1. Addiction: A Disease of the Brain
Charles P. O’Brien, MD, PhD
University of Pennsylvania
Philadelphia VA Medical Center

2. Annual Deaths USA
450,000
Clearly the legal drugs, nicotine and alcohol, cause many more deaths than the illegal drugs such as cocaine and heroin.
100,000
5,000
2,000

3. Is Addiction a Disease? Volitional aspects at start
Involuntary behavior in dependent
state
Chronic disease: relapses and
remissions
No cures, stable long term remission
with risk of relapse
Objections to the concept of addiction as a disease of the brain come from the fact that all drug taking is volitional at first. Many people do take the risks of trying drugs, but only a minority go on to develop abuse or addiction. This minority is strongly influenced by the luck or lack of luck in their genes because heredity plays a major role. After a person is hooked, addiction behaves as a chronic disease with relapses and remissions just as other chronic diseases such as hypertension, diabetes, arthritis or asthma.

4. What is Addiction/Dependence?
Drug use “out of control”
NOT necessarily
Daily use
Tolerance
Physiol. Dependence
Withdrawal
It is important to distinguish addiction from tolerance and physiological dependence which are normal responses to repeated administration of many types of drugs including drugs of abuse.

5. Use Abuse Addiction Use Use Abuse Use Abuse Addiction Use
This slide depicts the fact that many people use drugs. Some go on to abuse and some develop addiction.
Use

6. Which drug has the highest rate of addiction among those who try it?
Heroin
Cocaine
Nicotine
Alcohol
Marijuana

7. Risk of Addiction Tobacco 75.6% 24.1% 31.9% Cocaine 16.2 2.7 16.7
Ever used Dependence Risk
Tobacco 75.6% % %
Cocaine
Heroin
Alcohol
Cannabis
Anthony et al, 1994.
This slide presents data from the US population showing the relative risk of developing addiction among those who use at all.

8. DA increased in Nucleus Accumbens
Nicotine
Alcohol
Opiates
Cocaine
Slides 8 and 9 show the common properties of drug of abuse which is to activate the reward system. Activation is measured by increases in dopamine in the extracellular fluid of the Nucleus Accumbens.

9. Effects of Drugs on Dopamine Levels
100
200
300
400
500
600
700
800
900
1000
1100 1 2 3 4
5 hr
Time After Amphetamine
% of Basal Release DA
DOPAC
HVA
Accumbens
AMPHETAMINE
100
200
300
400 1 2 3 4
5 hr
Time After Cocaine
% of Basal Release DA
DOPAC
HVA
Accumbens
COCAINE
100
150
200
250 1 2
3 hr
Time After Nicotine
% of Basal Release
Accumbens
Caudate
NICOTINE
100
150
200
250 1 2 3 4
5hr
Time After Morphine
% of Basal Release
Accumbens
0.5
1.0
2.5 10
Dose (mg/kg)
MORPHINE
Source: Di Chiara and Imperato

10. BRAIN DOPAMINE SYSTEM CG PreF Striatum OFC nucleus accumbens VTA/SN CA
PUT
NAc
OFC
nucleus
accumbens
VTA/SN

11. Resultant of interacting variables
Outcomes:
No use
Use
Abuse
Addiction
Agent (Drug)
Host
Environment + - + -
The development of addiction is the resultant of multiple simultaneous variables some of which protect the individual from becoming addicted and others increase the probability of progressing to addiction. + -

12. Agent Availability Dose Price, Purity
Gateway hypothesis vs. Random cigarettes/marijuana most available
Crack as gateway drug in certain areas
Slides 13 to 16 illustrate some of the variables that influence progression to addiction.

13. Host Individual vulnerability Heredity Rapidity of tolerance
Metabolism (nicotine, alcohol)
Amount of reward
Psychiatric Disorders,
“self medication”

14. Inherited Factors Initial Drug Exposure
Dose - Plasma level
Absorption
Disposition
Flushing Response
Perception of Pleasant Effect
Rapidity of Tolerance Development

15. Environment
Role models
Other reinforcers
Stress
Boredom
Peer pressure

16. Tolerance Innate Acquired Pharmacokinetic Pharmacodynamic
Behavioral Tolerance
Conditioned Tolerance
This slide describes types of tolerance. Tolerance is a reduction in drug effect with repeated administration. Cross tolerance refers to the common tolerance seen within drug classes so that tolerance to one implies tolerance to another.

17. Cross Tolerance Useful in choosing detox Medications heroin-methadone
alcohol-oxazepam

18. Dependence Withdrawal Syndrome (normal reactions, not necessarily
a sign of addiction)
This slide refers to physiological dependence, the common reaction to repeated drug use.

