Neurobiology of Addiction

Transcription

1 Neurobiology of Addiction Cindy Miner, Ph.D. Deputy Director Office of Science Policy and Communications National Institute on Drug Abuse National Institutes of Health Department of Health and Human Services Chief Resident Immersion Training Program Cape Cod, MA May, 2009

2 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

3 Past Month Use of Selected Illicit Drugs among Persons Aged 12 or Older: National Survey on Drug Use and Health, SAMHSA

4 Percent Using in Past Month Past Month Illicit Drug Use, by Age: Age in Years Source: 2007 National Survey on Drug Use & Health (SAMHSA)

5 * Denotes significant difference between recent peak year and current year. Percent of Students Reporting Any Illicit Drug Use in Past Year, by Grade * * * th Grade 10th Grade 12th Grade

6 2005 Monitoring the Future Study Prevalence of Drugs Among High School Seniors Drug Prev.* Drug Prev.* Marijuana/Hashish 33.6 MDMA (Ecstasy) 3.0 Vicodin** 9.5 Methamphetamine 2.5 Amphetamines 8.6 "Ice" 2.3 Sedatives** 7.2 Crack 1.9 Tranquilizers** 6.8 LSD 1.8 OxyContin** 5.5 Ketamine 1.6 Cocaine (any form) 5.1 Steroid** 1.5 Inhalants 5.0 PCP 1.3 Cocaine Powder 4.5 Rohypnol 1.2 Ritalin** 4.4 GHB 1.1 * Percentage reporting use in past year. **Nonmedical use.

7 Percent of Initiates ADDICTION IS A DEVELOPMENTAL DISEASE starts in adolescence and childhood Age at Which Marijuana Use Is First Initiated Child <12 Teen Young Adult Adult >25 Source: Gfroerer, JC et al., SMA , OA, SAMHSA Data from National Survey of Drug Use and Health.

8 % in each age group who develop ADDICTION IS A DEVELOPMENTAL DISEASE starts in adolescence and childhood 1.8% 1.6% TOBACCO THC ALCOHOL first time dependence 1.4% 1.2% 1.0% 0.8% 0.6% 0.4% 0.2% 0.0% Age Age at tobacco, at alcohol and at cannabis dependence as per DSM IV NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003.

9 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

10 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

11 % saying very serious problem Americans Views of the Seriousness of Health Problems (Top Ten of Thirty-Six Problems) Drug abuse Cancer Drunk driving Heart disease HIV/AIDS Violence Child abuse Smoking Alcohol abuse Stress 82% 78% 75% 74% 73% 71% 69% 68% 65% 65% Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000

12 NIDA Research From Molecules To Managed Care Drug Courts Community Coalitions

13

14 Your Brain on Drugs Front of brain Back of brain 1-2 Min YELLOW shows places in brain where cocaine goes (Striatum)

15 Advances in Science Have Revolutionized Our Fundamental Views of Drug Abuse and Addiction

16 Drug Abuse Is A Preventable Behavior Drug Addiction Is A Treatable Disease Partnership for a Drug Free America

17 Drug Addiction: A Complex Behavioral and Neurobiological Disorder HISTORICAL - previous history - expectation - learning ENVIRONMENTAL - social interactions - stress - conditioned stimuli DRUGS BRAIN MECHANISMS PHYSIOLOGICAL - genetics - circadian rhythms - disease states - gender BEHAVIOR ENVIRONMENT

18 Drug Abuse Risk Factors Community Peer Cluster Family Individual

19 Drug/Alcohol Related Traffic Accidents Sexually Transmitted Diseases (Including HIV/AIDS) Suicidal Behavior Drug Abuse Community Peer Cluster Family Individual Delinquency Academic Failure and Dropping Out of School Juvenile Depression Unwanted Pregnancies Running Away From Home

20 Effects of a Social Stressor on Brain DA D2 Receptors and Propensity to Administer Drugs Individually Housed Group Housed Dominant 50 Subordinate Becomes Dominant 40 Isolation Can Change Neurobiology * * 10 Becomes Subordinate 0 Morgan, D. et al. Nature Neuroscience, 5: , S Cocaine (mg/kg/injection)

21 We Know There s A Big Genetic Contribution To Drug Abuse and Addiction And the Nature of this Contribution Is Extremely Complex

22 Genes associated with Drug Abuse: CYP2A6 tobacco dependence FAAH (endogenous cannabinoid regulator) problem drug use Mu-opioid receptior in heroin addiction

23 DA Receptor Levels and Response to MP 2.5 unpleasant response 0 pleasant response Subjects with low receptor levels found MP pleasant while those with high levels found MP unpleasant

24 ADDICTION INVOLVES MULTIPLE FACTORS Biology/Genes Environment DRUG Brain Mechanisms Addiction

25 Brain Development the Emotional Brain vs. the Reasoned Brain Teens Emotions Adults When reading emotion, teens (left) rely more on the amygdala, while adults (right) rely more on the frontal cortex. Deborah Yurgelon-Todd, 2000 Giedd et al., Yurgelun-Todd et al., 2000; 2004

