Transdisciplinary Addiction Science GMS MS710

Course Syllabus Thursdays 10AM-12PM

E201 Description: This introductory course will cover the broad field of addiction with a focus on drug dependence. In one segment of the course, students will learn about the spectrum of drug dependence disorders and modalities for diagnosis and treatment. Another segment will present a wide variety of approaches for studying addiction using the tools of epidemiology, genetics, pharmacology, neurobehavior, and animal models. Emphasis will be placed on transdisciplinary approaches which are essential for understanding and combating addiction disorders. In addition, students will be exposed to the impact of addiction on the family and society, and to public policy issues addressing the prevention of addiction. Lecture Series Overview 1. Introduction / History of Addiction Research - Lindsay Farrer / Conan Kornetsky

2. Epidemiology of Addiction - Tim Heeren

3. Genetic Basis of Addiction - Lindsay Farrer

4. Current Approaches in Diagnosis & Treatment of Substance Use Disorders - Alexander

Walley

5. Neurobehavioral & Neuroimaging Studies of Alcoholism - Marlene Oscar Berman

6. Animal Models of Addiction - Kathleen Kantak

7. Neurochemistry & Neurobiology of Addiction - Pietro Cottone / Valentina Sabino

8. Russian Addiction (Narcology) Services – Efforts to Improve Patient HIV-Related

Outcomes - Jeffrey Samet

9. Development of Pharmacological Treatments for Substance Use Disorders - Gary Kaplan

10. Impact of Drug Addiction on Family & Society - Lena Lundgren

11. Clinical Trials for Addiction Disorders - Richard Saitz

12. Prevention of Addiction - Michael Siegel

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Lecture Outlines

Lecture 1 (September 4): Introduction / History of Addiction Research Lindsay A. Farrer, Ph.D., Chief, Biomedical Genetics Professor of Medicine, Neurology, Ophthalmology, Epidemiology, and Biostatistics

Conan Kornetsky, Ph.D. Professor of Pharmacology & Experimental Therapeutics

Summary: This lecture will introduce the students to addiction as it pertains to diagnosis, treatment, research, and public policy. Insight into contemporary approaches in these domains will be provided by historical analysis.

Objectives: To give to the student some understanding of the history and attitudes and beliefs of drug abuse through the years by both the lay public and investigators.

Outline: 1. Introduction

a) Overview of course and learning objectives b) Class organization c) Evaluation and grading

2. A History of Drug Addiction Opium

a) The opium poppy b) Clinical and non-clinical use c) Early users (1875-1939)

Cocaine a) Early conclusions about addiction b) The Narcotic Farm c) Historical views of addiction, circa 1960’s

Juvenile addiction NY City 3. Animal models in the study of drug addiction

a) Drug self-administration in animals, the operant condition model and the role of the brain reward system.

Required Readings:

- Wikler, A. A Psychodynamic Study of a Patient During Experimental Self-Regulated Re-addiction to Morphine Psychiatric Quarterly, 26:270-293, 1952

- Yale Reports. The Doctor and the Treatment of Narcotic Addiction –Daniel X. Freedman, Conan Kornetsky and Vincent Dole, 2/6/66.

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Lecture 2 (September 11): Epidemiology of Addiction

Tim Heeren, Ph.D. Professor of Biostatistics Boston University School of Public Health Summary: This lecture will first give a brief overview of some of the goals, strengths, and weaknesses of addictions-related epidemiologic research. Then, focusing of a few studies, we will discuss early predictors of substance use problems in early adulthood. Finally, we will take a look at some statistical methods currently being used in epidemiologic studies of substance use and substance use disorders.

Objectives:

1. To provide an introduction to epidemiological research into substance use and substance use disorders.

2. To provide an overview into early life predictors of substance use disorders in early adulthood.

3. To provide an overview of some current methods in epidemiological research into substance use disorders

Outline:

1. Overview: the use of epidemiology in alcohol and substance use research 2. Case studies: epidemiological studies of substance use disorders in emerging and early

adulthood a. Prenatal alcohol exposure b. Early life predictors of adult drinking c. Age of onset and substance use disorders 3. Case studies: current methods in epidemiological substance use research a. Drinking trajectories b. Latent class analysis of alcohol use disorder criteria c. Structural equation modeling of the relationship between impulsivity and alcohol misuse

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Required Readings:

- Rossow I and Norstrem T. The use of epidemiology in alcohol research. Addiction, 108:20-25, 2012.

- Stone AL, Becker LG, Huber AM, Catalano RF. Review of risk and protective factors of substance use and problem use in emerging adulthood. Addictive Behaviors, 37:747-775, 2012.

