eBriefing

The Addicted Brain and New Treatment Frontiers: 6th Annual Aspen Brain Forum

The Addicted Brain: New Treatment Frontiers
Reported by
Carina Storrs

Posted December 13, 2016

Presented By

Aspen Brain Forum

Science Translational Medicine

The New York Academy of Sciences

Overview

Teenagers and people in their early 20s face the highest risk of using drugs and becoming addicted. At the same time, substance use disorders could have the greatest harms in this age group. Studies suggest that young people who are heavy alcohol drinkers and marijuana users could have reductions in brain volume and impaired cognitive performance.

The Sixth Annual Aspen Brain Forum convened on May 18–20, 2016. It focused on the neural underpinnings of addiction in general, and why adolescents could face an elevated risk of substance use disorders. Scientists, policy makers, and representatives from the criminal justice system explained the devastating impact that drug use and addiction, both for legal drugs such as alcohol and illicit drugs such as cocaine, have on individual behavior and society.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
Meaghan Creed, PhD (University of Geneva)
Thomas Eissenberg, PhD (Virginia Commonwealth University)
David R. Gastfriend, MD (Treatment Research Institute; American Society of Addiction Medicine)
Yasmin Hurd, PhD (Icahn School of Medicine at Mount Sinai Hospital)
Thomas L. Kash, PhD (University of North Carolina School of Medicine)
Peter W. Kalivas, PhD (Medical University of South Carolina)
Patrick J. Kennedy (One Mind; Kennedy Forum)
George F. Koob, PhD (National Institute on Alcohol Abuse and Alcoholism, U.S. National Institutes of Health)
David M. Lovinger, PhD (National Institute on Alcohol Abuse and Alcoholism, U.S. National Institutes of Health)
Eric J. Nestler, MD, PhD (Icahn School of Medicine at Mount Sinai Hospital)
Susan F. Tapert, PhD (University of California San Diego; Veterans Affairs San Diego Healthcare System)
Rachel F. Tyndale (Centre for Addiction and Mental Health; University of Toronto)
Nora D. Volkow, MD (National Institute on Drug Abuse, U.S. National Institutes of Health) Any reference to NIDA or the NIH, or Dr. Volkow, should not be viewed as an endorsement of The New York Academy of Sciences, its products, or services.
Susan R. B. Weiss, PhD (National Institute on Drug Abuse, U.S. National Institutes of Health)

Presented by


How to cite this eBriefing

The New York Academy of Sciences. The Addicted Brain and New Treatment Frontiers: Sixth Annual Aspen Brain Forum. Academy eBriefings. 2016. Available at: www.nyas.org/addiction2016-eB

Public Lecture: Arrested Development — The Teenage Brain and Substance Abuse


Moderator: Claudia Wallis (Scientific American Mind)

  • 00:01
    1. Introduction by Claudia Wallis
  • 04:30
    2. Remarks by Jeremy Waletzky
  • 08:25
    3. Remarks by Nora Volkow
  • 12:38
    4. Remarks by Gregory Canova
  • 20:55
    5. Remarks by Cheryl Healton
  • 27:20
    6. Parental monitoring; New areas of research
  • 33:05
    7. Drug courts' success rates; Lessons from the truth campaign
  • 44:10
    8. Impact of marijuana legalization
  • 55:58
    9. Audience Q and A; Conclusio

Keynote: Disease of Addiction — Significance to Brain Development, Function, and Behavior


Nora D. Volkow (National Institute on Drug Abuse, U.S. National Institutes of Health)
  • 00:01
    1. Introduction and overview
  • 09:54
    2. Oral/intravenous methylphenidate studies
  • 17:43
    3. Studying differences in vulnerability
  • 24:25
    4. Motivation and executive control circuits; Studying dopamine D2 receptor expression
  • 32:44
    5. Multiple factors contributing to addiction; Summary and acknowledgement

Synaptic Plasticity and Circuitry Mediating Relapse to Drug Use


Peter W. Kalivas (Medical University of South Carolina)
  • 00:01
    1. Introduction; Relapse; Competing stimuli and intrusive thinking
  • 05:48
    2. The tetrapartite synapse
  • 11:55
    3. The rat models of drug use and relapse
  • 18:20
    4. Consequence of synaptic glutamate spillover; Measuring MMP activity; Potentiation
  • 24:40
    5. Clinical trials; Acknowledgements and conclusio

Deconstructing Aversive Brain Networks that Drive Addiction


Thomas L. Kash (University of North Carolina School of Medicine)
  • 00:01
    1. Introduction
  • 06:20
    2. The role of 5HT in alcohol induced anxiety; Mouse studies
  • 12:17
    3. 5HT modulation of BNST microcircuits; Mouse studies
  • 17:15
    4. The 5-HT-CRF circuit in the BNST; Working model; Mouse studies
  • 24:46
    5. Summary, acknowledgements, and conclusio

Tolerance and Dependence: Neural Adaptations to Chronic Drug and Alcohol Exposure


David M. Lovinger (National Institute on Alcohol Abuse and Alcoholism, U.S. National Institutes of Health)
  • 00:01
    1. Introduction
  • 05:24
    2. OFC-DMS projections and habitual behavior
  • 09:48
    3. Delta-9-THC; CB1 deletion experiments
  • 17:29
    4. CIE exposure experiments; Effects of mGluR2 loss
  • 24:57
    5. A new technique; Conclusion

Alcohol's Dynamic Effect on Neurodevelopment


Susan F. Tapert (University of California San Diego; Veterans Affairs San Diego Healthcare System)
  • 00:01
    1. Introduction
  • 02:30
    2. The effects of adolescent binge drinking; Longitudinal study of initiation
  • 09:48
    3. Volume changes after drinking; Brain activation and early drinking
  • 15:15
    4. The role of media
  • 18:51
    5. Summary; Large scale studies; Acknowledgements and conclusio

Electronic Cigarettes and Adolescents


Thomas Eissenberg (Virginia Commonwealth University)
  • 00:01
    1. Introduction
  • 02:21
    2. Describing electronic cigarettes; Current use among high school students
  • 07:55
    3. Nicotine delivery in different products; Differences in nicotine intake
  • 14:00
    4. Other toxicants; Concerns; Conclusion

Keynote: Dark Side of Addiction — Alcohol Abuse and the Stress System


George F. Koob (National Institute on Alcohol Abuse and Alcoholism, U.S. National Institutes of Health)
  • 00:01
    1. Introduction and overview; Conceptual framework
  • 09:05
    2. Opponent process; Between-system neuroadaptation
  • 13:07
    3. Brain actions of CRF
  • 22:12
    4. The effects of dynorphin expression
  • 29:48
    5. The extended amygdala; Neural circuits of the preoccupation/anticipation stage
  • 34:40
    6. Summary, acknowledgements, and conclusio

Optogenetically-inspired Deep Brain Stimulation Reverses Cocaine-evoked Synaptic Plasticity


Meaghan Creed (University of Geneva)
  • 00:01
    1. Introduction; Drug-evoked plasticity
  • 05:26
    2. Optogenetic reversal of synaptic plasticity; Experiment and conclusions
  • 10:45
    3. Deep brain stimulation; Experiment and conclusions
  • 19:40
    4. OiDBS occludes mGluR-LTD; Acknowledgement

Pharmacologic Approaches to Resolving the Opioid Epidemic


David R. Gastfriend (Treatment Research Institute; American Society of Addiction Medicine)
  • 00:01
    1. Introduction
  • 03:17
    2. Mediators and moderators; Goals of pharmacotherapy; Agonists vs. antagonists
  • 09:05
    3. Regarding methadone and buprenorphine
  • 16:12
    4. Treatment retention in MMT and BUP; Naltrexone
  • 23:56
    5. Treatment retention in naltrexone; Healthcare costs; Relapse prevention and mortality
  • 28:05
    6. Current trials and evaluations; Conclusio

