NIDA Research. Advances in Drug Abuse and Addiction from NIDA: Implications for Treatment

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1 Advances in Drug Abuse and Addiction from NIDA: Implications for Treatment Timothy P. Condon, Ph.D. Deputy Director National Institute on Drug Abuse National Institutes of Health Department of Health and Human Services California Society of Addiction Medicine Addiction Medicine Review Course 2006 San Francisco, California October 6, 2006 NIDA Research From Molecules To Managed Care Drug Courts Community Coalitions Advances in Science Are Bringing Us New Understanding of Drug Abuse & Addiction AND This Knowledge Is Allowing Us To Develop More Targeted Strategies for Its Prevention and Treatment 1

2 Social Network Organism Organ Cell Proteins/pathways Gene Adapted from Pennisi Science 2003 Priority Areas for NIDA Prevention Research (Children and Adolescents) genetics development environment co-morbidity Treatment Interventions (New Targets) HIV/AIDS Research Training Researchers What have we learned? 2

3 HISTORY - previous history - expectation - learning DRUGS BIOLOGY - genetics - circadian rhythms - disease states - gender BRAIN MECHANISMS ADDICTION ENVIRONMENT - social interactions - stress - conditioned stimuli What have we learned about Vulnerability? Why do some people become addicted while others do not? Drug Abuse Risk Factors Community Peer Cluster Family Individual 3

4 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 We Know There s s A Big Genetic Contribution To Drug Abuse and Addiction And the Nature of this Contribution Is Extremely Complex Genetic component of common traits Trait Heritability Type II (adult-onset) diabetes Type I (insulin-dependent) diabetes Hypertension Peanut allergy Cataract (age-related) Alcoholism Nicotine Cocaine and stimulants Heroin and opiates Marijuana

5 Some Genes associated with Drug Abuse: CYP2A6 tobacco dependence FAAH (endogenous cannabinoid regulator) problem drug use Mu-opioid receptior in heroin addiction DA Receptor Levels and Response to MP unpleasant response pleasant response Subjects with low receptor levels found MP pleasant while those with high levels found MP unpleasant High Levels of Dopamine D2 Receptors May Provide Protection Against Alcoholism in Unaffected Members of Alcoholic Families Researchers also found that increased D2 receptors in the family positive subjects correlated with metabolism in the frontal regions and with positive emotionality Volkow, N. D. et al. Arch Gen Psychiatry 2006;63:

6 Genetic Variation Predicts Naltrexone Treatment Response for Alcohol Dependence Cumulative Survival (Time to Relapse) Days Naltrexone/ Asp40 Allele (A/G, G/G) (n=23) Naltrexone/ Asn40 Allele (A/A) (n=48) Placebo/ Asp40 Allele (A/G, G/G) (n=18) Placebo/ Asn40 Allele (A/A) (n=41) Source: Oslin DW et al., Neuropsychopharmacology 28, , Genetics Gene/ Environment Interaction Environment What have we learned about other aspects of vulernability? 6

7 Drug Addiction is a Developmental Disease that Starts in Adolescence and Childhood % in each age group who develop first-time cannabis use disorder 1.6% 1.4% 1.2% 1.0% 0.6% 0.8% 0.4% 0.2% 0.0% Age Age at cannabis use disorder as per DSM IV NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003 Addiction Is a Developmental Disease starts in childhood and adolescence % in each age group to develop first-time dependence TOBACCO THC ALCOHOL Age Age at tobacco, at alcohol and at cannabis dependence, as per DSM IV National Epidemiologic Survey on Alcohol and Related Conditions, 2003 The Adolescent Brain Is Still Undergoing Development Amygdalo-cortical Sprouting Continues Into Early Adulthood Brain areas where volumes are smaller in adolescents than young adults Source: Sowell, E.R. et al., Nature Neuroscience, 2(10), pp , During Adolescence the COGNITION-EMOTION Connection is Still Forming Source: Cunningham, M et al., J Comp Neurol 453, pp ,

