Neurobiology of Addiction

Cindy Miner, Ph.D.Deputy Director

Office of Science Policy and CommunicationsNational Institute on Drug Abuse

National Institutes of Health

Department of Health and Human Services

Chief Resident Immersion Training Program

Cape Cod, MA

May, 2009

In 2007, an estimated 19.9 million

Americans, or 8 percent of the

population aged 12 or older, were

current illicit drug users.

Sources: 2007 National Survey on Drug Use and Health (NSDUH), SAMHSA

Past Month Use of Selected Illicit Drugs

among Persons Aged 12 or Older: 2007

2007 National Survey on Drug Use and Health, SAMHSA

Past Month Illicit Drug Use, by Age: 2007P

erce

nt

Usi

ng

in

Pa

st M

on

th

Age in Years

12-13 14-15 16-17 18-20 21-25 26-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65+

Source: 2007 National Survey on Drug Use & Health (SAMHSA)

Percent of Students Reporting Any

Illicit Drug Use in Past Year, by

Grade

0

10

20

30

40

50

60

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05

8th Grade 10th Grade 12th Grade

* Denotes significant difference

between recent peak year and

current year.

*

*

*

Prevalence of Drugs Among High School Seniors2005 Monitoring the Future Study

* Percentage reporting use in past year. **Nonmedical use.

Drug Prev.* Drug Prev.*Marijuana/Hashish 33.6 MDMA (Ecstasy) 3.0Vicodin** 9.5 Methamphetamine 2.5Amphetamines 8.6 "Ice" 2.3Sedatives** 7.2 Crack 1.9Tranquilizers** 6.8 LSD 1.8OxyContin** 5.5 Ketamine 1.6Cocaine (any form) 5.1 Steroid** 1.5Inhalants 5.0 PCP 1.3Cocaine Powder 4.5 Rohypnol 1.2Ritalin** 4.4 GHB 1.1

Source: Gfroerer, JC et al., SMA 02-3711, OA, SAMHSA – Data from National Survey of Drug Use and Health.

Child<12

Teen12-17

Young Adult18-25

Adult>25

Per

cen

t of

Init

iate

s

80

70

60

50

40

30

20

10

0

Age at Which Marijuana UseIs First Initiated

ADDICTION IS A DEVELOPMENTAL DISEASE

starts in adolescence and childhood

NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003.

Age

Age at tobacco, at alcohol and at cannabis dependence as per DSM IV

0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

1.4%

1.6%

1.8%

5 10 15 21 25 30 35 40 45 50 55 60 65

% i

n e

ach

age

gro

up

wh

o d

evel

op

firs

tti

me

dep

end

ence

THCALCOHOL

TOBACCO

ADDICTION IS A DEVELOPMENTAL DISEASEstarts in adolescence and childhood

Estimated Economic Cost to Society from

Substance Abuse and Addiction:

Illegal Drugs: $161 Billion/Year

Alcohol: $185 Billion/Year

Tobacco: $138 Billion/Year

Total: $484 Billion/Year

Economic Costs of Substance Abuse

• Health Care Expenditures

– Alcohol and Drug Abuse Services

– Medical Consequences

• Productivity Impacts (Lost Earnings)

– Premature Death

– Impaired Productivity

– Institutionalized Population

– Incarceration

– Crime Careers

– Victims of Crime

• Other Impacts on Society

– Crime

– Social Welfare Administration

– Motor Vehicle Crashes

– Fire Destruction

Americans’ Views of the Seriousnessof Health Problems(Top Ten of Thirty-Six Problems)

65%

65%

68%

69%

71%

73%

74%

75%

78%

82%

Stress

Alcohol abuse

Smoking

Child abuse

Violence

HIV/AIDS

Heart disease

Drunk driving

Cancer

Drug abuse

% s

ay

ing

“v

ery

ser

iou

sp

rob

lem

”