Personalized Treatment Using Genetics: An Illustration from Tobacco


Rachel F. Tyndale (Centre for Addiction and Mental Health; University of Toronto)
  • 00:01
    1. Introduction
  • 03:01
    2. Nicotine clearance; Smoking and slow metabolism; Cessation
  • 07:42
    3. Variations in treatment response; PNAT randomized trial
  • 13:46
    4. Likelihood to quit smoking; European data
  • 18:27
    5. Bupropion and CYP2B6; Conclusion

State of the Science of Cannabis Research: Update from the NIH Marijuana Summit, March, 2016


Susan R. B. Weiss (National Institute on Drug Abuse, U.S. National Institutes of Health)
  • 00:01
    1. Introduction and conference overview
  • 05:08
    2. The endocannabinoid system; Cannabinoid receptors; Mechanism of action
  • 14:01
    3. Effects on the devolping brain
  • 21:40
    4. The ABCD Study; Psychosis; Policy research; Conclusio

Translational Overview of the Neurobiology of Addiction and Societal Implications


Yasmin Hurd (Icahn School of Medicine at Mount Sinai Hospital)
  • 00:01
    1. Introduction
  • 03:52
    2. Heroin abuse and epigenetic disturbances
  • 10:15
    3. Cannabis studies; Effects on the fetus
  • 18:28
    4. Germline effects of cannabis; Acknowledgemetns and conclusio

Closing Keynote: My Journey — Making Mental Health Essential Health


The Honorable Patrick J. Kennedy (Former United States Representative, Rhode Island; Co-Founder, One Mind; and Founder, Kennedy Forum)
  • 00:01
    1. Introduction
  • 09:48
    2. Parity and the political challenge; Impact on healthcare
  • 19:19
    3. Persistance of bad care; Cannabis, legalization, and addiction
  • 26:40
    4. The downside of legalization; The condition of addiction; Conclusio

Resources

Websites

Life of the Party at UCSB

National Association of Drug Court Professionals. What Are Drug Courts?

The Marijuana and Cannabinoids: A Neuroscience Research Summit. National Institutes of Health. 2016.

The System We Need [video]. The Kennedy Forum.

Truth Initiative

Jeremy Waletzky. A Personal Story of Despair and Hope, and the Origin of the Jacob P. Waletzky Award. National Institute on Drug Abuse. December 2, 2015.

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Speakers

Organizers

Joseph Dial
Joseph Dial

Chair, Scientific Advisory Board, The Aspen Brain Forum Foundation
website | publications

Dial has helped coordinate four Aspen Brain Forum conferences, as well as created, organized and moderated the 2012 Aspen Brain Forum conference on cracking the neural code. Dial previously served as executive director of the Mind Science Foundation, co-sponsoring conferences with His Holiness the Dalai Lama, as well as overseeing the funding of textbooks on neuroscience and consciousness, international consciousness conferences, and empirical consciousness research resulting in articles in Science, Nature, Nature Neuroscience, Lancet Neurology, Scientific American, and Scientific American Mind. Dial served as executive director of the Texas Film Commission and the Texas Music Office. He lived in Rio de Janeiro, Brazil where he co-wrote and co-produced a film about classical music maestro, Heitor Villa-Lobos. He wrote a screenplay based on the New York Times bestseller Einstein's Dreams, which he optioned. Dial lives in San Antonio and manages his family ranching business in South Texas. He speaks Spanish, Portuguese, and French.

David R. Gastfriend
David R. Gastfriend, MD

Treatment Research Institute; American Society of Addiction Medicine
website | publications

In nearly a decade of leadership at Alkermes, Gastfriend conducted biological, clinical, health economics and policy research on behalf of the company's efforts in the field of addiction treatment. For 25 years, Gastfriend served on the faculty of Harvard Medical School, notably as the director of the Addiction Research Program at Massachusetts General Hospital and founder of the MGH/McLean Hospital Fellowship in Addiction Psychiatry. He is considered the world's leading expert on two important treatment tools from both the biological and psychosocial realms: the opioid blocker Vivitrol, and the American Society of Addiction Medicine (ASAM) Criteria Software.

Staci A. Gruber
Staci A. Gruber, PhD

McLean Hospital, Harvard Medical School
website

Gruber is director of the Cognitive and Clinical Neuroimaging Core and associate professor of psychiatry at Harvard Medical School. Her clinical and research focus is the application of neurocognitive models and multimodal brain imaging to better characterize neurobiological risk factors for substance abuse and psychopathology. Gruber's lab has examined the etiologic bases of neural models of dysfunction in patients with psychiatric disorders as well as marijuana-abusing adults. She has published in numerous journals and been the focus of national and international symposia and press conferences.

Gruber is involved in the application of behavioral science to help shape policies regarding juvenile advocacy. Her ongoing initiative to educate policymakers, judges, attorneys and the public has had local and national impact. She also directs the MIND program, designed to clarify the effects of recreational and most recently, medical, marijuana on brain structure, function, and quality of life.

Peter W. Kalivas
Peter W. Kalivas, PhD

Medical University of South Carolina
website

The Kalivas lab studies neuroplasticity underlying the development of addiction to drugs of abuse, as well as the learning and memory deficits associated with impoverished rearing environments. Research is at the level of protein biochemistry, neural circuitry and behavioral modeling. The current focus for both addiction and isolation rearing is in adaptations in excitatory neurotransmission. In collaboration with electrophysiologists in the department, the team is are elucidating the fundamental role of extracellular glutamate homeostatis in regulating neurotransmission and neuroplasticity. This has led to preclinical and clinical evaluations of specific proteins as targets in treating addiction, including metabotropic glutamate receptors and the cystine–glutamate exchanger.

Katrina L. Kelner
Katrina L. Kelner, PhD

Science Translational Medicine
website | publications

As managing editor of Science's research journals, Katrina L. Kelner oversees the editorial practices and policies of Science Signaling and Science Translational Medicine. Kelner has been a scientific editor with AAAS and Science Magazine since 1985. Trained as a neuroscientist, with a PhD in Cell Biology / Neuroscience and a PRAT postdoctoral fellowship from the NIH, she handled papers in the area of neuroscience at Science as an associate and senior editor. Since then, she has served as Biology Perspectives editor, deputy managing editor for commentary and, most recently, deputy editor for life sciences. Her current interests revolve around application of basic science advances and tools to clinical problems. She has spoken on numerous panels and at meetings on current advances in biology, the peer review-process, data sharing, and conflict of interest in scholarly publishing.

George F. Koob
George F. Koob, PhD

National Institute on Alcohol Abuse and Alcoholism, U.S. National Institutes of Health
website

George F. Koob is director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), where he provides leadership in the national effort to reduce the public health burden associated with alcohol misuse. As NIAAA Director, Koob oversees a broad portfolio of alcohol research ranging from basic science to epidemiology, diagnostics, prevention, and treatment.

Koob earned his doctorate in behavioral physiology from Johns Hopkins University. Prior to taking the helm at NIAAA, he served as chair of the Scripps' Committee on the Neurobiology of Addictive Disorders and director of the Alcohol Research Center at the Scripps Research Institute. Koob has conducted neurophysiological research at the Walter Reed Army Institute of Research and in the Arthur Vining Davis Center for Behavioral Neurobiology at the Salk Institute for Biological Studies. He has authored more than 650 peer-reviewed scientific papers and is a co-author of the textbook The Neurobiology of Addiction.

Orla M. Smith
Orla M. Smith, PhD

Science Translational Medicine
website

Orla Smith is acting editor at Science Translational Medicine. She received a BSc in zoology, from King's College, University of London; a PhD in biochemistry from the Royal Free Hospital School of Medicine, University of London; and completed post-doctoral research at the Medical College of Wisconsin and Johns Hopkins Medical Institutions.

Rachel F. Tyndale
Rachel F. Tyndale, PhD

Centre for Addiction and Mental Health; University of Toronto

Rachel Tyndale is senior scientist and head of the Pharmacogenetics Lab in the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health. She is also the Endowed Chair in Addictions and professor in the Departments of Psychiatry, Pharmacology and Toxicology at the University of Toronto.