8 Gogtay, Giedd, et al. (2004) Proc. Natl. Acad. Sci. USA 101, Right Lateral and Top Views of the Dynamic Sequence of GM Maturation Over the Cortical Surface Source: Gogtay, Nitin et al. (2004) Proc. Natl. Acad. Sci. USA 101, Copyright 2004 by the National Academy of Sciences Frontal and Amygdalar Activity Differ in Adults and Adolescents Correlation Between Age and PFC Activity During Fear Face Processing Teen Adjusted FMRI Response [42,44,6] Adult Age When Reading Emotion When Reading Emotion Adults Rely More on Frontal Cortex Frontal Activation Increases with Age Teens Rely More on the Amygdala Yurgelun-Todd et al., Percept Mot Skills, 99:2, 2004 Killgore et al., NeuroReport, v12(2),

9 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 The Adolescent Brain Responds to Drugs Differently than the Adult Brain Treatment of adolescent rats (but not young adults) with Nicotine leads to Increases in Nicotine Self Administration Increases in Nicotine Receptors Source: Adriana, W. et al., J of Neurosci, 23(11), pp , June 1, Adolescent Exposure to Cannabinoids Alters the Response of VTA Dopamine Neurons to Drugs of Abuse Percent baseline firing rate vehicle pretreated CB adolescent CB adult 1 10 Morphine (mg/kg) Source: Pistis, M. et al., Biol Psychiatry, 56: 86-94, Percent baseline firing rate Percent baseline firing rate vehicle pretreated CB adolescent Cocaine (mg/kg) vehicle pretreated CB adolescent.1 1 Amphetamine (mg/kg) 9

10 ADDICTIVE DISORDERS OFTEN CO-EXIST WITH MENTAL DISORDERS Mental Disorder Comorbid Disorders Addictive Disorder Results: Lifetime Disorders % Any Alcohol Any Drug Any Mood Any Anxiety 3.6 Antisocial Personality US Population Source: Results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) % Lifetime Mood Disorders Among Those with Drug Disorders 40.9 Any Mood 33.2 Major Depression Dysthymia Mania Hypomania With Any Drug Disorder Source: Results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) 10

11 % Lifetime Anxiety Disorders Among Those with Drug Disorders 29.9 Any Anxiety 3.6 Panic with Agoraphobia 9.0 Panic without Agoraphobia 10.7 Social Phobia 17.1 Specific Phobia With Any Drug Disorder Source: Results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) 9.2 Generalized Anxiety COMORBIDITY Smoking and Mental Illness 44% of all cigarettes consumed in the US are by individuals with a current psychiatric disorder 75% of patients in addiction and mental health treatment programs smoke cigarettes Source: Lasser, K et al., JAMA 284(20), November 22/29, Comorbidity is a Reality 11

12 What have learned about how drugs work? Natural Rewards Elevate Dopamine Levels % of Basal DA Output Empty FOOD Box Feeding NAc shell Time (min) Source: Di Chiara et al. DA Concentration (% Baseline) Sample Number ScrScr Bas Female 1 Present SEX Scr Mounts Intromissions Ejaculations Source: Fiorino and Phillips Scr Female 2 Present Copulation Frequency 12

13 % of Basal Release Effects of Drugs on Dopamine Release Accumbens AMPHETAMINE DA DOPAC HVA hr Time After Amphetamine % of Basal Release Accumbens COCAINE DA DOPAC HVA hr Time After Cocaine % of Basal Release NICOTINE Accumbens Caudate % of Basal Release Accumbens MORPHINE Dose (mg/kg) hr Time After Nicotine hr Time After Morphine Source: Di Chiara and Imperato Nuclear Circuitry Mediating the Activation of Goal-Directed Behavior Medial dorsal thalamus Ventral pallidum Nucleus accumbens core Prefrontal cortex Enter basal ganglia motor generator Dopamine Glutamate GABA GABA/Neuropeptide Cannabinoid receptors??? Ventral tegmental area Basolateral amygdala Hippocampus Extended amygdala Central amygdala nucleus, bed nucleus of the stria terminalis nucleus accumbens shell Adapted from Kalivas and Volkow, Am J Psychiatry 162:8, Aug 2005 Circuits Involved In Drug Abuse and Addiction CONTROL INHIBITORY CONTROL PFC OFC SCC MOTIVATION/ DRIVE ACG NAcc Amyg Hipp VP REWARD MEMORY/ LEARNING 13