26 Exposure to drugs of abuse during adolescence could have profound effects on Brain Development & Brain Plasticity Understanding drug abuse and addiction from a Development Perspective has important implications for their Prevention & Treatment

27 Why Do People Take Drugs In The First Place?

28 People Take Drugs To: Feel good (sensation seeking) Feel better (self medication)

29 A Major Reason People Take a Drug is They Like What it Does to Their Brains

30 How do drugs work in the brain? We Know That Despite Their Many Differences, most Abused Substances Enhance the Dopamine and Serotonin Pathways

31 Dopamine Pathways Serotonin Pathways frontal cortex Functions reward (motivation) pleasure,euphoria motor function (fine tuning) compulsion perserveration striatum nucleus accumbens hippocampus substantia nigra/vta raphe Functions mood memory processing sleep cognition

32 % of Basal DA Output DA Concentration (% Baseline) Natural Rewards Elevate Dopamine Levels 200 FOOD NAc shell 200 SEX Empty Box Feeding Time (min) 100 Sample Number ScrScr BasFemale 1 Present Scr Mounts Intromissions Ejaculations Scr Female 2 Present Copulation Frequency Source: Di Chiara et al. Source: Fiorino and Phillips

33 % of Basal Release % of Basal Release % of Basal Release % of Basal Release Effects of Drugs on Dopamine Release Accumbens AMPHETAMINE hr Time After Amphetamine DA DOPAC HVA Accumbens COCAINE DA DOPAC HVA hr Time After Cocaine NICOTINE Accumbens Caudate Accumbens MORPHINE Dose (mg/kg) hr Time After Nicotine hr Time After Morphine Source: Di Chiara and Imperato

34 Science Has Generated A Lot of Evidence Showing That Prolonged Drug Use Changes the Brain In Fundamental and Long-Lasting Ways

35 Dopamine D2 Receptors are Lower in Addiction DA DA Cocaine DA DA DA DA DA DA DA DA DA DA Reward Circuits Non-Drug Abuser Alcohol DA DA DA DA DA DA Heroin control addicted Reward Circuits Drug Abuser

36 Amygdala Nature Video Cocaine Video Anterior Cingulate

37 CRAVING CRAVING INDUCTION IN PET SETTING 5 N = Neutral STIMULI Cocaine

38 Memories Appear to Be A Critical Part of Addiction

39 Signal Intensity (AU) Cocaine Craving: Population (Cocaine Users, Controls) x Film (cocaine, erotic) Cingulate Ant Cing Cocaine Film IFG Controls Cocaine Users Garavan et al A.J. Psych 2000

40 Signal Intensity (AU) Cocaine Craving: Population (Cocaine Users, Controls) x Film (cocaine, erotic) Cingulate Ant Cing Cocaine Film Erotic Film IFG Controls Cocaine Users Garavan et al A.J. Psych 2000

41 Drugs Are Usurping Brain Circuits and Motivational Priorities

42 Dopamine Transporters in Methamphetamine Abusers Dopamine Transporters (Bmax/Kd) Normal Control Normal Controls Meth Abusers Methamphetamine Abuser p < Methamphetamine abusers have significant reductions in dopamine transporters. BNL - UCLA - SUNY NIDA - ONDCP - DOE

43 Dopamine Transporter Bmax/Kd Dopamine Transporters in Methamphetamine Abusers Time Gait (seconds) Delayed Recall (words remembered) 4 Motor Task Loss of dopamine transporters in the meth abusers may result in slowing of motor reactions. Memory Task Loss of dopamine transporters in the meth abusers may result in memory impairment. BNL/UCLA/SUNY NIDA, ONDCP, DOE

44 [C-11]d-threo-methylphenidate Normal Control DAT Recovery with prolonged abstinence from methamphetamine Methamphetamine Abuser (1 month detoxification) Methamphetamine Abuser (24 month abstinent) Source: Volkow, N.D. et al., Journal of Neuroscience, 21(23), pp , December 1, 2001.

45 Circuits Involved In Drug Abuse and Addiction CONTROL INHIBITORY CONTROL OFC PFC SCC MOTIVATION/ DRIVE ACG NAcc Amyg Hipp VP REWARD MEMORY/ LEARNING

46 Non Addicted Brain Control STOP Saliency/ Reward Drive/ Motivation Memory

47 Non Addicted Brain Addicted Brain Control Control STOP Saliency Drive Saliency Drive GO Memory Memory

48 The Brains of Addicts Are Different From the Brains of Non-Addicts And Those Differences Are An Essential Element of Addiction

49 A Major Task for Drug Treatment is Changing Brains Back! Pharmacologically Behaviorally

50 Treating the ADDICTED Brain REWARD CONTROL DRIVE Decrease the rewarding value of drugs REWARD CONTROL DRIVE Increase the rewarding value of non-drug reinforcers MEMORY MEMORY REWARD CONTROL DRIVE MEMORY Weaken learned positive associations with drugs and drug cues REWARD CONTROL DRIVE MEMORY Strengthen frontal control