Tyndale is investigating genetic risk factors for drug dependence to better understand the mechanisms involved with drug abuse and to optimize treatment approaches. Drugs under study include ethanol, opiates, benzodiazepines and amphetamines with a focus on nicotine and smoking. Another area of her research involves the study of the unique regulation, function, and toxicity of cytochrome P450 enzymes in the central nervous system. Tyndale is assessing how commonly used drugs such as nicotine or ethanol regulate these enzymes and the subsequent impact on treatment drugs, as well as drugs of abuse.

Nora D. Volkow
Nora D. Volkow, MD

National Institute on Drug Abuse, U.S. National Institutes of Health
website | publications

Any reference to NIDA or the NIH, or Dr. Volkow, should not be viewed as an endorsement of the New York Academy of Sciences, its products, or services.

Nora D. Volkow is director of the National Institute on Drug Abuse (NIDA) at the National Institutes of Health. She earned her medical degree from the National University of Mexico in Mexico City, where she received the Robins award for best medical student of her generation. Her psychiatric residency was at New York University, where she earned the Laughlin Fellowship Award. At the Department of Energy's Brookhaven National Laboratory, Volkow held several leadership positions, including director of nuclear medicine, chair of the medical department, and associate director for life sciences. In addition, Volkow was a professor in the Department of Psychiatry and associate dean of the medical school at the State University of New York–Stony Brook.

Volkow has published more than 600 peer-reviewed articles, written more than 95 book chapters and non-peer-reviewed manuscripts, and edited three books on neuroimaging for mental and addictive disorders.

Melanie Brickman Borchard
Melanie Brickman Borchard, PhD, MSc

The New York Academy of Sciences
website

Melanie Brickman Borchard serves as director of Life Sciences Conferences at the New York Academy of Sciences. Brickman Borchard has nearly 15 years of experience in public health, primarily as a researcher focused on the juncture of health, demography, policy, and geography.

Prior to joining the Academy, Brickman Borchard was associate director of the Institute on Science for Global Policy (ISGP). Additionally, Brickman Borchard spent nearly a decade as a research associate for the Center for International Earth Science Information Network (CIESIN) of Columbia University, where she worked on a range of projects related to health, disease, poverty, urbanization, and population issues. She also taught as an adjunct professor at Baruch College's School of Public Affairs.

She received her PhD in medical geography from University College London, and her MSc in medical demography from the London School of Hygiene and Tropical Medicine.

Erick T. Tatro, PhD

The New York Academy of Sciences
publications


Keynote Speakers

Patrick J. Kennedy
The Honorable Patrick J. Kennedy

Former United States Representative, Rhode Island; Co-Founder, One Mind; and Founder, Kennedy Forum
website

As former congressman Kennedy is best known as the lead sponsor of the Mental Health Parity and Addiction Equity Act of 2008, passed with bi-partisan support and signed into law by President George W. Bush. The Parity Law provides millions of Americans with access to mental health treatment by requiring insurance companies treat illnesses of the body the same as diseases of the brain.

In addition to the Parity Law, Kennedy authored and co-sponsored dozens of bills to increase the understanding and treatment of neurological and psychiatric disorders, including the Positive Aging Act, the Foundations for Learning Act, the National Neurotechnology Initiative Act, the Genomics and Personalized Medicine Act, the COMBAT PTSD Act, the Nurse–Family Partnership Act, the Alzheimer's Treatment and Caregiver Support Act, and the Ready, Willing, and Able Act, which called on the Department of Homeland Security to deploy a civilian response system to blunt the psychological impact of terrorism.

George F. Koob
George F. Koob, PhD

National Institute on Alcohol Abuse and Alcoholism, U.S. National Institutes of Health
website


Nora D. Volkow
Nora D. Volkow, MD

National Institute on Drug Abuse, U.S. National Institutes of Health
website | publications


Speakers

Michael R. Bruchas, PhD

Washington University School of Medicine
website | publications

Honorable Gregory P. Canova, JD

King County Superior Court (2000–2015); King County Drug Court (2012–2015)

Gregory P. Canova earned his BA at Washington State University, and his JD at University of Southern California Law School. He was an associate at Culp Dwyer law firm from 1972 to 1974. Judge Canova has served as deputy prosecuting attorney and senior deputy prosecuting attorney with King County Prosecuting Attorney's Office–Criminal Division; division chief and senior assistant attorney general with the Attorney General's Office–Criminal Division; and was elected to King County Superior Court in 2000. He was an instructor with the State Judicial College from 2005–2007, and is a past chair of the King County Superior Court Jury Committee.

Meaghan Creed, PhD

University of Geneva
publications

Ronald G. Crystal, MD

Weill Cornell Medical College
website | publications

Thomas Eissenberg, PhD

Virginia Commonwealth University
website | publications

Thomas Eissenberg is director of the Center for the Study of Tobacco Products, whose mission is to develop and apply regulatory science to the evaluation of tobacco products and to train the next generation of tobacco regulatory scientists.

Barry J. Everitt, ScD

University of Cambridge
website | publications

Barry Everitt's research is concerned with the neural and psychological mechanisms underlying learning, memory, motivation and reward, especially related to drug addiction. A major research theme is the impact of learning on drug addiction—both its development and its persistence. Thus, taking drugs might begin as a voluntary, or goal-directed, action but may transform in time to become a compulsive habit. This transition from initial drug use to addiction may occur through the progressive engagement of different pavlovian and instrumental learning systems in the brain. Everitt's group has begun to define the neural basis of these learning mechanisms underlying addiction and is also investigating the molecular and neurochemical basis of memory "reconsolidation," the process by which drug and fear (and other memories) become labile when reactivated at retrieval and which holds promise for future treatments of addiction and other neuropsychiatric disorders.

Diana H. Fishbein, PhD

The Pennsylvania State University
website | publications

Diana H. Fishbein is the C. Eugene Bennett Chair of the Prevention Research Center at Penn State University and she directs the Center's Program for Translational Research on Adversity and Neurodevelopment. She also holds adjunct appointments at Johns Hopkins University, the University of Maryland School of Medicine, Georgetown University, and the NIDA Intramural Research Program. Fishbein’s studies utilize transdisciplinary developmental methods to understand interactions between neurobiological processes and environmental factors, and ways in which they influence intervention outcomes. This research suggests that neurobiological mechanisms interact with psychosocial experiences and environmental contexts to alter trajectories either toward or away from risk behaviors. Moreover, there are indications that trajectories can be normalized with interventions targeted to these underling mechanisms. Given the inherent translational nature of this research, she co-founded the National Prevention Science Coalition to Improve Lives (NPSC) to transfer knowledge from the basic to the applied sciences, practical settings and health policies. Fishbein has published about 100 papers and several books.

Cheryl Healton, DrPH, MPA

College of Global Public Health, New York University
website | publications

Cheryl Healton is director of the NYU Global Institute of Public Health, dean of the College of Global Public Health, and a professor of Global Public Health at NYU. Prior to this appointment, Healton served as president CEO of Legacy, the foundation created by a settlement agreement between the States Attorneys General and the tobacco industry. During her tenure with the foundation, she guided a highly acclaimed, national youth tobacco prevention counter-marketing campaign that has been credited in part with reducing youth smoking prevalence to near record lows. In 2007, Legacy spearheaded a national coalition of public and private organizations to launch the first-ever national smoking cessation campaign since the Fairness Doctrine, a brief period during which public health groups received free time on the airwaves to counter televised ads to sell tobacco.

Healton holds a doctorate from Columbia University's School of Public Health and a master's degree in public administration from NYU Wagner in Health Policy and Planning.

Yasmin Hurd, PhD

Icahn School of Medicine at Mount Sinai Hospital
website | publications

Yasmin Hurd is the Ward–Coleman Chair of Translational Neuroscience and the director of the Center for Addictive Disorders within the Mount Sinai Behavioral Health System.

Hurd's multidisciplinary research investigates the neurobiology underlying addiction disorders and related psychiatric illnesses. A translational approach is used to examine molecular and neurochemical events in the human brain and comparable animal models in order to ascertain neurobiological correlates of behavior. A major focus of the research is directed to risk factors of addiction disorders including genetics as well as developmental exposure to drugs of abuse.