14 DA D2 Receptor Availability Prolonged Drug Use Changes The Brain In Fundamental and Long-Lasting Lasting Ways AND We Have Evidence That These Changes Can Be Both Structural and Functional Dopamine D2 Receptors are Lower in Addiction Cocaine DA DA DA DA DA DA DA DA DA DA DA DA Meth Reward Circuits Non-Drug Abuser Alcohol DA DA DA DA DA DA Heroin control addicted Reward Circuits Drug Abuser 14

15 Repeated drug exposure (e.g., via neurotrophic factors, ΔFosB, CREB?) Normal responses to drugs Use-dependent plasticity leading to sensitized responses to drug and environmental cues Nestler, 2001 Chronic cocaine increases density of dendritic spines and neuronal branching in the nucleus accumbens Branches COC 8 CTL COC CTL COC 45 CTL COC CTL Robinson, T.E. & Kolb, B. Eur. J. of Neuro Ferrario, C.R. et al. Biol. Psychiatry, Repeated Drug Abuse Increases Genetic Transcription Resulting in Long-term Structural Changes Dopamine Dendritic Spines Adapted from Nestler E.J. Science & Practice Perspectives, 5(1)

16 AND We Have Evidence That These Changes Can Be Both Structural and Functional Dopamine Transporters in Methamphetamine Abusers Normal Control Dopamine Transporters (Bmax/Kd) Normal Controls Methamphetamine Abuser p < Meth Abusers Methamphetamine abusers have significant reductions in dopamine transporters. BNL - UCLA - SUNY NIDA - ONDCP - DOE Dopamine Transporters in Methamphetamine Abusers Dopamine Transporter Bmax/Kd 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 16

17 Circuits Involved In Drug Abuse and Addiction CONTROL INHIBITORY CONTROL PFC OFC SCC MOTIVATION/ DRIVE ACG NAcc Amyg Hipp VP REWARD MEMORY/ LEARNING We Do Know that the Brain Circuitry Involved in Addiction Has Similarities to that of Other Motivational Systems Cocaine Craving: Population (Cocaine Users, Controls) x Film (cocaine, erotic) Cingulate Signal Intensity (AU) Cocaine Film Ant Cing IFG Controls Cocaine Users Garavan et al A.J. Psych

18 Cocaine Craving: Population (Cocaine Users, Controls) x Film (cocaine, erotic) Cingulate Signal Intensity (AU) Cocaine Film Erotic Film Ant Cing IFG Controls Cocaine Users Garavan et al A.J. Psych 2000 This Results in Motivational Toxicity and Compulsive Drug Use (Addiction) Relapsers and Nonrelapsers Make Decisions Differently MA abusers who relapse after treatment appear to make decisions using different brain regions than those who remain abstinent (90% accuracy) Areas affected: right insula, right inferior parietal lobule, right middle temporal gyrus, left caudate/putamen, left cingulate gyrus Paulus, M. P. et al. Arch Gen Psychiatry 2005;62:

19 Cue-Induced Brain Activity Changes Better Predictor of Relapse in Cocaine-Dependent Patients than Subjective Reports of Craving left precentral cortex left posterior cingulate & right superior temporal cortices right lingual & inferior occipital cortices Kosten et al, Neuropsychopharmacology (2006) 31, Circuits Involved In Drug Abuse and Addiction CONTROL INHIBITORY CONTROL PFC OFC SCC MOTIVATION/ DRIVE ACG NAcc Amyg Hipp VP REWARD MEMORY/ LEARNING Brain Glucose Metabolism in Cocaine Abusers (n = 20) and Controls (n = 23) 60 CG CG micromol/100g/min micromol/100g/min Controls Controls Abusers OFC P < 0.01 Abusers P <