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

Drug abuse

Smoking

HIV/AIDS

Child abuse

Violence

Stress

Cancer

Drunk driving

Heart disease

Alcohol abuse

NIDA Research

…To Managed Care

From Molecules…

…Drug Courts

…Community Coalitions

Your Brain on Drugs

1-2 Min 3-4 5-6

6-7 7-8 8-9

9-10 10-20 20-30

YELLOW shows

places in brain

where cocaine goes

(Striatum)

Front of brain

Back of brain

Advances in Science

Have Revolutionized Our

Fundamental Views of

Drug Abuse and Addiction

Drug Abuse Is A Preventable Behavior

Partnership for a Drug Free America

Drug Addiction Is A Treatable Disease

DRUGS

BRAIN MECHANISMS

BEHAVIOR

ENVIRONMENT

HISTORICAL

ENVIRONMENTAL

- previous history- expectation- learning

- social interactions- stress- conditioned stimuli

- genetics- circadian rhythms- disease states- gender

PHYSIOLOGICAL

Drug Addiction:

A Complex Behavioral and Neurobiological Disorder

Community

Peer Cluster

Family

Individual

Drug Abuse Risk Factors

Drug Abuse

Drug/Alcohol Related Traffic Accidents

Delinquency

Academic Failure and DroppingOut of School

Juvenile Depression

Sexually Transmitted Diseases (Including HIV/AIDS)

Running Away From Home

Unwanted Pregnancies

Suicidal Behavior

Community

Peer Cluster

Family

Individual

Becomes Subordinate

IndividuallyHoused

GroupHoused

Morgan, D. et al. Nature Neuroscience, 5: 169-174, 2002.

**

S.003 .01 .03 .1

0

10

20

30

40

50

Cocaine (mg/kg/injection)

Dominant

Subordinate

Becomes Dominant

Isolation Can Change Neurobiology

Effects of a Social Stressor on Brain DA D2 Receptors and Propensity to Administer Drugs

We Know There’s ABig Genetic Contribution ToDrug Abuse and Addiction…

And the Nature of this ContributionIs Extremely Complex

Genes associated with Drug Abuse:

CYP2A6 tobacco dependenceFAAH (endogenous cannabinoid regulator) problem drug use

Mu-opioid receptior in heroin addiction

2.5

0

unpleasant response

pleasant response

DA Receptor Levels and Response to MP

Subjects with low receptor levels found MP pleasant while those with high levels found MP unpleasant

Biology/Genes Environment

DRUG

Addiction

Brain Mechanisms

ADDICTION INVOLVES MULTIPLE FACTORS

Brain Development

…the “Emotional” Brain vs. the “Reasoned” Brain

When reading emotion, teens (left) rely more on the

amygdala, while adults (right) rely more on the frontal cortex.

Deborah Yurgelon-Todd, 2000

Emotions

Giedd et al., 2001-2004

Yurgelun-Todd et al., 2000; 2004

Teens Adults

• Understanding drug abuse and addiction from a

Development Perspective has important implications

for their Prevention & Treatment

• Exposure to drugs of abuse during adolescence couldhave profound effects on Brain Development & Brain Plasticity

Why Do People Take Drugs In

The First Place?

People Take Drugs To:

Feel good (sensation seeking)

Feel better (self medication)

A Major Reason People Take

a Drug is They Like What

it Does to Their Brains

We Know That Despite

Their Many Differences, most

Abused Substances Enhance the

Dopamine and Serotonin Pathways

How do drugs work in the brain?

Dopamine Pathways

Functions

•reward (motivation)

•pleasure,euphoria

•motor function

(fine tuning)

•compulsion

•perserveration

Serotonin Pathways

Functions

•mood

•memory

processing

•sleep

•cognition

nucleus

accumbens

hippocampus

striatum

frontal

cortex

substantia

nigra/VTA

raphe

0

50

100

150

200

0 60 120 180

Time (min)

% o

f B

as

al D

A O

utp

ut

NAc shell

Empty

Box Feeding

Source: Di Chiara et al.