Suggested Readings:

- Alati R, Mamun AA, Williams GM, O’Callaghan M, Najman JM, Bor W. In utero alcohol exposure and prediction of alcohol disorders in early adulthood: a birth cohort study. Arch Gen Psychiatry, 63:1009-1016, 2006.

- Alati R, Najman JM, Kinner SA, Mamun AA, Williams GM, O’Callaghan M, Bor W. Early predictors of adult drinking: a birth cohort study. American Journal of Epidemiology, 162(11):1098-1107, 2005.

- King KM and Chassin L. A prospective study of the effects of age of initiation of alcohol and drug use on young adult substance dependence. J Stud Alcohol Drugs, 68:256-265, 2007.

- Maggs JL and Schulenberg JE. Trajectories of alcohol use during the transition to adulthood. Alcohol Research and Health, 28(4):195-201, 2005.

- Beseler CL, Taylor LA, Kraemer DT, Leeman RF. A latent class analysis of DSM-IV alcohol use disorder criteria and binge drinking in undergraduates. Alcoholism: Clinical and Experimental Research, 36(1):153-161, 2012.

- Courtney KE, Arellano R, Barkley-Levenson E, Galvan A, Poldrack RA, MacKillop J, Jentsch JD, Ray LA. The relationship between measures of impulsivity and alcohol misuse: an integrative structural equation modeling approach. Alcoholism: Clinical and Experimental Research, 36(6):923-931, 201

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Lecture 3 (September 18): Genetic Basis of Addiction Lindsay A. Farrer, Ph.D. Chief, Biomedical Genetics Professor of Medicine, Neurology, Ophthalmology, Epidemiology and Biostatistics

Summary: This lecture will explore the genetic basis for addiction in humans. The session will begin with a discussion of the evidence from family and twin studies for the genetic component to dependence on various substances including nicotine, alcohol, cocaine, opioids and cannabis. There will be some didactic on methodologies for genetic linkage and association studies including genome-wide association studies. This will be followed by a demonstration of how these approaches have been applied in substance dependence with a focus on phenotype definition and discussion of qualitative versus quantitative trait outcomes. Finally, the lecture will introduce contemporary genetics research approaches in addictions including next generation sequencing and bioinformatics.

Objectives: At the end of the session, students will be able to:

- Describe methodologies for determining the strength of the genetic component for addictions;

- Differentiate the strengths and limitations for genetic linkage, candidate gene association, GWAS and next generation sequencing approaches to identify genes for addiction;

- Articulate principles for family-based and case-control designs for genetic discovery in the addictions;

- Read and understand scientific papers focused on these topics.

Outline: 1. Review of basic principles of genetics

a. Mendelian Inheritance b. Complex Inheritance c. Quantitative traits d. Linkage and association

2. Twin studies of addiction 3. Candidate gene studies of addiction 4. Genome-wide association studies of addiction

Required Readings:

- Tsuang, M.T., Lyons, M.J., Eisen, S.A., Goldberg, J, True, Lin N, W, Meyer, J.M., Tooney R, Faraone SV, and Eaves, L. Genetic influences on DSM-III-R drug abuse and dependence: A study of 3,372 twin pairs. Am J Med Genet (Neuropsych. Genet) 1996;67:473-477

- Agrawal A, Verweij KJ, Gillespie NA, Heath AC, Lessov-Schlaggar CN, Martin NG, Nelson

EC, Slutske WS, Whitfield JB, Lynskey MT. The genetics of addiction-a translational perspective. Transl Psychiatry. 2012 Jul 17;2:e140. doi: 10.1038/tp.2012.54.

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- Wang JC, Kapoor M, Goate AM. The genetics of substance dependence. Annu Rev Genomics Hum Genet. 2012;13:241-261

Suggested Readings:

- Gelernter J, Yu Y, Weiss R, Brady K, Panhuysen C, Yang B, Kranzler HR, Farrer LA. Haplotype spanning TTC12 and ANKK1, adjacent to the DRD2 locus, is strongly associated to nicotine dependence din two distinct American populations. Human Molecular Genetics 2006; 15:3498-3507.

- Panhuysen CI, Kranzler HR, Yu Y, Weiss RD, Brady K, Poling J, Farrer LA, Gelernter J. Confirmation and generalization of an alcohol dependence locus on chromosome 10q. Neuropsychopharmacology 2010; 35:1325-1332

- Haller G, Druley T, Vallania FL, Mitra RD, Li P, Akk G, Steinbach JH, Breslau N, Johnson E, Hatsukami D, Stitzel J, Bierut LJ, Goate AM. Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence. Hum Mol Genet. 2012; 21:647-655

- Xie P, Kranzler HR, Krystal JH, Farrer LA, Zhao H, Gelernter J. Deep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence. Addiction Biology 2014; 19:955-964.