Thomas L. Kash, PhD

University of North Carolina School of Medicine
website | publications

Thomas Kash received his BS in chemistry from the State University of New York at Syracuse, then worked briefly in the Medical Department at Brookhaven National Labs, before moving to Manhattan earn his PhD in neuroscience at the Weill Medical College at Cornell University in working on GABA-A receptor structure/function in Neil Harrison's lab. Kash later moved to the Winder Lab at Vanderbilt University in Nashville, TN. While a post-doc, Kash's work focused on examining the impact of alcohol and neuropeptide signaling on synaptic function in the amygdala. In 2009, Kash moved to the University of North Carolina to start his own lab. Kash lives in the rural buffer between Chapel Hill and Durham with his wife, daughter, 1 dog, more goats than one would need, 2 llamas and 7 chickens.

Mark A. R. Kleiman, PhD

publications

Mark Kleiman is a professor of public policy at the NYU Marron Institute of Urban Management, where he leads the crime and justice program. Prior to joining NYU, he served as a professor of public policy at UCLA's Luskin School of Public Affairs, taught at Harvard's John F. Kennedy School of Government, and served as the first Thomas C. Schelling Professor at the University of Maryland. Kleiman is also an adjunct scholar at the Center for American Progress. Previously, he worked for the Office of Policy and Management Analysis in the Criminal Division of the U.S. Department of Justice. From 1982–1983 he was the director of the same office, and a member of the National Organized Crime Planning Council.

Kleiman attended Haverford College, graduating with a BA economics, philosophy, and political science. For his graduate education, Kleiman attended John F. Kennedy School of Government at Harvard University, earning an MPP and a PhD in public policy.

Silvia Lopez-Guzman, MD

New York University
publications

David M. Lovinger, PhD

National Institute on Alcohol Abuse and Alcoholism, U.S. National Institutes of Health
website | publications

David Lovinger received a BA in psychology from the University of Arizona and a PhD in psychology from Northwestern University. At Northwestern, he worked with Dr. Aryeh Routtenberg studying the roles of Protein Kinase C and its substrate, the GAP-43/F1 protein, in hippocampal long-term potentiation. His postdoctoral research at the NIAAA focused on the effects of alcohol on ligand-gated ion channels. In 1991, Lovinger moved to the Vanderbilt University School of Medicine as an assistant professor, where he rose to the rank of professor. At Vanderbilt, he was also the deputy director for biomedical science and the director of the Neuroscience Core within the Kennedy Center. Lovinger joined the NIAAA in 2001 as a senior investigator and chief of the Laboratory of Integrative Neuroscience. His laboratory is currently studying the modulation and plasticity of synaptic transmission at corticostriatal synapses and the mechanisms by which abused substances effect synaptic transmission.

A. Thomas McLellan, PhD

Treatment Research Institute
website | publications

A. Thomas McLellan is co-founder of the Treatment Research Institute (TRI). From 2009 to 2010, he was science advisor and deputy director of the White House Office of National Drug Control Policy (ONDCP. At ONDCP, McLellan worked on a broad range of drug issues, including formulation and implementation of the President's National Drug Control Strategy and promotion of drug treatment through the broader revamping of the national health care system. From 2000–2009, he was editor-in-chief of the Journal of Substance Abuse Treatment. McLellan is the recipient of distinguished awards including the life achievement awards of the American and British Societies of Addiction Medicine; the Robert Wood Johnson Foundation Innovator Award; and awards for distinguished contribution to addiction medicine from the Swedish and Italian medical associations. In the 1980s, with colleagues from the Center for the Studies of Addiction at the University of Pennsylvania, McLellan introduced the Addiction Severity Index and the Treatment Services Review.

P. Read Montague, PhD

Virginia Polytechnic Institute and State University; University College London
website | publications

Read Montague's work centers broadly on human social cognition, decision-making, and willful choice with a goal of understanding the detailed underlying neurobiology of these functions in health and disease. Montague's work particularly focuses on computational neuroscience—the connection between physical mechanisms present in real neural tissue and the computational functions that these mechanisms embody. He is also actively engaged in translating computational neuroscience into the domain of mental health through work in computational psychiatry. His laboratory uses theoretical, computational, and experimental approaches to these issues. In particular, the group now employs novel approaches to functional neuroimaging, new biomarkers for mental disease, spectroscopy, real-time voltammetry, and computational simulations. Work in the laboratory is supported by the National Institutes of Health, National Science Foundation, Kane Family Foundation, Autism Speaks, MacArthur Foundation, Dana Foundation, and Wellcome Trust.

Eric J. Nestler, MD, PhD

Icahn School of Medicine at Mount Sinai Hospital
website | publications

Eric J. Nestler serves as a board director for the biopharma company BERG. He is the Nash Family Professor of Neuroscience, chair of the Department of Neuroscience and director of the Friedman Brain Institute at the Mount Sinai Medical Center. He is active in six research projects funded by the National Institute on Drug Abuse and the National Institute of Mental Health, as well as a member of the Scientific Advisory Board of the National Alliance for Research in Schizophrenia and Depression and of the International Mental Health Research Organization, and a member of the board of directors of the McKnight Endowment Fund in Neuroscience.

Nestler received his BA, PhD and MD from Yale University. He completed his residency in psychiatry at both McLean Hospital in Massachusetts and Yale, then served as the director of the Division of Molecular Psychiatry at Yale until 2000. He later served as chair of the Department of Psychiatry at the University of Texas Southwestern Medical Center at Dallas.

Olusegun Owotomo, MD, MPH

University of Texas at Austin

Emma J. Rose, PhD

The Pennsylvania State University
publications

Michael D. Scofield, PhD

Medical University of South Carolina
website | publications

Michael Scofield received his bachelor's degree in biology and biotechnology from Worcester Polytechnic Institute in 2005 and his PhD in biomedical sciences from the University of Massachusetts Medical School in 2010. In his graduate work, he studied transcription factor assembly at the promoter of the b4 subunit of the neuronal nicotinic acetylcholine receptor. He joined the Kalivas lab in 2011 and is currently investigating the role that gliotransmission plays in mediating the changes in neuroplasticity responsible for relapse. Outside the lab, Michael enjoys music, movies and walking his dog.

Lindsay M. Squeglia, PhD

Medical University of South Carolina
website | publications

Susan F. Tapert, PhD

University of California San Diego; Veterans Affairs San Diego Healthcare System
website

Susan Tapert is professor and associate vice chair of academic affairs in the UC San Diego Department of Psychiatry. She became interested in addictive behavior research as an undergraduate at University of Washington, working with Dr. G. Alan Marlatt at the Addictive Behaviors Research Center. Her focus on adolescence started during her graduate studies with Dr. Sandra A. Brown in the San Diego State University / University of California San Diego Joint Doctoral Program in Clinical Psychology, where she specialized in neuropsychology and behavioral medicine. Her dissertation was on the reciprocal effects of neuropsychological functioning and substance use in youth. Following an American Psychological Association accredited clinical psychology internship at Brown University, she completed a post-doctoral fellowship at UCSD on functional magnetic resonance imaging under the mentorship of Dr. Gregory G. Brown.

Jeremy Waletzky, MD

The George Washington University

Claudia Wallis

Scientific American Mind
website | publications

Claudia Wallis is currently a contributor to Time magazine. She has worked at Time as a staff reporter and editor, and has produced 35 cover stories on education, science, health, psychology, children and family issues. Wallis was the founding editor of Time for Kids magazine, and served as editor-at-large from 2003–2007. A two-time National Magazine Award finalist, Wallis plans to examine how the rising number of students diagnosed across the spectrum of autism disorders is challenging educators and the solvency of school districts.

Susan R. B. Weiss, PhD

National Institute on Drug Abuse, U.S. National Institutes of Health
website | publications

Susan Weiss is director of the Division of Extramural Research at the National Institute on Drug Abuse (NIDA), which oversees NIDA's extramural programs, research training, operations planning, and trans-NIH initiatives. Weiss is also a senior science advisor to NIDA's director. Previously, she served as chief of the Science Policy Branch and acting director of NIDA's Office of Science Policy and Communications.