FOOD

100

150

200

DA

Co

nc

en

tra

tio

n (

% B

as

eli

ne

)

MountsIntromissionsEjaculations

15

0

5

10

Co

pu

latio

n F

req

uen

cy

Sample

Number

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

ScrScr

BasFemale 1 Present

ScrFemale 2 Present

Scr

Source: Fiorino and Phillips

SEX

Natural Rewards Elevate Dopamine Levels

0

100

200

300

400

500

600

700

800

900

1000

1100

0 1 2 3 4 5 hr

Time After Amphetamine

% o

f B

as

al R

ele

as

e

DADOPACHVA

Accumbens AMPHETAMINE

0

100

200

300

400

0 1 2 3 4 5 hrTime After Cocaine

% o

f B

as

al R

ele

as

e

DADOPACHVA

AccumbensCOCAINE

0

100

150

200

250

0 1 2 3 4 5hrTime After Morphine

% o

f B

as

al R

ele

as

e

Accumbens

0.51.02.510

Dose (mg/kg)

MORPHINE

0

100

150

200

250

0 1 2 3 hr

Time After Nicotine

% o

f B

as

al R

ele

as

e

AccumbensCaudate

NICOTINE

Source: Di Chiara and Imperato

Effects of Drugs on Dopamine Release

Prolonged Drug Use Changes

the Brain In Fundamental

and Long-Lasting Ways

Science Has Generated A Lot of

Evidence Showing That…

Dopamine D2 Receptors are Lower in Addiction

control addicted

Cocaine

Heroin

Alcohol

DA

DA

DA

DA DADA

DA

Reward Circuits

DADA DA

DA

DA

Reward Circuits

DA

DA

DA

DA DA

DA

Drug Abuser

Non-Drug Abuser

Amygdala

Anterior Cingulate

Nature Video Cocaine Video

CRAVING INDUCTION IN PET SETTING

N = 13

CR

AV

ING

5

4

3

2

1

0

-1

Neutral Cocaine

STIMULI

Memories Appear to Be

A Critical Part of Addiction

Cocaine 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

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

Drugs Are Usurping

Brain Circuits

and

Motivational Priorities

Dopamine Transporters in Methamphetamine Abusers

Methamphetamine abusers have significant reductions in dopamine transporters.

Normal Control

Methamphetamine Abuser p < 0.0002

Do

pa

min

e T

ran

sp

ort

ers

(Bm

ax/K

d)

Normal

Controls

Meth

Abusers

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

BNL - UCLA - SUNY

NIDA - ONDCP - DOE

Dopamine Transporters in Methamphetamine Abusers

BNL/UCLA/SUNY

NIDA, ONDCP, DOE

Motor Task

Loss of dopamine transporters

in the meth abusers may result

in slowing of motor reactions.

Memory TaskLoss of dopamine transporters

in the meth abusers may result

in memory impairment.

7 8 9 10 11 12 131.0

1.2

1.4

1.6

1.8

2.0

Time Gait(seconds)

468101214161.0

1.2

1.4

1.6

1.8

2.0

Delayed Recall(words remembered)

Do

pam

ine T

ran

sp

ort

er

Bm

ax/K

d

DAT Recovery

with prolonged

abstinence from

methamphetamine

Normal Control

Methamphetamine Abuser

(1 month detoxification)

Methamphetamine Abuser

(24 month abstinent)

[C-11]d-threo-methylphenidate

Source: Volkow, N.D. et al., Journal of Neuroscience, 21(23), pp. 9414-9418, December 1, 2001.