51 Medications for Relapse Prevention Non-Addicted Addicted Brain Brain Control Control Interfere with drug s reinforcing effects Executive function/ Inhibitory control Vaccines Enzymatic degredation Naltrexone DA D3 antagonists CB 1 antagonists Biofeedback Modafinil Bupropion Stimulants Saliency Drive Drive STOP GO Strengthen prefrontalstriatal communication Adenosine A2 antagonists DA D3 antagonists Memory Memory Interfere with conditioned memories (craving) Teach new memories Antiepileptic GVG N-acetylcysteine Cycloserine Counteract stress responses that lead to relapse CRF antagonists Orexin antagonists

52 Treating A Brain Disease Must Go Beyond Just Fixing The Chemistry

53 We Need to Treat the Whole Person!

54 The Most Effective Treatment Strategies Will Attend to All Aspects of Addiction: Biology Behavior Social Context

55 Components of Comprehensive Drug Addiction Treatment

56 We Have A Variety Of Effective Treatment Options In The Clinical Toolbox

57 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

58 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

59 DISCOVERY/SCREENING ROADBLOCK #1: Lack of Pharmaceutical Industry Interest in Developing Medications to Treat Addiction PRE-CLINICAL RESEARCH CLINICAL STUDIES NDA REVIEW POST-MARKETING SYNTHESIS AND PURIFICATION PHASE I PHASE II PHASE III ADVERSE REACTION SURVEILLANCE PRODUCT DEFECT REPORTING PHASE IV ANIMAL TESTING SHORT-TERM LONG-TERM ACCELERATED APPROVAL TREATMENT USE PARALLEL TRACK SURVEYS/ SAMPLING TESTING POST APPROVAL INSPECTIONS AVG: 18 MOS. IND AVG: 5 YEARS NDA AVG: 24 MOS. APPROVAL The Process of NEW DRUG DEVELOPMENT Is Long and Expensive

60 ROADBLOCK #2: Erosion of the Medical Community s Involvement in Preventing and Treating Drug Abuse and Addiction Primary Care Physicians Are Often Reluctant To Treat Substance Abuse or Fail to Link This With Their Patients Other Medical Conditions

61 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):

62 ROADBLOCK #3: Although Treatments For Addiction Are Available, They Are Not Being Widely Used By Those Who Need Them In 2007 An Estimated 22.3 Million Americans Were Dependent On or Abused Any Illicit Drugs or Alcohol But Only 3.9 Million (17%) of These Individuals Had Received Some Type of Treatment In the Past Year Self Help Group Outpatient Rehab Inpatient Rehab Outpatient Mental Health Center Hospital Inpatient Private Doctor s Office Emergency Room Prison or Jail Location TX Received Source: 2007 NSDUH, National Findings, SAMHSA, OAS, Numbers in Millions

63 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

64 Percent of Patients Who Relapse 40 to 60% 30 to 50% 50 to 70% 50 to 70% Relapse Rates Are Similar for Drug Dependence and Other Chronic Illnesses Drug Dependence Type I Diabetes Hypertension Asthma Source: McLellan, A.T. et al., JAMA, Vol 284(13), October 4, 2000.

65 10 Outcome In Hypertension Pre During Post Treatment Research Institute

66 10 Outcome In Addiction Pre During Post Treatment Research Institute

67 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?

68 For More Information NIDA Public Information Office: Or National Clearinghouse on Alcohol and Drug Information (NCADI):

69 ADDICTION IS A DISEASE OF THE BRAIN as other diseases it affects the tissue function Decreased Brain Metabolism in Drug Abuse Patient High Control Cocaine Abuser Decreased Heart Metabolism in Heart Disease Patient Low Healthy Heart Diseased Heart Sources: From the laboratories of Drs. N. Volkow and H. Schelbert

70 ADDICTION CAN BE TREATED Partial Recovery of Brain Dopamine Transporters in Methamphetamine (METH) Abuser After Protracted Abstinence 3 0 Normal Control METH Abuser (1 month detox) METH Abuser (24 months detox) Source: Volkow, ND et al., Journal of Neuroscience 21, , ml/gm

71 NIDA Screening and Treatment Resources for Medical and Health Professionals

72 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

73 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

74 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.

75 Website and Online Tool Demo

76 Quick Reference Guide

77 Online Resource Guide

78 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

79 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

80 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

81 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

82 Reviewer Data

83 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?

84 Review of Screening Tools Physicians (n=24) Researchers (n=9) 2 0 Accurate Complete Clear and Comprehensible Resources Included

85 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

86 Percent of Reviewers Who Felt Materials Would Be Useful Physicians Researchers Resource Guide Web-based Tool PDF of Tool QRG

87 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?

88 100 Physicians Who Would Implement or Recommend NIDA Screening Tools Implement Recommend Yes No