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

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

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.

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.

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

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

Risk of Addiction Tobacco 75.6% 24.1% 31.9% Cocaine 16.2 2.7 16.7 Ever used Dependence Risk Tobacco 75.6% 24.1% 31.9% Cocaine 16.2 2.7 16.7 Heroin 1.5 0.4 23.1 Alcohol 91.5 14.1 15.4 Cannabis 46.3 4.2 9.1 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.

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.

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

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

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. + -

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.

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

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

Environment Role models Other reinforcers Stress Boredom Peer pressure

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.

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

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

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

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.

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.

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

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

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

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)

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

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 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Weeks Weeks

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.

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

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. 30023 Childress ‘97 Cocaine Pt. 30023

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

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

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

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

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?