PFC

ACG

OFCSCC

Hipp

NAcc

VP

Amyg

REWARD

CONTROLINHIBITORY

CONTROL

MOTIVATION/DRIVE

MEMORY/LEARNING

Circuits Involved In Drug Abuse and Addiction

Control

Drive/

Motiva-

tion

Saliency/

Reward

Memory

STOP

Non Addicted Brain

Addicted Brain

Control

DriveSaliency

Memory

STOP

Non Addicted Brain

GO

Control

DriveSaliency

Memory

The Brains of Addicts

Are Different From

the Brains of Non-Addicts

…And Those Differences

Are An Essential Element

of Addiction

A Major Task for Drug Treatment is

Changing Brains Back!

Behaviorally

Pharmacologically

CONTROL

REWARD DRIVE

CONTROL

DRIVE

MEMORY

CONTROL

DRIVE

MEMORY

CONTROL

Strengthenfrontal control

MEMORY

Weaken learnedpositiveassociationswith drugsand drugcues

REWARD

Decreasethe rewardingvalue ofdrugs REWARD

Increase the rewarding valueof non-drugreinforcers

Treating the ADDICTED Brain

DRIVE

MEMORY

REWARD

Medications for Relapse Prevention

Addicted Brain

Drive

Control

Saliency

Memory

GO Strengthen prefrontal-striatal communication

Executive function/Inhibitory control

Interfere with conditioned memories (craving)

Teach new memories

Counteract stress responsesthat lead to relapse

Interfere with drug’sreinforcing effects

VaccinesEnzymatic degredationNaltrexoneDA D3 antagonistsCB1 antagonists

BiofeedbackModafinilBupropionStimulants

Antiepileptic GVGN-acetylcysteine

Cycloserine

CRF antagonistsOrexin antagonists

STOPDrive

Control

Memory

Non-Addicted Brain

Saliency AdenosineA2 antagonistsDA D3 antagonists

Treating A Brain Disease

Must Go Beyond Just

Fixing The Chemistry

We Need to Treat the

Whole Person!

The Most Effective Treatment

Strategies Will Attend to All Aspects

of Addiction:

• Biology

• Behavior

• Social Context

Components of Comprehensive Drug

Addiction Treatment

www.drugabuse.gov

We Have A Variety Of Effective

Treatment Options In The

Clinical Toolbox

Developing and Testing Addiction

Medications and Behavioral Therapies• More than 60 compounds are being tested as potential

treatments– Cocaine

– Opiates

– Methamphetamine

– Nicotine immunotherapies or vaccines

• Applying powerful new computerized drug development techniques

• Wide variety of behavioral treatments tested in variety of settings as stand-alone and as adjuncts to medications– Motivational incentives

– Aftercare

Some Behavioral Treatments with a Strong Science Base

• Behavioral Treatments for MJ Abuse

• Behavioral Treatments for Smoking Cessation

• Cognitive-Behavioral Treatment

• Combined Pharmacotherapies and Behavioral Therapies

• Complementary and Alternative Treatments

• Multisystemic Therapy

• Contingency Management Treatments*

• Dialectical Behavioral Therapy• Drug Counseling• Family Treatments• Group Behavior Therapy• HIV Risk Reduction• Motivational

Interviewing/Enhancement*• Seeking Safety (PTSD)• Work Therapy

PRE-CLINICAL

RESEARCH CLINICAL STUDIES NDA REVIEW POST-MARKETING

AVG: 18 MOS.

IND

AVG: 5 YEARS

NDA APPROVAL

DIS

CO

VE

RY

/SC

RE

EN

ING

SYNTHESIS

AND

PURIFICATION

ANIMAL

TESTING

AVG: 24 MOS.