Prior to coming to NIDA, Weiss served as senior director of research at the National Mental Health Association (now Mental Health America), where she applied her research and scientific expertise to the organization's strategic planning, public education, and advocacy efforts.

Weiss has received multiple awards, including NIH Plain Language Awards, NIH and NIDA Director's Awards, and the Ziskind–Somerfeld Senior Investigator Award from the Society for Biological Psychiatry. She graduated from the State University of New York–Stony Brook, and received her PhD in psychology from the University of Maryland.

Carina Storrs

Carina Storrs is a freelance science writer based in New York City. She covers health, technology, and sustainability topics for various print and online publications and diverse audiences. She has a PhD in microbiology from Columbia University and a Master's degree in journalism with a certificate in science, health and environmental reporting from New York University.

Sponsors

Bronze Sponsor

Braeburn Pharmaceuticals

Academy Friends

Addiction Technology Transfer Centers

Gosnold on Cape Cod

The Newport Academy

The Peter G. Dodge Foundation

Grant Support

Indivior Inc. has provided unrestricted funding to support the program.

This event was supported by the National Institute On Drug Abuse of the National Institutes of Health under Award Number R13DA041813. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Media Partner

  • WNYC

Presented by

Substance use is common among teenagers and young adults. In the most recent Monitoring the Future survey of students across the United States in 2015, 35% of 12th grade students said they had tried alcohol in the past month, and nearly 40% said they had been drunk in the past year. Although alcohol and tobacco cigarette use are on the decline, use of illicit drugs has been steady, and a growing number of adolescents are using marijuana and electronic cigarettes. In 2015, more high school seniors said they smoked marijuana everyday (6%) than smoked tobacco cigarettes (5.5%).

Adolescents are at greater risk of developing a drug addiction than older adults. In adolescents the prefrontal cortex, which is the seat of executive function, is not yet fully developed, so it is difficult for them to make rational decisions and regulate emotions. In this group, there are also weaker connections between the prefrontal cortex and the nucleus accumbens, a component of the limbic system involved in reward, as Nora D. Volkow discussed in her keynote address. The role of dopamine in modulating the connections between the prefrontal cortex and nucleus accumbens has been well studied, but Peter W. Kalivas presented data on how the neurotransmitter glutamate could also modulate neuroplasticity in this network.

Some evidence shows that neuroplasticity and changes in activity in numerous brain networks contribute to addiction. Addiction turns on the stress system in the brain, which likely plays a critical role in the withdrawal stage, keynote speaker George F. Koob argued in his address. Barry J. Everitt and David M. Lovinger described specific brain networks that could be involved in the progression to addiction, and how they could be regulated by dopamine and the endocannabinoid system. Changes in brain network activity associated with drug use and withdrawal correlate with changes in gene expression profiles in neurons, according to speaker Eric J. Nestler.

Besides being more susceptible to drug addiction, adolescents may also suffer more harm from drug use than adults. Cross-sectional studies have found teens with a recent history of intense binge drinking have lower white and gray matter volumes in their cerebellums than non-drinking controls, based on brain imaging. In addition, young people who start using marijuana in their early teens have more changes in brain structure and function than their peers who start smoking later, as Staci A. Gruber outlined in her talk. However, it has been unclear whether drug use causes these changes or these changes precede and possibly predispose teens to drug use. Susan F. Tapert presented her longitudinal research exploring alterations in brain structure and function that coincide with the start of heavy alcohol use in middle and high school students.

In some cases, effective treatments are already available. The patch, bupropion, and varenicline help improve cigarette smoking quit rates, although genetics influence which treatment is most effective, said Rachel F. Tyndale. David R. Gastfriend talked about the important role of treatments such as methadone and naltrexone in reducing opioid use, but stressed that less than half of people in the U.S. who are addicted to opioids receive treatment. Research on new addiction treatments has also made exciting progress. Ronald G. Crystal presented his group's work to develop a cocaine vaccine, which they found reduces drug use in animal models. The team will soon start testing in humans.

Experts want to draw more attention to the effect of drug use among adolescents, and promote stricter regulations on access to legal drugs. The National Institutes of Health convened a landmark conference exploring what's known and what still needs to be studied about the effects of marijuana on the developing brain, according to Susan R. B. Weiss, who provided an overview of the event. Mark A. R. Kleiman argued that regulation of recreational marijuana has been inadequate, and the outcomes from this legal lassitude could be akin to those seen for alcohol. Four states have legalized recreational marijuana, and 24 states and the District of Columbia have legalized medical marijuana. Former congressman Patrick J. Kennedy concluded the forum by outlining the areas of mental health and addiction care that need improvements. It will take greater awareness and effort across sectors, including continued research, increased willingness on the part of clinicians and insurance providers to address addiction, and heightened interest among policymakers to make progress against the problem, he said.

Panelists

Claudia Wallis, Moderator

Managing Editor, Scientific American Mind

Gregory P. Canova

King County Superior Court (2000–2015); King County Drug Court (2012–2015)

Cheryl Healton

College of Global Public Health, New York University

Nora D. Vokow

National Institute on Drug Abuse

Jeremy Waletzy

George Washington University

Highlights

Young people are more susceptible than adults to developing drug addiction.

Researchers are studying vaccines and transcranial magnetic stimulation as possible treatments for addiction.

Policy makers need to create more public education programs directed at young people.

Drug courts are cost effective and could help people recover from drug addiction.

From neuroscience to criminal justice

The panel that opened the forum represented diverse perspectives on substance abuse in adolescents, from the neuroscience of addiction to policy and criminal justice. Moderator Claudia Wallis started by asking the panelists to briefly summarize their views on the topic. Jeremy Waletzy shared the tragic story of losing his son Jacob at the age of 29 to cocaine use. "One of the things that was so clear to me was that if there were a treatment that would work, Jacob would have taken it," Waletzy said. To support the development of such treatments, Waletzy and his wife created the Society for Neuroscience Jacob P. Waletzky Memorial Award for Innovative Research in Drug Addiction and Alcoholism to recognize young scientists who have made important contributions to understanding drug addiction.

Nora D. Volkow, who has pioneered the use of brain imaging to study how drugs affect the brain, explained how even children such as Jacob who grow up in a supportive environment can become addicted. In response to a question from the moderator about research on treatments, Volkow said "we are very excited about ... the possibility of using vaccines to actually treat [substance use disorder]." The technical challenge right now, she added, "is to create more potent vaccines." Volkow also mentioned transcranial magnetic stimulation (TMS) as a potential strategy to strengthen connections in brain networks that are weaker in people who are addicted.

In the criminal justice system, drug courts are a relatively new way to handle people who have been convicted of dealing illegal drugs. They are an alternative to the "revolving door" of sending addicted people to jail or prison where they do not receive treatment, get released, and commit the same crimes, said Gregory P. Canova. Felons entering drug court avoid prison and receive treatment and close monitoring, such as meeting regularly with a judge and receiving random biweekly urine tests. King County, Washington, where Canova was a drug court judge, became the twelfth drug court in the U.S. in 1994; now there are 2100 drug courts across the country. Peer-reviewed studies indicate that drug courts help addicts reclaim their lives and save taxpayer dollars compared to the traditional criminal court approach.

But how effective drug courts are at keeping people from using drugs? Canova said that those data are limited, especially for young adults, because few drug courts work with this age group. However, efforts to track drug court graduates overall at the county and national level by the National Association of Drug Court Professionals suggest these programs reduce the recidivism rate by 40% to 45%. Currently many individuals are in drug court because they committed property offenses to support their habit rather than drug offenses, Canova noted.

Cheryl Healton addressed drug use from a public health perspective, discussing how little emphasis has been put on public education and cultural tactics to prevent people from trying drugs in the first place, or from becoming regular users. The Philip Morris campaign, "Think, don't smoke!" was an ineffective way to appeal to adolescents who are rebellious and sensation seekers, she said. The Truth Campaign, which Healton worked on and which focused on teens' rebelling against the tobacco industry, has reduced youth smoking by 22%.