20 Non Addicted Brain Addicted Brain Control STOP Control Saliency Drive Saliency Drive GO Memory Memory Nuclear Circuitry Mediating the Activation of Goal-Directed Behavior Medial dorsal thalamus Ventral pallidum Nucleus accumbens core Prefrontal cortex Enter basal ganglia motor generator Dopamine Glutamate GABA GABA/Neuropeptide Cannabinoid receptors??? Ventral tegmental area Basolateral amygdala Hippocampus Extended amygdala Central amygdala nucleus, bed nucleus of the stria terminalis nucleus accumbens shell Adapted from Kalivas and Volkow, Am J Psychiatry 162:8, Aug 2005 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 20

21 Implication: Brain changes resulting from prolonged use of drugs may be reflected in compromised cognitive functioning Is there recovery? 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 We Need to View and Treat Addiction As A Chronic, Relapsing Illness 21

22 We Have A Variety Of Effective Treatment Options In The Clinical Toolbox Some Behavioral Treatments with a Strong Science Base Behavioral Treatments Contingency Management for MJ Abuse Treatments* Behavioral Treatments Dialectical Behavioral Therapy Drug Counseling for Smoking Cessation Family Treatments Cognitive-Behavioral Group Behavior Therapy Treatment HIV Risk Reduction Combined Motivational Pharmacotherapies and Interviewing/Enhancement* Behavioral Therapies Seeking Safety (PTSD) Work Therapy Multisystemic Therapy Medications Development Methadone Naltrexone Clonidine Buprenorphine Bupropion NRT 22

23 We Have A Variety Of Effective Treatment Options In The Clinical Toolbox But We Need To And Can Do Better Interventions targeting: Reward/Saliency Motivation Relapse (stress, craving, conditioned-cues, other?) Inhibitory Control HIV/AIDS 23

24 Drugs of Abuse Have Had A Major Impact on the HIV/AIDS Epidemic % of Cases Proportions of AIDS Cases in Adults & Adolescents 70 by Exposure in the USA Injection drug use Men who have sex with men (MSM) Heterosexual contact MSM who inject drugs Year of Diagnosis Source: Centers for Disease Control and Prevention (CDC) % of Cases Proportions of AIDS Cases in Adults and Adolescents by Race/Ethnicity in the USA White, not Hispanic Black, not Hispanic Hispanic Asian/Pacific Islander Year of Diagnosis Source: Centers for Disease Control and Prevention (CDC) American Indian/ Alaska Native Drug Addiction Treatment is HIV Prevention 24

25 So What Will Happen with all this research? If a Tree Falls in the Forest, and No One Is Around Does It Really Make a Sound? If Research is Done and Only Published in Peer Reviewed Journals 25

26 that Remain on the Shelves. Community Bedside Bench TRANSLATIONAL BOTTLENECK Source: Hyman, S.E. and Fenton, W.S. Science, 299, pp , January 17,

27 Few Treatment Programs Use Treatment Innovations N=766 public- and private-sector treatment units, Buprenorphine Naltrexone Nicotine Patch Acupuncture Manualized MET Motivational Incentives Source: Roman et al., National Treatment Center Study, 2004 Developing an Evidence-Based-Practice is Only One Piece of the Translation Puzzle Intervention Access & Engagement Organization Structure & Climate Provider Knowledge & Behavior External Environment (stigma, financing) What Are We Doing About All of This? 27

28 Our Strategy Involves BLENDING RESEARCH and PRACTICE Bringing Science-Based Technologies Into Ongoing Community Practice Blending Research and Practice National Drug Abuse NIDA Criminal Treatment Clinical Trials Justice Drug Abuse Network (CTN) Treatment Studies (CJ-DATS) CTN Sites Research Centers Coordinating Center National Drug Abuse Treatment Washington Node U. Washington Oregon Node OHSU California/Arizona Node UCSF/U. Arizona Pacific Node UCLA Ohio Valley Node U. Cincinnati New England Node New York Node Yale NYU Long Island Node Tri state NY State Psych. Inst. U. Pittsburgh Delaware Valley Node U. Pennsylvania Mid-Atlantic Node JHU/MCV North Carolina Node Duke Northern NE Node McLean/Harvard Southwest Node U. New Mexico Texas Node UT Southwestern South Carolina Node MUSC Florida Node U. Miami A research infrastructure of 17 RRTCs & 240 CTPs across 34 States, and Puerto Rico 28