- Gelernter J, Kranzler HR, Sherva R, Almasy L, Koesterer R, Anton R, Preuss UW, Ridinger M, Rujescu D, Wodarz N, Zill P, Han S, Zhao H, Farrer LA. Genomewide association study of alcohol dependence: Significant findings in African- and European-Americans including numerous novel risk loci. Molecular Psychiatry 2014; 19:41-49.

- Gelernter J, Sherva R, Koesterer R, Zhao H, Kranzler HR, Farrer LA. Genomewide association

study of cocaine dependence and related traits: FAM53B identified as a risk gene. Molecular Psychiatry 2014; 19:717-723.

- Gelernter J, Kranzler HR, Sherva R, Koesterer R, Sun J, Bi J, Almasy L, Zhao H, Farrer LA.

Genomewide association study of opioid dependence and related traits: multiple associations mapped to calcium and potassium pathways. Biological Psychiatry 2014; 76:66-74.

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Lecture 4 (September 25): Current Approaches in Diagnosis & Treatment of Substance Use Disorders

Alexander Y. Walley, MD, MSc Assistant Professor of Medicine Clinical Addiction Research and Education Unit, General Internal Medicine Boston University School of Medicine

Summary: This lecture will review the diagnostic criteria and current treatment approaches for for substance use disorders. Treatment approaches include existing evidence-based behavioral therapy and FDA-approved medications. The lecture will also include an introduction to treatment delivery systems..

Objectives:

1) Learners will be able to list the current diagnostic criteria for substance use disorders 2) Learners will understand the existing clinical treatment approaches for substance use

disorders, including alcohol, opioids, stimulants, and benzodiazepines

Outline:

1. Diagnostic criteria for substance use disorders – DSM IV and V 2. Alcohol Disorders

a. Behavioral Treatment b. Pharmacological Treatment

3. Opioid Disorders a. Maintenance treatment with methadone b. Maintenance treatment with buprenorphine c. Naltrexone treatment

4. Stimulant Disorders a. Cocaine b. Methamphetamine c. Contingency management

5. Benzodiazepine Disorders a. Medically managed withdrawal treatment (detoxification)

6. Polysubstance Disorders

Required Readings:

- Helping Patients Who Drink Too much: A Clinician’s Guide. www.niaaa.nih.gov/guide - McLellan TA et al. Drug Dependence: A Chronic Medical Illness. JAMA 2000 284: 1689-

95. - Prendergast M, Podus D, Finney J, Greenwell L, Roll J. Contingency management for

treatment of substance use disorders: A meta-analysis. Addiction. 2006;101(11):1546-1560.

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Supplemental Reading

- Saitz R. Unhealthy Alcohol Use. N Engl J Med 2005;352:596-607. - McLellan, AT et.al , JAMA 1993 - Johnson RE et al. NEJM 343:1290-7, 2000 - Krupitsky E, et al. Lancet, 2011 - Wu LT, Blazer DG, Patkar AA, Stitzer ML, Wakim PG, Brooner RK. Heterogeneity of

stimulant dependence: A national drug abuse treatment clinical trials network study. Am J Addict. 2009;18(3):206-218.

- Vocci FJ, Montoya ID. Psychological treatments for stimulant misuse, comparing and contrasting those for amphetamine dependence and those for cocaine dependence. Curr Opin Psychiatry. 2009.

- Mendelson JH, Mello NK. Management of cocaine abuse and dependence. N Engl J Med. 1996;334(15):965-972.

- Lineberry TW, Bostwick JM. Methamphetamine abuse: A perfect storm of complications. Mayo Clin Proc. 2006;81(1):77-84.

- Lee NK, Rawson RA. A systematic review of cognitive and behavioural therapies for methamphetamine dependence. Drug Alcohol Rev. 2008;27(3):309-317.

- Denis C, Fatséas M, Lavie E, Auriacombe M. Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings. Cochrane Database Syst Rev. 2006 Jul 19;(3):CD005194

- Barker MJ, Greenwood KM, Jackson M, Crowe SF. Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: A meta-analysis. Arch Clin Neuropsychol. 2004;19(3):437-454.

- Leri F, Bruneau J, Stewart J. Understanding polydrug use: Review of heroin and cocaine co-use. Addiction. 2003;98(1):7-22.

- Pennings EJ, Leccese AP, Wolff FA. Effects of concurrent use of alcohol and cocaine. Addiction. 2002;97(7):773-83.