ADVERSE

REACTION

SURVEILLANCE

PRODUCT DEFECT

REPORTING

SURVEYS/

SAMPLING

TESTING

POST APPROVAL

INSPECTIONS

SHORT-TERM

LONG-TERM

PHASE I

PHASE II

PHASE III PHASE IV

ACCELERATED APPROVAL

PARALLEL TRACK

TREATMENT USE

The Process of NEW DRUG DEVELOPMENTIs Long…and Expensive

ROADBLOCK #1: Lack of Pharmaceutical IndustryInterest in Developing Medications to Treat Addiction

Primary Care Physicians Are Often Reluctant To Treat Substance Abuse or Fail to Link This

With Their Patients’ Other Medical Conditions

ROADBLOCK #2: Erosion of the Medical Community’s Involvement in Preventing

and Treating Drug Abuse and Addiction

ADDICTION CONTRIBUTES TO MANY SERIOUS MEDICAL CONSEQUENCES

• Mental Illness

• Cancer

• Infectious Diseases

(HIV/HCV)

• Cardiac

• Pulmonary

• Learning Disorders

• Obesity

• Cerebrovascular

(strokes)

• Trauma

(accidents) Source: Fowler JS et al., PNAS. 2003;100(20):11600-5.

In 2007 An Estimated 22.3 Million Americans

Were Dependent On or AbusedAny Illicit Drugs or Alcohol

But…Only 3.9 Million (17%) of These Individuals

Had Received Some Type ofTreatment In the Past Year

Source: 2007 NSDUH, National Findings, SAMHSA, OAS, 2008.

Self Help Group

Outpatient Rehab

Inpatient Rehab

Outpatient Mental Health Center

Hospital Inpatient

Private Doctor’sOffice

Emergency Room

Prison or Jail

Numbers in Millions0 .5 1.0 1.5 2.0 2.5

2.2

1.7

1.0

0.9

0.8

0.6

0.5

0.3

Location TX Received

ROADBLOCK #3: Although Treatments For Addiction Are Available, They Are Not

Being Widely Used By Those Who Need Them

Drug Addiction is a chronic illness that can

be treated as readily as hypertension,

diabetes and asthma

Findings from a study sponsored by:Physician Leadership on

National Drug Policy, March 1998

Relapse Rates Are Similar for Drug Dependence and

Other Chronic Illnesses

0

10

20

30

40

50

60

70

80

90

100

Drug Dependence

Type I Diabetes

Hypertension Asthma

40

to

60

%

30

to

50

% 50

to

70

%

50

to

70

%

Source: McLellan, A.T. et al., JAMA, Vol 284(13), October 4, 2000.

Per

cen

t o

f P

ati

ents

Wh

o R

elap

se

0

2

4

6

8

10

Pre During Post

Treatment Research Institute

Outcome In Hypertension

0

2

4

6

8

10

Pre During Post

Treatment Research Institute

Outcome In Addiction

If we treat a diabetic and symptoms don’t

subside….what do we do?

Would we increase the dose?

Would we change medications?

Would we change treatment approaches?

Would we fail to provide ongoing

treatment for a diabetic?

For More Information

NIDA Public Information Office:

301-443-1124

Or

www.nida.nih.gov

www.drugabuse.gov

National Clearinghouse on Alcohol and

Drug Information (NCADI):

1-800-729-6686

www.drugabuse.gov

Healthy Heart Diseased Heart

Decreased Heart Metabolism in Heart Disease Patient

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

Control Cocaine Abuser

Decreased Brain Metabolism in Drug Abuse Patient

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

High

Low

Partial Recovery of Brain Dopamine Transportersin Methamphetamine (METH)

Abuser After Protracted Abstinence

Normal Control METH Abuser(1 month detox)

METH Abuser(24 months detox)

0

3

ml/gm

Source: Volkow, ND et al., Journal of Neuroscience 21, 9414-9418, 2001.

ADDICTION CAN BE TREATED

NIDA Screening and Treatment Resources

for Medical and Health Professionals

Overview

• Why screen for drug use in general medical settings?

• Website

• Demo of Online Screening Tool

• Quick Reference Guide

• Online Resource Guide

• Data from Review

• Press Conference

• Scientific Meeting

Why screen for drug use

in general medical settings?

