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Addiction: A Disease of the Brain

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

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Addiction: A Disease of the Brain

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

  2. Annual Deaths USA 450,000 100,000 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

  4. What is Addiction/Dependence? • Drug use “out of control” • NOT necessarily Daily use Tolerance Physiol. Dependence Withdrawal

  5. Use Abuse Addiction Use Use Abuse Use Abuse 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 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.

  8. DA increased in Nucleus Accumbens • Nicotine • Alcohol • Opiates • Cocaine

  9. COCAINE AMPHETAMINE Accumbens 1100 Accumbens 400 1000 900 DA 800 DA 300 % of Basal Release DOPAC 700 DOPAC % of Basal Release HVA HVA 600 500 200 400 300 100 200 100 0 0 0 1 2 3 4 5 hr Time After Amphetamine Time After Cocaine MORPHINE NICOTINE 250 Accumbens 250 Dose (mg/kg) 200 Accumbens 0.5 200 Caudate 1.0 % of Basal Release 2.5 % of Basal Release 150 10 150 100 0 1 2 3 hr 100 0 1 2 3 4 5 hr 0 0 0 1 2 3 4 5hr Time After Nicotine Time After Morphine Effects of Drugs on Dopamine Levels Source: Di Chiara and Imperato

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

  11. Resultant of interacting variables Outcomes: No use Use Abuse Addiction Agent (Drug) Host Environment + - + - + -

  12. Agent • Availability • Dose • Price, Purity • Gateway hypothesis vs. Random cigarettes/marijuana most available • Crack as gateway drug in certain areas

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

  14. Inherited FactorsInitial 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

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

  18. Dependence Withdrawal Syndrome (normal reactions, not necessarily a sign of addiction)

  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

  21. Compulsion • An irresistible impulse to act, regardless of the rationality of the motivation • A strong irrational impulse to carry out a given act

  22. ASI Problem Severity Profile of a Cocaine Dependent Physician Problem Area

  23. ASI Problem Severity Profile of a Cocaine Dependent Teen Mother 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) 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. Caloric Intake Systolic and Calories mmHg Diastolic Blood Pressure Body Weight kg Pulse Rate BEATS / MIN. Pupillary Diameter mm Body Temperature Respiratory Rate oC BREATHS / MIN. Abstinence Scores Daily Dose Level POINTS mg / DAY 0 5 10 15 20 25 30 0 5 10 15 20 25 30 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

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

  30. Amygdala Nature Video Cocaine Video 2.5 2.0 1.5 Anterior Cingulate 1.0 .5 0 Pt. 30023 Childress ‘97 Cocaine Pt. 30023

  31. Orbitofrontal Nature Video Opiate Video 2.5 2.0 1.5 Anterior Cingulate 1.0 .5 0 Opiate Patient 01 Pt. Op_1.1

  32. Amygdala Nature Video Sexual Video Anterior Cingulate Pt. SX_4

  33. 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?

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