- Peirce JM, Petry NM, Stitzer ML, et al. Effects of lower-cost incentives on stimulant abstinence in methadone maintenance treatment: A national drug abuse treatment clinical trials network study. Arch Gen Psychiatry. 2006;63(2):201-208.

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Lecture 5 (October 2): Neurobehavioral and Neuroimaging Studies of Alcoholism

Marlene Oscar Berman, Ph.D. Professor of Neurology, Psychiatry, and Anatomy & Neurobiology; Director, Ph.D. Program in Behavioral Neuroscience; Research Career Scientist, VA Boston Healthcare System

Summary: Issues and models proposed to explain the multiple neuropsychological effects of alcoholism-related brain damage will be reviewed together with research findings relevant to three such models: Premature Aging; Right Hemisphere Dysfunction; and Frontal Lobe Dysfunction. Our research with chronic long-term alcoholic individuals has shown the following:

• There is evidence of “accelerated aging” in brain function and structure. • Perceptual processing deficits (with neutral stimuli) are no greater for the right

hemisphere (RH) than for the left hemisphere (LH). However, (a) tests of emotional functions, and (b) structural neuroimaging measures may be sensitive to RH deficits.

• Frontal brain systems are vulnerable to the effects of alcoholism. • Neuroimaging measures highlight the importance of considering brain networks affected

by alcoholism. • By some measures, alcoholism appears to affect men and women differently.

Objectives: At the end of the session, students will be able to:

1. understand the complexity of alcoholism-related brain damage and its effects on mental functions; 2. appreciate the importance of individual differences when considering the effects of long-term chronic alcoholism; 3. learn how changes in the brain are reflected in behavioral abnormalities.

Outline:

PART I. BACKGROUND • Definitions and Concepts • A Sampling of Deficits Observed in Association with Alcoholism • Right Hemisphere Deficits • Frontal System Deficits • Three Hypotheses We Have Tested: • Premature Aging • Right Hemisphere Hypothesis • Frontal System Hypothesis

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• Final Conclusions PART II. RESEARCH • Characteristics of the Research Participants: Alcoholics with and without Korsakoff’s Syndrome • Experimental Approaches to Testing the Hypotheses

• Behavioral Studies: Comparative Neuropsychology Tasks;. • Dichotomous Stimulation Techniques; Emotional Tasks

• Neuroimaging Studies: fMRI, Structural MRI, DT-MRI • Final Conclusions Repeated

Required Readings:

- Oscar-Berman, M., Valmas, M.M., Sawyer, K.S., Ruiz, S.M., Luhar, R.B., & Gravitz, Z.R. (2013). Profiles of impaired, spared, and recovered neuropsychological processes in alcoholism. In A. Pfefferbaum & E.V. Sullivan (Eds), Alcohol and the Nervous System. Handbook of Clinical Neurology 3rd Series. New York: Elsevier (in press).

- Oscar-Berman, M. (2012). Function and dysfunction of prefrontal brain circuitry in alcoholic Korsakoff’s syndrome. Neuropsychology Review, 22(2), 154-169. DOI 10.1007/s11065-012-9198-x

Suggested Readings:

- Oscar-Berman, M. (2010). Comparative neuropsychology. In: The Corsini Encyclopedia of Psychology, I. B. Weiner & W.E. Craighead, Eds. NY: Wiley, pp. 365-366.

- Oscar-Berman, M. & Marinkovic, K. (2007). Alcohol: Effects on neurobehavioral functions and the brain. Neuropsychology Review, 17, 239-257. DOI: 10.1007/s11065-007-9038-6

- Ersche, Karen D. & Sahakian, Barbara J. (2007).The Neuropsychology of amphetamine and opiate dependence: Implications for treatment. Neuropsychology Review, 17, 317-336. DOI 10.1007/s11065-007-9033-y

- Roussotte, Florence, Soderberg, Lindsay & Sowell, Elizabeth, (2010). Structural, metabolic, and functional brain abnormalities as a result of prenatal exposure to drugs of abuse: Evidence from neuroimaging. Neuropsychology Review, 20, 376-397. DOI 10.1007/s11065-010-9150-x

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Lecture 6 (October 9): Animal Models of Addiction

Kathleen M. Kantak, PhD. Director Laboratory of Behavioral Neuroscience

Department of Psychological and Brain Sciences Summary: This lecture will explore the methods commonly used to study drug addiction in preclincal animal models ranging from fruit flies to non-human primates. Particular attention is paid to how different phases of the addiction cycle are modeled in animals. Objectives: 1. To acquire basic knowledge of a variety of behavioral approaches to study drug addiction in

animals. This will prepare students for the upcoming lectures on the neurochemistry, neurobiology and pharmacology of addiction.