29 CJ-DATS Update Criminal Justice Drug Abuse Treatment Studies 6 studies in the field focused on: Reducing HIV risk behavior 9 Research Centers 1 Coordinating Center Screening for mental illness Transitioning from prison to community 2 juvenile justice studies being developed Community re-entry entry and HIV risk behaviors 2 HIV studies being developed: Men Women NIDA NATIONAL INSTITUTE ON DRUG ABUSE U.S. Department of Health & Human Services SAMHSA Partnerships Are Essential In Advancing the Science of Addiction and in Translating Promising Strategies into Practice NIJ Blending Research and Practice Science to Services Initiative SAMHSA CSAT CSAP CMHS NIH NIDA NIAAA NIMH 29

30 NIDA/SAMHSA Blending Initiative The Blending Initiative encompasses three primary components: NIDA Research SAMHSA Programs Blending Conferences Blending Teams State Agency Partnerships Researcher- Policy-Maker- Provider Dialogue: Inform clinical trials & share research results Research Dissemination & Application: A Recipe for Success One part CSAT One part NIDA A pinch of $$ Ok a few more $$$ Some TLC A dash of luck Shake vigorously and. SAMHSA/CSAT Addiction Technology Transfer Centers (ATTCs) ATTCs Puerto Rico Puerto Rico ATTC As of July 11,

31 NIDA/SAMHSA Blending Process Research Findings Hand-Off Meeting Create the charge for the Blending Team, based on research results and how it can address critical needs in the treatment field Blending Team Goal is to develop dissemination strategies & products. Each Blending Team is composed of 3 ATTC members & 3 NIDA members Dissemination Products are Released at the Same Time Research is Published Five Blending Teams 1) Buprenorphine Treatment: A Training for Multidisciplinary Addiction Professionals 2) Short-Term Opioid Withdrawal Using Buprenorphine 3) Utilizing the Addiction Severity Index (ASI) 4) Motivational Interviewing Assessment: Supervisory Tools for Enhancing Proficiency (MIA-STEP) 5) Promoting Awareness of Motivational Incentives (PAMI) Second Component: Blending Teams Current Status of Product Development 1) Buprenorphine Treatment 2) Buprenorphine Detoxification 3) Addiction Severity Index (ASI) 4) Motivational Interviewing (MI) 5) Promoting Awareness of Motivational Incentives (PAMI) Expected completion date: Fall 2006 Expected completion date: Winter 2006 Team Assigned Hand-Off Meeting Blending Team Meeting Product Development Product Revisions Final Approval Dissemination 31

32 NIDA NATIONAL INSTITUTE ON DRUG ABUSE U.S. Department of Health & Human Services SAMHSA Partnerships Are Essential In Advancing the Science of Addiction and in Translating Promising Strategies into Practice NIDA s Networking Initiative S P P P S S S S P P S P S CTN Sites CEWG P CJ-DATS Multi-Site Prevention Trials NGC SATH- CAPs S State Grants TPRCs TTURCs ATTCs Puerto Rico Puerto Rico ATTC As of July 11, 2006 Priority Areas for NIDA Prevention Research (Children and Adolescents) genetics development environment co-morbidity Treatment Interventions (New Targets) HIV/AIDS Research Translating Research into Practice 32

33 We Need Addiction Medicine to Continue to Study Drug Abuse & Addiction at All Levels and to Help Ensure that Promising Strategies Are Adopted in Clinical Practice Official Journal of the AMERICAN PSYCHIATRIC ASSOCIATIO N Volume 162 Number 8 August 2005 Where Do We Need to Go From Here? We Need to Work TOGETHER to Advance the SCIENCE and to STIGMA Erase the STIGMA Visit Our 33

34 Addiction is the Quintessential Biobehavioral Disorder 34