Natural Rewards Elevate Dopamine Levels

0

50

100

150

200

0 60 120 180

Time (min)

% o

f B

asal D

A O

utp

ut NAc shell

Empty

Food Sex

Box Feeding

100

150

200

DA

Con

cen

trati

on

(%

Baselin

e)

SampleNumber

1 2 3 4 5 6 7 8

Female Present

All Drugs Abused by Humans Raise Brain Dopamine Levels in the Nucleus Accumbens

Nestler, Nature Neurosci, 2005

`̀

Time After Methamphetamine

Dop

am

ine (

nM

)

METHAMPHETAMINE2000

1500

1000

500

0

55

112.52.5

Dose (mg/kg IV)

0 20 40 60 80min

0

100

150

200

250

0 1 2 3 hrTime After Nicotine

% o

f B

asal R

ele

ase NICOTINE

Di Chiara et al.

TYROSINE

DA

DOPA

DA

DA

DA

DA

TYROSINE

DA

DOPA

DA

DA

DA

DADA DA DA

DADADA

methyl pheni date

RRRRRR

-10 0 10 20 30 40-202468

10

Self-

Rep

ort

s(0

-10

)Change in Dopamine

Bmax/kd (Placebo - MP)

“High”

Increases in Dopamine are Associated with Perceived “High”

racloprideraclopride

DA DA

Volkow et al., JPET 291(1):409-415, 1999.

NAccNAcc VPVP

REWARDREWARD

HippHipp

Amyg

AmygMEMORY/LEARNING

2. Memory circuit

“People, Places and Things…”

Cocaine Film

Cocaine Craving:Population (Cocaine Users, Controls) x Film (cocaine )

Garavan et al A .J. Psych 2000

IFG

Ant Cing

Cingulate

Sig

nal In

ten

sit

y (

AU

)

Controls Cocaine Users

Cocaine Film Erotic Film

Cocaine Craving:Population (Cocaine Users, Controls) x Film (cocaine, erotic)

Garavan et al A .J. Psych 2000

IFG

Ant Cing

Cingulate

Sig

nal In

ten

sit

y (

AU

)

Controls Cocaine Users

Dopamine Release Increases when Viewing Cocaine Cues: [11C]Raclopride

Binding In Cocaine Abusers (n=18) Viewing a Neutral and a Cocaine-Cue Video

Viewing a video of cocaine scenes decreased specific binding of

[11C]raclopride presumably from DA increases

Neutral video

Volkow et al J Neuroscience 2006

3. Motivation & Executive Control Circuits

ACGACG

OFCOFCSCCSCC

INHIBITORY CONTROL

INHIBITORY CONTROL

EXECUTIVEFUNCTIONEXECUTIVEFUNCTION

PFCPFC

MOTIVATION/DRIVE

MOTIVATION/DRIVE

Dopamine is also associated with motivation and executive function via regulation of frontal activity.

ControlsMethamphetamineAbusers

OFC

um

ol/1

00g

r/m

in

4

0

Controls

Alcoholics

con

trol

ad

dic

ted

Bra

in g

lucose m

eta

bolism

30

40

50

60

70

80

90

2.9

3 3.1

3.2

3.3

3.4

3.5

3.6

D2 Receptors (BPND)

1.5 2 2.5 3 3.5 425

30

35

40

45

50

D2R VS(Bmax/Kd)

Meta

bolis

m CG

(micr

omol/

100g

/min)

1.5 2 2.5 3 3.5 422

24

26

28

30

32

34

36

38

D2R VS(Bmax/Kd)

Meta

bolis

m OF

C(m

icrom

ol/10

0g/m

in)

1.5 2 2.5 3 3.5 430

35

40

45

50

D2R VS(Bmax/Kd)

Meta

bolis

m Pr

efro

ntal

(micr

omol/

100g

/min)

3035

40

45

50

55

60

65

1.8

2 2.2

2.4

2.6

2.8

3 3.2

3.4

ControlControl Cocaine Abuser Cocaine Abuser

DA D2 receptors

Relationship Between Brain Glucose Metabolism and Striatal D2 Receptors

Volkow et al., PNAS 2011 108(37): 15037-42

ACGACG

OFCOFCSCCSCC

HippHipp

NAccNAccVPVP

AmygAmyg

REWARDREWARD

INHIBITORY CONTROL

INHIBITORY CONTROL

MEMORY/LEARNING MEMORY/

LEARNING

EXECUTIVEFUNCTIONEXECUTIVEFUNCTION

PFCPFC

Becomes severely disrupted in ADDICTION

MOTIVATION/DRIVE

MOTIVATION/DRIVE

The fine balance in connections that normally exists between brain areas active in reward, motivation, learning and memory, and inhibitory control

DriveOFCDriveOFC

Saliency NAcSaliency NAc

MemoryAmygdalaMemoryAmygdala

Control CG Control CG

Non-Addicted Brain

Non-Addicted Brain

AddictedBrain

AddictedBrain

STOP STOP

GOGODriveDrive

MemoryMemory

Saliency Saliency

ControlControl

DriveDrive

MemoryMemory

Saliency Saliency

Stress Reactivity

Stress Reactivity

Effective Strategies Attend to Multiple Aspects

of Addiction:

• Behavior

• Biology

• Social Context

A Double Blind, Placebo Controlled Trial Of NEPICASTAT

(Dβh Inhibitor) In Cocaine Dependence[Biotie/NIDA]

Nepicastat attenuates cue-induced reinstatement of

cocaine seekingSchroeder et al.,

Neuropsychopharmacology. 2013Devoto et al., Addict Biol. 2013

Nepicastat increases DA in PFC (but not in Nac)

Improving Prefrontal Function

NIDA Criminal Justice Drug

Abuse Treatment Studies (CJ-DATS)

NIDA Criminal Justice Drug

Abuse Treatment Studies (CJ-DATS)

National Drug Abuse

Treatment Clinical Trials

Network (CTN)

National Drug Abuse

Treatment Clinical Trials

Network (CTN)

Research Centers

CTN SitesCTN Sites



Left, dMPFC activation associated with argument strength (AS) by “message sensation value” MSV interaction predicted cotinine levels one month after add presentation. Wang A et al. J. Neurosci.

2013;33:7420-7427

Brain and Behavioral Impact of Televised

Anti-Tobacco Public Service Announcements: Predictive Value

Addressing Drugs and Crime

Public Health Approach - disease - treatment

Public Safety Approach - illegal behavior - punish

High Attrition High Recidivism

Successful Reentry Programs Use an Integrated Public Health-Public

Safety Strategy

Blends functions of criminal justice and treatment systems

to optimize outcomes

Community-based treatment

Opportunity to avoid incarceration or criminal record

Close supervision

Consequences for noncompliance are certain and immediate

Summary: Drug Addiction is a Brain Disease Involving Reward, Memory and

Control Circuits•Addiction comes about by laying down and strengthening new memory connections in various circuits in the brain.

•Long-lasting brain changes are responsible for the distortions of thought and emotionthat characterize addicts, including the compulsion to use drugs that is the essence of addiction. •Policies to prevent and treat addiction can benefit from an understanding of the science of addiction.

www.drugabuse.gov

Documents

Implications for Policy The Science of Addiction: Implications for Policy Wilson M. Compton, MD, MPE Director, Division of Epidemiology, Services, and