Responding to Wallis's question about applying her approach to other substances, Healton said that alcohol would be most applicable because of its analogies with tobacco in terms of marketing and young people's motivations for using it. Nevertheless, "it would be one more grand experiment," akin to the Truth Campaign, Healton said. Another "grand social experiment," she said, is the legalization of recreational marijuana.

Several audience members discussed policy changes that could prevent youth from starting to use drugs. Volkow agreed that advertising contributes to prescription drug overuse, stating that advertising leads to more patients asking for drugs and more drugs being prescribed, often to patients who shouldn't be taking them.

In response to a question about whether stressful school environments affect drug use among young people, Volkow said studies have shown that young people are more likely to experiment with drugs if they are in a school where they perceive others are using drugs. Nevertheless, even though the school environment is stressful, it can create a rewarding social support system for young people. An audience member asked for the panel's opinion on UCSB's Life of the Party program, which advises students how to socialize safely. Healton responded that, although it is possible these programs could be an effective harm reduction strategy, other approaches such as programs in which students self-police and take a pledge to abstain from unsafe behavior in social settings could be more effective.

Speaker

Nora D. Volkow

National Institute on Drug Abuse, U.S. National Institutes of Health

Highlights

PET imaging studies have revealed dopamine levels are lower in the brains of people who are addicted to drugs.

Reduced expression of dopamine D2 receptors, which regulate dopamine's rewarding effects, could contribute to the development of addiction.

Adolescents have weaker connections between dopamine cells and the prefrontal cortex.

Greater social support could strengthen these connections and reduce the risk of addiction.

In her keynote address, Nora D. Volkow of the National Institute on Drug Abuse described brain imaging studies revealing how the dopamine system is hijacked in the brains of people addicted to drugs, and how this system is more likely to become disrupted in children and adolescents.

Unique vulnerabilities of adolescent brains

In PET imaging studies, Volkow and her colleagues found that, dopamine levels are less strongly induced in the nucleus accumbens and striatum of people addicted to cocaine after exposure to cocaine or methylphenidate, compared with non-addicted people. This dampening of dopamine induction is likely why people who are addicted to drugs continue to take them even though they are less rewarding, Volkow said.

People who are addicted to drugs regularly encounter stimuli that trigger cravings. The decision to take the drug is regulated by the prefrontal cortex, and the balance between dopamine D1 receptors, which stimulate the rewarding effects of drugs, and dopamine D2 receptors that counteract the D1 pathway. Studies by Volkow's group and others have demonstrated that expression levels of D2 receptors are lower in people addicted to drugs. This reduced expression could be involved in the process of addiction, as overexpressing D2 receptors in rats that self-administer high levels of alcohol or cocaine led to animals reducing their drug intake.

Volkow presented a model in which D2 receptors prevent compulsive drug consumption by inhibiting GABA cells in the striatum, which in turn inhibit the thalamus from stimulating the prefrontal cortex. As this model would predict, studies of people addicted to drugs show a link between low D2 levels and low activity in the prefrontal cortex.

Lower levels of dopamine D2 receptors could reduce prefrontal cortex activity and increase the risk of addiction.

This is your brain on family

Adolescents, a group at higher risk of addiction than adults, have weaker connectivity between dopamine cells and the prefrontal cortex compared with young adults. This connectivity is even weaker in adolescents who have attention deficit hyperactivity disorder and in children who have been neglected. However, some evidence suggests that these differences could be reversed. A study of orphans in Romania found that children who went to live with supportive families had stronger connections with the frontal areas of their brains than children who stayed at the orphanage. "You may not choose your genes, you may not choose where you are born, but we can create a supportive system that can help us counteract some of the negative effects of the environment or that may come from a genetic vulnerability," Volkow said.

Adolescents who have experienced social neglect have weaker connectivity between dopamine cells in the limbic system and the prefrontal cortex that drives decision making and control.

Speakers

Peter W. Kalivas

Medical University of South Carolina

Michael R. Bruchas

Washington University School of Medicine

Thomas L. Kash

University of North Carolina School of Medicine

David M. Lovinger

National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health

Barry J. Everitt

University of Cambridge

Highlights

Glutamate release in the tetrapartite synapse could underlie drug-seeking behavior.

The development of habitual behavior is associated with a shift from the ventral to the dorsolateral striatum.

The orbitofrontal cortex and the dorsal medial striatum synapse, mediated by the endocannabionid system, could also drive habitual behavior.

New optogenetics tools allow researchers to manipulate neural circuits and deliver drugs in freely moving animals.

Thinking of drinking

When people with a history of addiction are exposed to drug cues, such as an invitation from a friend to meet at the bar, they have difficulty deciding not to pursue the drug, explained Peter W. Kalivas, of the Medical University of South Carolina. The neural basis for this loss of inhibition is the tetrapartite synapse between the prefrontal cortex, the nucleus accumbens, the astroglial process, and the extracellular matrix. In response to food or drug cues, the prefrontal cortex releases glutamate, which the nucleus accumbens take up via NMDA receptors and the glutamate transporter on the surface of astroglial cells. Drug cues, unlike food cues, inhibit expression of the glutamate transporter, causing glutamate to spill out of the synapse.

A subpopulation of interneuron cells called nNOS neurons takes up this glutamate via mGluR5 receptors. As a result, these neurons release nitric oxide, which is important for the activation of the extracellular matrix metalloproteinase enzyme MMP-9, which in turn cleaves and activates a small peptide ligand called RGD (named for its RGD, or Arg-Gly-Asp, domains). Once activated, RGD binds to beta-3 integrin on the surface of nucleus accumbens cells, which increases the spine head diameter and glutamate receptor levels in these cells, potentiating or exciting the postsynaptic terminus and inducing drug seeking, as Michael Scofield, a postdoctoral fellow in the Kalivas lab, explained in his Hot Topic Talk. The researchers found that about 25% of nucleus accumbens cells are potentiated following drug cues, possibly creating a strong signal for drug seeking and overwhelming the signal to engage in other behaviors.

These findings suggest new approaches for treating drug addiction, Kalivas said. Studies have found that restoring glutamate transporter levels on glial cells using N-acetylcysteine prevents relapse in animal models of drug addiction, and a number of studies suggest it could reduce cocaine craving and cigarette and marijuana use in humans, although it is still considered experimental.

Many clinical trials are underway testing this compound and a phase 2 trial was completed in 2015 that addressed the ability of N-acetylcysteine to prevent drug relapse among military veterans with PTSD and substance abuse disorder.

Drug use increases glutamate release at the tetrapartite synapse could set off a cascade of events that signal drug seeking behavior.

Wired for addiction

The development of an addiction involves engaging in a goal-directed behavior to obtain an outcome such as a drug effect, and then repeating that behavior until it becomes habitual. "The key thing for addiction is some individuals lose control over those habitual behaviors and become compulsive," said Barry J. Everitt of the University of Cambridge.

Everitt's group modeled the progression from goal-directed to habitual and then compulsive cocaine use in rats. In one setup, rats learn to press one lever to gain access to a second lever, which they can then press to receive an infusion of cocaine. This goal-directed behavior requires the nucleus accumbens in the ventral striatum and the basolateral amygdala. However, if rats train long enough on this task, they will start pressing the levers even if no cocaine is produced, indicating their behavior has become habitual. Researchers have determined the shift from goal-directed to habitual behavior correlates with a shift from activity in the ventral striatum to the dorsolateral striatum. Disconnecting the dorsolateral striatum from the ventral striatum prevents animals from developing a cocaine-seeking habit.

Trying to measure how a habit becomes a compulsive behavior is "at the heart of what we are doing now," Everitt said. His team has created a system in which rats receive a mild foot shock if they press the levers for cocaine. Although most of the rats abstain from seeking cocaine, even after training on the task for several weeks, about 20% persist despite the punishment. Everitt and other researchers have observed several factors associated with this compulsive behavior in rats, including low dopamine D2 receptors in the ventral striatum, a smaller nucleus accumbens, and lower activity in the prefrontal cortex. These findings suggest strategies for treating addiction, such as transcranial magnetic stimulation and cognitive behavioral therapy, which could help restore inhibitory control, Everitt said.