2. To gain perspectives on the advantages and limitations of each species used in the preclinical

assessment of drug addiction. 3. To instill an appreciation for the translational relevance of the addiction cycle, as studied in

animals, to the human condition. Outline:

1. Common behavioral approaches a) Self-Administration b) Conditioned Place Preference c) Intracranial Self-Stimulation d) Conditioned Reinforcement, Tolerance and Withdrawal

2. Model organisms for addiction research a) Drosophila b) Zebrafish c) Mice d) Rats e) Monkeys

3. Modeling the addiction cycle in animals a) Acquisition b) Maintenance c) Escalation d) Extinction e) Relapse/Craving

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Required Readings: - O'Brien CP, Gardner EL. Critical assessment of how to study addiction and its treatment:

human and non-human animal models. Pharmacol Ther. 2005;108:18-58

Suggested Readings: - Kaun KR, Devineni AV, Heberlein U. Drosophila melanogaster as a model to study drug

addiction. Hum Genet.131:959-75. - Klee EW, Schneider H, Clark KJ, Cousin MA, Ebbert JO, Hooten WM, et al. Zebrafish: a

model for the study of addiction genetics. Hum Genet.131:977-1008.

- Fowler CD, Kenny PJ. Utility of genetically modified mice for understanding the neurobiology of substance use disorders. Hum Genet.131:941-57.

- O'Connor EC, Chapman K, Butler P, Mead AN. The predictive validity of the rat self-administration model for abuse liability. Neurosci Biobehav Rev.35:912-38.

- Weerts EM, Fantegrossi WE, Goodwin AK. The value of nonhuman primates in drug abuse research. Exp Clin Psychopharmacol. 2007;15:309-27.

- Sanchis-Segura C, Spanagel R. Behavioural assessment of drug reinforcement and addictive features in rodents: an overview. Addict Biol. 2006;11:2-38.

- Crabbe JC, Harris RA, Koob GF. Preclinical studies of alcohol binge drinking. Ann N Y Acad Sci.1216:24-40.

- Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, Markou A, et al. Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2004;27:739-49.

- Nic Dhonnchadha BA, Kantak KM. Cognitive enhancers for facilitating drug cue extinction: insights from animal models. Pharmacol Biochem Behav.99:229-44.

- Epstein DH, Preston KL, Stewart J, Shaham Y. Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology (Berl). 2006;189:1-16.

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Lecture 7 (October 16): Neurochemistry and Neurobiology of Addiction

Pietro Cottone, Ph.D. Assistant Professor of Pharmacology & Experimental Therapeutics and Psychiatry Laboratory of Addictive Disorders

Valentina Sabino, Ph.D. Assistant Professor of Pharmacology & Experimental Therapeutics and Psychiatry

Summary:

This lecture will provide information about the molecular mechanisms of action of the most common drugs of abuse. Neurocircuitries involved in the different stages of drug addiction will be described, with a focus on the neurochemical and molecular changes taking place in the transition to dependence.

Objectives: At the end of the session, students will be able to:

1. Describe the mechanism of action of psychostimulants, opiates, alcohol, and cannabinoids

2. Describe the neuroanatomy and neurochemistry of drug addiction. 3. Explain the neurochemical and molecular adaptations characterizing the transition to

dependence.

Outline:

1. Addiction Definitions: Drug Use, Abuse, Dependence, Addiction 2. Classification of drugs of abuse 3. Mesolimbic system and reward neurotransmission 4. Mechanism of action of most common drugs of abuse (psychomotor stimulants, opiates,

alcohol, cannabinoids) 5. Transition to addiction and stages of the addiction cycle 6. Molecular neuroadaptations in addiction 7. Animal models

Required Readings:

- Neurocircuitry of addiction. Koob GF, Volkow ND. Neuropsychopharmacology (2010); 35(1): 217-38.

- Experimental psychiatric illness and drug abuse models: from human to animal, an overview. Edwards S, Koob GF. Methods Mol Biol. (2012); 829: 31-48.

Suggested Reading:

- Neurobiology of Addiction, by George F. Koob and Michel Le Moal, 2006, Elsevier, Inc., London.

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Midterm Exam – October 23 Lecture 8 (October 30): Russian Addiction (Narcology) Services –

Efforts to Improve Patient HIV-Related Outcomes Jeffrey Samet, M.D., M.A., M.P.H. Chief, General Internal Medicine Professor of Medicine and Community Health Science

Summary: This lecture will explore the linked epidemiology of substance use and HIV in Russia and the structural barriers preventing adequate treatment. Dr. Samet will also describe his research on substance use and HIV-risk reduction in Russia, including an intervention to coordinate HIV and addiction care in St. Petersburg.