19. Tolerance/Withdrawal
Neither necessary nor sufficient
Patients with tolerance/withdrawal
---no addiction
Patients with addiction--- no
tolerance/withdrawal

20. Sensitization Reverse of tolerance Stimulants - increased effect with
repeated, spaced dosing
Sensitization is the opposite of tolerance and refers to increased responsivity to the same dose of a drug taken repeatedly.

21. Compulsion
An irresistible impulse to act, regardless of the rationality of the motivation
A strong irrational impulse to carry out a given act
Addiction produces compulsive drug use. The compulsion can be overcome, but it is difficult; therefore most persons who develop addiction have a tendency to relapse at some time in the future even after excellent treatment.

22. ASI Problem Severity Profile of a Cocaine Dependent Physician
This slides illustrates the profile of the Addiction Severity Index in a person who has a severe drug problem, but few problems in other domains.
Problem Area

23. ASI Problem Severity Profile of a Cocaine Dependent Teen Mother
This slide shows the profile of the more common type of patient who has problems across all domains.
Problem Area

24. “Pure” addicts are rare
most have additional problems
treatment depends on additional problems
high treatment success rate for “pure” addicts

25. Plasma Nicotine Levels
Mean Plasma Nicotine
Levels (mg/ml)
This slide illustrates the importance of route of administration. Inhalation, as in smoking a cigarette, produces rapid arterial blood levels that are higher than venous levels and produce a prompt response in the brain.
Time after smoking Cigarette (minutes)

26. Factors Leading to Relapse
Psychiatric problems
- Depression
- Anxiety
Social Problems
- Unemployment
- Family problems
- Peer influence
Protracted Abstinence
Conditioned Responses

27. Diastolic Blood Pressure Body Weight
Systolic and
Caloric Intake
Calories
mmHg
Diastolic Blood Pressure
Body Weight kg
Pulse Rate
BEATS / MIN.
Pupillary Diameter mm
Body Temperature
Respiratory Rate oC
This slide depicts an experiment among inpatient heroin addicts that demonstrates long-term physiological changes up to 30 weeks after the last dose of opiate. This is called protracted abstinence.
BREATHS / MIN.
Daily Dose Level
Abstinence Scores
mg / DAY
POINTS
Weeks
Weeks

28. Conditioned Responses
Thousands of pairings of environmental cues with drug effects
Cellular level: changes in gene transcription
Persist long after last use of drug
This slide refers to craving induced by cues previously associated with drug use. The next series of slides demonstrates testing of brain changes using various types of brain imaging: regional cerebral blood flow (PET or fMRI) or PET using specific ligands to study neurotransmitter and receptor interactions.

29. Cue induced craving 25 years after last dose of nicotine
Not just recall of feeling
Compulsion, difficult to resist

30. Nature Video Cocaine Video
Amygdala
Nature Video Cocaine Video
2.5
2.0
1.5
Anterior Cingulate
1.0
This slide shows the effects of cocaine cues on increased blood flow to limbic structures such as the cingulate gyrus and the amygdula. .5 Pt
Childress ‘97
Cocaine Pt

31. Nature Video Opiate Video
Orbitofrontal
Nature Video Opiate Video
2.5
2.0
1.5
Anterior Cingulate
1.0
This slide shows activity in a drug-free opiate addict who also shows activation of limbic structures in response to opiate cues. .5
Opiate Patient 01
Pt. Op_1.1

32. Nature Video Sexual Video
Amygdala
Nature Video Sexual Video
Anterior Cingulate
This slide shows activation of limbic structures in a normal control who is a male who has been exposed to sexually arousing videos. To a varying extent pleasures tend to activate these regions of the brain and it has been demonstrated in human subjects in response to sexual stimuli and food stimuli as well as drug-related stimuli. Drugs of abuse tend to give the strongest activation to to reward systems and the current concept is that repeated use of these drugs with its strong activation of the reward system tends to highjack this system which has been developed for reinforcement of normal rewards but it becomes overtaken by the pursuit of drug-related rewards.
Pt. SX_4

33. This slide shows a C-11 raclopride scan showing competition for dopamine receptors during cue induced craving. Endogenous dopamine release is measured indirectly by competition for the the receptor between endogenous (unlabeled) and the labeled radio-ligand. The patient reports craving while dopamine is being released in the reward system. t

34. Conditioned drug effects
Craving
Autonomic (HR, Skin Temp, GSR)
Regional CBF
Regional Brain Metabolism
Neurotransmitter release (DA)
Immediate early genes (c Fos)

35. Discussion If addiction is a brain disease, where is the lesion?
How can you compare drug taking which is voluntary behavior to diabetes which is completely involuntary?