The brain circuit that involves the orbitofrontal cortex (OFC) and the dorsal medial striatum (DMS) could also help determine the balance between goal-directed and habitual behavior. Experimentally blocking the activity of the OFC in mice shifts the balance toward habit-forming behavior. THC, the primary psychoactive ingredient in marijuana, and natural endocannabinoids appear to dampen the efficacy of the synapse between the OFC and DMS, which increases habit-directed behavior.

David M. Lovinger, of the National Institute on Alcohol Abuse and Alcoholism, determined that the endocannabinoid receptor CB1 could be involved in the OFC-DMS circuit and in suppressing goal-directed behavior. Deleting the gene for CB1 specifically in the OFC of mice diminished synaptic activity. "If you can disrupt this inhibition [of CB1] in some way, you may be able to restore goal-directedness even in the face of ... drugs that push you toward habit," Lovinger said.

Alcohol can also dampen the OFC-DMS synapse, Lovinger said. His group found that putting mice in chambers where they inhaled alcohol vapor for three weeks hindered their ability to learn goal-directed behaviors in subsequent training sessions. Numerous studies suggest that G-protein coupled receptors at presynaptic OFC terminals, including CB1 and mGluR and opiate receptors, could be involved in regulating the switch between goal-driven and habitual behavior.

The endocannabinoid receptor CB1 in the orbitofrontal cortex (OFC) and dorsal medial striatum (DMS) synapse could suppress goal-directed behavior.

A third neural circuit involved in addiction is serotonin, which has a "dark side" in aversive behavior, as Thomas L. Kash, of the University of North Carolina School of Medicine, explained. Serotonin, or 5HT, is a complex neuromodulator produced by a brain region called the dorsal raphe nucleus, which projects to many brain regions involved in reward, stress and anxiety, impulsivity, and other functions.

One area that receives serotonergic input from the dorsal raphe nucleus is the bed nucleus stria terminalis or BNST, which is activated in response to stress and is thought to produce anxiety and the conditioned fear response in mice and people. Kash and his lab found that both the nucleus and BNST are activated in DBA/2J mice, which have a robust anxiety response, following a five-day exposure to ethanol vapor. These animals exhibited anxiety and fear in behavioral assays, which appeared to be mediated by serotonin; injecting the mice with a serotonin receptor antagonist blocked the response. Conversely, stimulating the rapid release of serotonin into the BNST using optogenetics, which is the use of light, can induce anxiety.

In subsequent experiments, Kash's lab identified a subpopulation of BNST neurons called corticotropin-releasing factor (CRF) neurons that are activated by serotonin and inhibit the ventral tegmental area and lateral hypothalamus, and mediate the aversive effects of alcohol in mice.

Lighting up the brain

Optogenetic approaches use optical probes to manipulate neural circuits letting researchers study the function of receptors and neuromodulators in live animals in real time. Channelrhodopsin, an algae-derived ion channel that depolarizes neurons in response to blue light, and inhibitory pumps, which can hyperpolarize and silence neurons, are the main molecular tools for this technique, said Michael R. Bruchas at Washington University School of Medicine.

Advances in material sciences have made it possible for Bruchas and his colleague John A. Rogers at the University of Illinois to create needle-like probes printed with LED devices, as well as detectors and sensors, that are fully implantable. This allows them to study freely moving animals in behavioral assays, without having them tethered to fiber optic cables. An additional benefit of these small probes is that they do not require much voltage, allowing them to run wirelessly on radio frequency energy. Taking the platform one step further, Bruchas and Rogers added microfluidic channels to the probe that can deliver drugs selectively to the brain. Drug administration from this optofluidic probe can also be controlled wirelessly in free moving animals, using a design that heats the probe and drives a piston to push drugs from the channels.

Speakers

Eric J. Nestler

Icahn School of Medicine at Mount Sinai Hospital

Thomas Eissenberg

Virginia Commonwealth University

Staci A. Gruber

McLean Hospital, Harvard Medical School

Diana H. Fishbein

The Pennsylvania State University

Susan F. Tapert

University of California San Diego; Veterans Affairs San Diego Healthcare System

Highlights

Changes in gene expression profiles occur following drug use and withdrawal in animal studies.

Longitudinal research suggests heavy alcohol consumption could cause reductions in brain volume in teenagers.

Smoking marijuana early in adolescence is linked with changes in brain volume and structure and poorer performance on executive function tests.

Interventions that decrease stress could change the trajectory of brain development and reduce addiction risk.

Use of electronic cigarettes among adolescents has surpassed that of tobacco cigarettes, but long-term health effects are not known.

Promoting plasticity

For many years, researchers have thought drug addiction could induce neuroplasticity, as chronic exposure to drugs of abuse leads to changes in synaptic activity and neuronal excitability and structure. Eric J. Nestler, of the Icahn School of Medicine at Mount Sinai Hospital discussed the changes in gene expression and chromatin modifications that could underlie this neuroplasticity.

Through a series of RNA sequencing experiments, Nestler's lab has demonstrated that gene expression changes correspond with behavioral changes in male and female mice in response to cocaine. Pups showed an increase in place preference following cocaine administration, although there were sex differences in the effect of social isolation. In both sexes, there were clear signatures of gene expression in the nucleus accumbens associated with place preference behavior.

A number of cellular changes occur in response to drug withdrawal, and gene expression studies have helped detail the molecular mechanisms associated with these changes. Short periods of withdrawal from cocaine or other drugs of abuse are associated with an increase in dendritic spine density in nucleus accumbens cells and thinner spiny heads that have less functional glutamate response. In contrast, long periods of withdrawal correlate with larger and more functional spiny heads. Nestler's lab identified a signaling pathway that promotes actin polymerization and the transcriptional upregulation of the Rap1b gene, causing a switch from larger, mushroom heads to thin spiny heads.

Short periods of withdrawal are associated with thinner, denser spiny heads in nucleus accumbens cells, whereas long periods of withdrawal are linked with larger more functional synapses.

Drinks, drugs, and development

Moving the focus to people, Susan F. Tapert of the University of California San Diego discussed research on whether alcohol consumption causes changes in brain development. She and her colleagues began a longitudinal study in the early 2000s, involving about 300 students from middle schools around San Diego who were not drinking alcohol or using drugs. The researchers are still following participants, and conducting interviews, memory and attention tests, and brain imaging scans.

Approximately 30% of the individuals in the study have started heavy alcohol use. Although this group had smaller volumes in the cerebellum and other brain regions prior to drinking, they also had larger reductions in gray matter in temporal lobe areas and less growth in gray matter in the corpus callosum and other areas, suggesting that heavy alcohol consumption can alter brain development.

Tapert concluded her talk by highlighting two large ongoing longitudinal studies that she is leading, the Adolescent Brain Cognitive Development (ABCD) study and the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. Both will conduct neuropsychological tests and brain imaging scans over time among adolescents who have started heavy drinking.

In her Hot Topic Talk, Lindsay M. Squeglia discussed her research in the Tapert lab to identify factors that could predict which students in the San Diego study would start drinking heavily in adolescence. Males were more likely to become heavy drinkers by age 18, as were teens who began dating before age 14, and those who had conduct disorders and high socioeconomic status. Other important predictors were poor performance on executive functioning tasks, thinner cerebral cortices, and less brain activation during working memory tests. Although it is too soon to put kids in a scanner to determine who will start drinking heavily, "one of my favorite parts about this [research] is that we are publishing the scripts that we used with the hopes that other groups will try to replicate these findings," said Squeglia, who is now at the Medical University of South Carolina.

Heavy drinking in teens is linked with increased reduction gray matter and reduced growth in white matter.

There is a growing use of marijuana among high school seniors, as reported in the 2015 Monitoring the Future survey, in which 68% of adolescents said they did not think regular marijuana use was harmful. "Perception of risk and harm continues to drop among our youth," said Staci A. Gruber of McLean Hospital at Harvard Medical School, asking "is marijuana really as harmless as our youth clearly believe?"