Objectives: At the end of this lecture, learners will be able to:

1. Define narcology and describe its history in Russia; 2. Recognize how substance abuse has contributed to the Russia HIV epidemic; and 3. Describe research that aims to reduce sex and drug risk in people who inject drugs

(PWID) in Russia.

Outline: 1. Russian Narcology

a. Definition b. History c. Legislation d. Registration e. Structure of narcology treatment

2. Process for treatment a. Inpatient/outpatient treatment b. Other rehabilitation services c. Pharmacotherapy d. Barriers to addiction treatment e. Linkage to Infectious Diseases specialty

3. Russia HIV Epidemic a. Timeline b. Prevalence and effect of injection drug and alcohol use c. Treatment and engagement of IDUs d. Recommendations to enhance the care of HIV-infected IDUs

4. HIV, alcohol, and drug use research in Russia: St. Petersburg/Boston collaboration a. HIV Seroprevalence b. LINC: Linking Infectious and Narcology Care c. PREVENT: Partnership to Reduce the Epidemic Via Engagement in Narcology

Treatment

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d. HERMITAGE: HIV’s Evolution in Russia – Mitigating Infection Transmission and Alcoholism in a Growing Epidemic

e. ARCH/ZINC Optional Readings: Samet JH. Russia and human immunodeficiency virus--beyond crime and punishment. Addiction. 2011 Nov;106(11):1883-5. Degenhardt L, Mathers B, Vickerman P, Rhodes T, Latkin C, Hickman M. Prevention of HIV infection for people who inject drugs: why individual, structural, and combination approaches are needed. Lancet. 2010 Jul 24;376(9737):285-301.

Lecture 9 (November 6): Development of Pharmacological Treatments in Addiction

Gary B. Kaplan, MD, Professor of Psychiatry and Pharmacology & Experimental Therapeutics, Boston University School of Medicine; Director of Mental Health, VA Boston Healthcare System

Summary: This lecture will explore the pharmacological basis for addiction treatment. The lecture begins with a review of the role of drug agonists, antagonists, and inverse agonists and their role in addiction pharmacotherapy. This will be followed by a discussion of the application of pharmacological treatment at the difference phases of substance use disorders. It focuses on the different receptor and neurotransmitter targets for addiction pharmacotherapy. Finally, it describes how synaptic and structural plasticity in addiction are relevant to future medication development in addiction. Objectives: At the end of the session, students will be able to:

- Understand how basic pharmacological approaches for drug agonists, antagonists, inverse agonists relate to addiction treatment

- Understand how pharmacological agents can be applied at different phases of addiction treatments such as withdrawal, maintenance and relapse prevention

- Describe the different targets for addiction pharmacotherapy at GABA, glutamate, and opioid receptors and at different ion channels

- Explain how changes in synaptic plasticity in key neuroanatomical pathways represent targets for future addiction pharmacotherapy

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Outline:

2. Understanding Basic Pharmacology and its Translation to Addiction Pharmacotherapy 3. Use of Drug Agonists, Partial Agonists and Antagonists in Addiction 4. Overdose reversal 5. Detoxification 6. Drug Substitution 7. Drug Antagonists 8. Aversive pharmacology (disulfiram) 9. Anti-craving agents 10. New Treatments Based on Glutamargic Transmission 11. New Treatments Based on GABAergic Transmission 12. Novel Treatments Based on Ion Channel Transmission 13. Synaptic Plasticity in Addiction and Novel Targets

Required Readings

- Kalivas PW, Volkow ND, New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry. 2011 Oct;16(10):974-86. doi: 10.1038/mp.2011.46.

- O'Brien CP. Review. Evidence-based treatments of addiction. Philos Trans R Soc Lond B Biol Sci. 2008 Oct 12;363(1507):3277-86. doi: 10.1098/rstb.2008.0105.

- Addolorato G, Leggio L, Hopf FW, Diana M, Bonci A. Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation. Neuropsychopharmacology. 2012 Jan;37(1):163-77. PMID: 22030714

Supplemental Readings

- Lüscher C, Malenka RC (2011): Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69: 650-663.