• Drug use is harmful and has many adverse consequences?

– Cardiovascular disease, stroke, cancer, HIV/AIDS, anxiety, depression, sleep problems, as well as financial difficulties and legal, work, and family problems can all result from or be exacerbated by drug use.

• The use of illicit drugs is more common than you might think.

– In 2007, an estimated 20 million Americans aged 12 or older (~8.0 percent of the population) were current illicit drugs users.

– Nearly 1 in 5 Americans aged 18-25.

Why screen for drug use

in general medical settings?

• Only a fraction of individuals who need specialty treatment for drug or alcohol addiction receive it each year.

– In 2007, of the more than 23 million persons aged 12 or older who needed specialized treatment for a drug or alcohol problem, most—almost 21 million—did not receive it.

• Using screening and brief intervention (SBI) procedures in general medical settings can make a difference in drug use behaviors.

– Research has demonstrated that SBI can reduce alcohol and tobacco use.

– A growing body of literature suggests SBI can also reduce illicit and nonmedical prescription drug use as well.

Website and Online Tool Demo

Quick Reference Guide

Online Resource Guide

Online Resource Guide

• Introduction

– Why screen for drug use in general medical settings?

– How do you screen and provide feedback—the 5 As

• Before you begin screening patients

– Determine staffing roles and train staff

– Decide how screening results will be used

– Find reimbursement information for your state (SAMHSA website)

– Establish relationships and linkages with treatment providers

Online Resource Guide

• NIDA-Modified ASSIST Screening Tool—Step 1: ASK about drug use

– Introduce yourself and establish rapport (script)

– Ask patients about lifetime drug use using the Prescreen Question

– Begin the NIDA-Modified ASSIST

• Tobacco and Alcohol

– Score the full NIDA-Modified ASSIST

Online Resource Guide

• Conducting a Brief Intervention

– Step 2: ADVISE patient according to screening results

• Review screening results with patient

• Provide medical advice about the patient’s drug use

– Step 3: ASSESS the patient’s readiness to quit

– Step 4: ASSIST patient in making a change

– Step 5: ARRANGE specialty assessment, drug treatment, follow-up visit.

• Refer patients as appropriate

• Schedule a follow-up appointment

• Offer continuing support

Online Resource Guide

• Appendix 1 – Recommendations to address patient resistance

• Appendix 2 – Sample Progress Notes

• Appendix 3 – Change Plan Worksheet

• Appendix 4 – Biological Specimen Testing

• Appendix 5 – Additional Resources

• References

Reviewer Data

Review of Screening Tools

• Reviewers

– Researchers (9) who participated in May meeting to review original screening instrument + additional experts on brief intervention.

– Physician Consultant Group (24) – Practicing primary care physicians from around the country selected from the AMA’s Physician Master File dataset

• Review Form

– On a scale of 1 (worst) to 10 (best), how would rate the materials on their accuracy, completeness, clarity, and resources?

Review of Screening Tools

0

2

4

6

8

10

Accurate Complete Clear and Comprehensible Resources Included

Physicians (n=24)

Researchers (n=9)

Review of Screening Tools

• Review Form (cont…)

– Do you think that the below listed items would be useful for primary care physicians and their practices?

• Resource Guide

• Web-based Screening Tool (in concept)

• PDF of Screening Tool

• Quick Reference Guide

Percent of Reviewers Who Felt

Materials Would Be Useful

0

10

20

30

40

50

60

70

80

90

100

Resource Guide Web-based Tool PDF of Tool QRG

Physicians

Researchers

Review of Screening Tools

• Review Form – For Practicing Physicians Only

– Is the screening tool something that you would implement in your practice?

– Are the screening tool and accompanying materials something that you would recommend to colleagues?

0

10

20

30

40

50

60

70

80

90

100

Yes No

Physicians Who Would Implement or Recommend NIDA

Screening Tools

Implement

Recommend