- Vocci FJ, Acri J, Elkashef A. Medication development for addictive disorders: the state of the science. Am J Psychiatry. 2005 Aug;162(8):1432-40. PMID: 16055764

- Kaplan GB, Heinrichs S, Carey RC (2011). Treatment of addiction and anxiety using extinction approaches: neural mechanisms and their treatment implications, Pharmacol Biochem Behav 97:619–625, 2011

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Lecture 10 (November 13): Impact of Drug Addiction on Family & Society

Lena Lundgren, MA, PhD. Associate Dean for Research Professor, Social Welfare Policy Boston University School of Social Work

Summary: This lecture will (1) review national data estimating the economic and social impact of alcohol and drug addiction; (2) describe disparities in access and use of treatment and the national “treatment gap”; (3) discuss how health professionals’ lack of training in empirically supported assessment and treatment methods affect the treatment gap; and, (4) describe recent policy and research efforts to reduce the treatment gap.

Objectives: 1. To provide an understanding of consequences of addiction at the national level. 2. To increase awareness about disparities in access/use of addiction treatment.

To increase knowledge of about the addiction health services research field, “real world research

Outline: 1. The economic and social cost of alcohol and drug addiction to the US. Review of

national level research including cost estimates on: a) Impact on the health care system b) Impact on family and child wellbeing c) Impact on Education d) Impact on Mental Health e) Impact on the Work Place

2. Consequences of alcohol and drug addiction for clinical work: a) Clinicians in these settings (health, child-welfare, mental health, work-place) will

continuously encounter and work with families and individuals with substance use disorders.

b) Clinicians need training in science based assessment and treatment. 3. Current Limitations affecting treatment utilization:

a) Need and availability of addiction treatment, a review of national data on number of individuals in need of addiction treatment and availability of addiction treatment slots.

b) Disparate access to treatment by racial/ethnic groups, income and employment. c) The Treatment Gap and how the Affordable Care Act may affect the treatment

gap. d) Limits in staff and organizational capacity to effectively implement science-based

assessment and treatment methods. e) Not enough RCTs, not enough RCT based methods implementable in “real world

settings.” 4. Next Steps for Addiction treatment utilization research and clinical implementation of

science- based assessment and treatment.

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Required Reading: - Rehm, J., Mathers, C., Popova, S., Thavorncharoensap, M., Teerawattananon, Y., & Patra, J.,

(2009). Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. The Lancet, 373(9682), 2223-2233.

- Bouchery, Hardwood, Sacks, Simon & Brewer, (2011) Economic cost of Excessive Alcohol

Consumption in the US. American Journal of Preventive Medicine. http://www.ajpmonline.org/article/S0749-3797(11)00538-1/fulltext

- National Drug Intelligence Center. (2011). The economic impact of illicit drug use on

American society. Retrieved from http://www.justice.gov/archive/ndic/pubs44/44731/44731p.pdf.

- Office on Child Abuse and Neglect, Children's Bureau.(2009). Protecting Children in

Families Affected by Substance Use Disorders. https://childwelfare.gov/pubs/usermanuals/substanceuse.cfm.

Recommended reading - Centers for Disease Control and Prevention. (2008). Smoking-attributable mortality, years of

potential life lost, and productivity losses—United States, 2000-2004. Morbidity and Mortality Weekly Report, 57(45), 1226-1228.

- National Institute on Drug Abuse. (2011). DrugFacts: Understanding drug abuse and

addiction. Retrieved from http://www.drugabuse.gov/publications/drugfacts/understanding-drug-abuse-addiction

- Lundgren, L., Chassler, D., Amodeo, M., D’Ippolito, M., Sullivan, L. (2012). Barriers to

implementation of evidence-based addiction treatment: A national study. Journal of Substance Abuse Treatment, 42, 231 – 238.

- McCarty, D., McConnell & Schmidt. (2010). “Priorities for Policy Research on Treatments

for Alcohol and Drug Use Disorders.” Journal of Substance Abuse Treatment, 87–95. - McLellan, T., Chalk, M., and Bartlett, J. (2007). Outcomes, performance and quality—

What’s the difference? Journal of Substance Abuse Treatment, 32:331-40. - McLellan, T., Carise, D., and Kleber, H. (2003). Can the national addiction treatment

infrastructure support the public’s demand for quality care? Journal of Substance Abuse Treatment, 25:117-21.

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Lecture 11 (November 20): Clinical Trials for Addiction Disorders

Richard Saitz MD, MPH Director, CARE Unit, Section of Internal Medicine, Boston Medical Center Professor of Medicine and Epidemiology

Summary: This lecture will describe and critically appraise clinical trials of treatments for people with addictions. Key examples and design issues will be reviewed.

Objectives:

1) Learners will become familiar with several examples of addiction clinical trials 2) Learners will gain skills in critical appraisal of addiction clinical trials 3) Learners will be able to list the key design issues relevant to addiction clinical trials

Outline:

1. Review of examples of addiction clinical trials 2. Principles of critical appraisal

a. Validity b. Results c. Generalizability

3. Critical appraisal of an addiction clinical trial 4. Special challenges in studying addiction treatments

a. Surrogate outcomes b. Anonymity/confidentiality c. Motivation to change

5. Key design issues a. Experimental design b. Participant selection c. Intervention fidelity d. Control groups e. Blinding f. Follow-up g. Outcomes h. Effectiveness versus efficacy

6. Exercise: design a trial

Required Readings:

- Guyatt, Gordon H. Sackett, David L.Cook, Deborah J. User's Guides to the Medical Literature: II. How to Use an Article About Therapy or Prevention: A. Are the Results of the Study Valid? JAMA. 270(21):2598-2601, December 1, 1993.

- Guyatt, Gordon H. MD, MSc. Sackett, David L. MD, MSc. Cook, Deborah J. MD, MSc. for the Evidence-Based Medicine Working Group. User's Guides to the Medical Literature: II. How to Use an Article About Therapy or Prevention: B. What Were the

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Results and Will They Help Me in Caring for My Patients? JAMA. 271(1):59-63, January 5, 1994.

- Anton RF, O’Malley SS, Ciraulo DA, et al. Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence: The COMBINE Study: A Randomized Controlled Trial. JAMA. 2006;295(17):2003-2017. doi:10.1001/jama.295.17.2003.

Supplemental Readings:

- Bucher HC. Guyatt GH. Cook DJ. Holbrook A. McAlister FA. Users' Guides to the Medical Literature XIX. Applying Clinical Trial Results A. How to use an Article Measuring the Effect of an Intervention on Surrogate End Points. JAMA. 282(8):771-778, August 25, 1999.

- Dans AL. Dans LF. Guyatt GH. Richardson S. Users' Guides to the Medical Literature: XIV. How to Decide on the Applicability of Clinical Trial Results to Your Patient. JAMA. 279(7):545-549, February 18, 1998.

- Kaner E, Bland M, Cassidy P, Coulton S, Dale V, Deluca P et al. Effectiveness of screening and brief alcohol intervention in primary care (SIPS trial): pragmatic cluster randomised trial. BMJ 2013: 346: e 8501

- Saitz R, Cheng DM, Winter M et al. Chronic care management for dependence on alcohol and other drugs. The AHEAD randomized trial. In press.

NO CLASS (November 27) – Thanksgiving vacation

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Lecture 12 (December 4): Research, Advocacy, and Policy in Addiction Prevention: From Tobacco to Alcohol

Michael Siegel, MD, MPH Professor, Department of Social and Behavioral Sciences Boston University School of Public Health

Summary: This session will investigate the role of research in understanding policies that can be most effective in preventing youth addiction to tobacco and alcohol. Drawing on the field of research on tobacco advertising, the session will start with a case study of national cigarette advertising policy. It will describe limitations in the research on the effect of cigarette advertising on youth smoking and how a new area of research was developed to overcome these limitations. It will explain how the results of this new line of research helped lead to the adoption of national policies to reduce youth exposure to cigarette advertising. It will then consider how these methods can be translated to the alcohol field. Finally, it will address the role of research in policy development in the field of addiction prevention.

Objectives: At the end of the session, students will be able to:

- Describe the limitations in the current research on the relationship between alcohol advertising and underage youth drinking behavior;

- Articulate a research strategy to overcome the limitations of current research on alcohol advertising effects on youth, drawing on the example of the tobacco advertising literature;

- Explain the role of research in the development and implementation of evidence-based policies to prevent youth smoking and underage youth drinking.

Outline:

1. State of the evidence linking cigarette advertising and youth smoking behavior in 1993 2. Reasons for the conflicting evidence

a. Specificity of the dependent variable b. Specificity of the independent variable

3. Strategy to overcome limitations of existing studies a. Re-characterization of dependent variable b. Re-characterization of independent variable

4. Current state of the evidence linking alcohol advertising and youth drinking behavior 5. Reasons for the conflicting evidence 6. Strategies for translating research paradigms from tobacco to alcohol 7. Preliminary results of these alcohol studies.

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Required Readings:

- Pollay RW, Siddarth S, Siegel M, Haddix A, Merritt RK, Giovino GA, Eriksen MP: The last straw? Cigarette advertising and realized market shares among youths and adults, 1979-1993. Journal of Marketing 1996; 60:1-16.

- King C, Siegel M, Jernigan DH, Wulach L, Ross C, Dixon K, Ostroff J. Adolescent exposure to alcohol advertising in magazines: An evaluation of advertising placement in relation to underage youth readership. Journal of Adolescent Health 2009; 45:626-633.

Lecture 13 (December 11): Student Presentations

FINAL EXAM -- December 18

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