Research has found that adolescents who use marijuana before the age of 18 perform worse on tests of memory, attention, and in some studies, IQ. But what are the differences between teens who start smoking early and those who start later in adolescence? In a study of 50 heavy marijuana users, Gruber and her colleagues found that those who started smoking before the age of 16 smoked almost twice as frequently and more than 2.5 times as much marijuana as later onset smokers. Early onset smokers also differed from late onset smokers and a group of 34 nonsmokers in brain function and structure, including having worse performance on the Stroop test of executive function and less white matter integrity based on diffusion tensor imaging.

These findings are "really important since states that are considering legislation for recreational and medical [marijuana] need to determine safe guidelines, particularly during critical periods of neurodevelopment," Gruber said. She also noted that recreational marijuana products have become more potent over the last two decades. In 2014 marijuana samples averaged about 12% delta-9 THC, the product's primary psychoactive component, compared with 4% in 1995.

Heading off addiction

Understanding brain development in children and adolescents can inform prevention strategies for drug addiction in these groups, said Diana H. Fishbein of Pennsylvania State University. Adolescents do not have a fully developed prefrontal cortex, and compared with adults, have more activity in the nucleus accumbens and less activity in the amygdala, the brain's threat-detection system. Environmental factors such as chronic stress could also alter the trajectory of adolescent brain development through neurobiologic and epigenetic changes.

"There are some very good emerging articles on this that lead us to believe that with intervention we can alter trajectories for children who have been exposed to stress," Fishbein said. One of those interventions is the PATHS Curriculum, which teaches self-regulation. In her study of students in kindergarten through second-grade students in Baltimore City schools, she found PATHS improved inhibitory control, stress physiology and emotion regulation, thereby reducing behavioral problems. Fishbein has conducted other studies in adolescents and adults showing moderation of intervention effects by level of executive functioning and suggest that these processes are improved by intervention. Other studies have tested executive function-promoting interventions among four-year-olds in Head Start programs, and a family-based stress intervention among preschool-age children.

Another promising intervention is mindfulness-based stress reduction. Although most studies have examined its effect on brain function in adults, one study found an association between mindfulness and greater inhibitory control among fourth and fifth-grade students. Fishbein and her colleagues are working to determine the emotional and neurocognitive mediators of intervention responsivity. Although there are many evidence-based preventive interventions, their effect sizes are no more than small to modest. Such findings suggest that the process of identifying mediators and moderators is critical to guide program refinements to better target underlying generators of the behavior they aim to prevent. Only then can a greater number of recipients benefit, Fishbein said.

In adolescents, reward sensitivity develops before inhibitory control in the prefrontal cortex, leading to increases in risk-taking behaviors.

Addressing unknowns of e-cigarettes

Whereas the number of U.S. high school students that use tobacco cigarettes has been decreasing over the last decade, the number using electronic cigarettes has been on the rise since 2011. In 2015, 16% of high school students said they used e-cigarettes in the last month, whereas only 9.3% reported using tobacco cigarettes, according to the National Youth Tobacco Survey. These devices deliver nicotine, which can lead to structural and chemical structures in the brains of adolescents, however very little is known about the long-term health effects of e-cigarettes.

Some of the many questions surrounding these devices concern the amount of nicotine they deliver, as Thomas Eissenberg, of Virginia Commonwealth University, explained. Studies have found big variations in the amount of nicotine delivered by e-cigarettes depending on the power of the device. Certain devices deliver very low levels of nicotine to the body, and Eissenberg worries the tobacco industry is using these products to introduce youth to nicotine, whereas other devices deliver much more nicotine than tobacco cigarettes.

Another question about these devices concerns the flavorings. The nicotine is dissolved in propylene glycol, vegetable glycerine, or a combination of the two, and it almost always contain flavorants that have been tested for food safety but not for inhalation safety. But with vape shops selling flavors such as blue cotton candy and Apple Jacks cereal, "you have got to wonder who are these flavors designed to appeal to," Eissenberg said.

Speaker

George F. Koob

National Institute on Alcohol Abuse and Alcoholism, U.S. National Institutes of Health

Highlights

Addiction is associated with shift from activity in the brain's reward system to the stress system.

The peptides corticotropin-releasing factor and dynorphin increase in response to stress and reward system activity, respectively.

Antagonists that block these peptides reduce alcohol intake in rats.

Striving for balance

Addiction correlates with decreased activity in the reward system in the brain and increased activity in the stress system. The brain's attempt to reestablish the balance between the two systems drives addictive behavior, said George F. Koob of the National Institute on Alcohol Abuse and Alcoholism, in his keynote. Repeated exposure to drugs of abuse activates the stress system, which then contributes to the negative emotional state of withdrawal. Koob argued that this is one of the three stages of addiction, along with binge/intoxication and preoccupation.

Activation of the brain's stress system could play an important role in addiction.

At the heart of the stress system are two peptides: corticotropin-releasing factor (CRF) in the amygdala and dynorphin in the ventral striatum. Acute stress causes the release of high levels of CRF. Research by Koob's group and others has found that a CRF antagonist can block excessive use of alcohol and other addictive drugs in rats. Glucocorticoids increase CRF levels in the amygdala, but block CRF in the paraventricular nucleus, which has the same effect as the CRF antagonist in blocking alcohol intake and dependence.

Activation of the dopamine or opioid receptor reward system induces expression of the neurotransmitter dynorphin, which in turn shuts off the dopamine system in which Koob said could be one of the mechanisms for the decrease in dopamine that Volkow discussed in her presentation. His group demonstrated that blocking dynorphin signaling through the kappa-opioid receptor, by injecting rats with an antagonist of the receptor, prevents animals from escalating their alcohol intake.

"These two systems provide a potentially rich framework for not only medication development but for behavioral treatments for addiction," such as cognitive behavioral therapy, Koob said.

The peptide corticotropin-releasing factor (CRF) and dynorphin, which are increased in response to the stress and reward system respectively, drive the consumption of drugs of abuse.

Speakers

Meaghan Creed

University of Geneva

Ronald G. Crystal

Weill Cornell Medical College

David R. Gastfriend

Treatment Research Institute at the American Society of Addiction Medicine

Rachel F. Tyndale

Centre for Addiction and Mental Health, the University of Toronto

Highlights

Deep brain stimulation inspired by optogenetics tools reverses cocaine-induced neuroplasticity in mice.

A cocaine vaccine reduces drug-seeking behavior in animal models and will soon enter clinical testing in cocaine users.

Methadone, buprenorphine, and extended-release naltrexone all reduce opioid death rates; the best treatment choice depends on patient factors.

Nicotine metabolism genes influence the effectiveness of smoking cessation therapies.

The anti-drug

Even after prolonged periods of abstinence, exposure to drug cues can induce craving and behavioral changes in addicted people. Underlying this effect is the synaptic plasticity caused by cocaine and other drugs of abuse in the brain's reward system, driven by shifts in the AMPA receptor subunits that change the amount and type of synaptic transmission. "Can we reverse this cocaine-evoked synaptic plasticity and thus abolish the drug adaptive behavior?" asked Meaghan Creed of the University of Geneva.

To answer this question, Creed and her colleagues used optogenetics in mice. If cocaine is potentiating the strength of excitatory transmissions, then inducing depotentiation through optogenetics could reverse the drug-seeking behavior in mice. They expressed channelrhodopsin in the medial prefrontal cortex which, in response to light illumination, caused the release of glutamate specifically into the nucleus accumbens and depotentiation that successfully abolished the drug-adapted behavior in mice.

Next, Creed asked "can we achieve this with a more readily translatable therapy?" She and her colleagues were able to demonstrate the same reversal of drug-adapted behavior in mice using deep brain stimulation (DBS), along with a D1 antagonist, instead of channelrhodopsin and light illumination. They call the system optogenetic-inspired DBS, or OiDBS.

Optogenetic-inspired deep brain stimulation (OiDBS) combines low frequency stimulation and a D1 receptor antagonist to restore normal synaptic plasticity in cocaine addicted mice.

Vaccines could provide an effective option for preventing addiction by keeping drugs of addiction from getting to the brain. However, drugs of abuse are small molecules that would be poorly recognized by the immune system, as Ronald G. Crystal of Weill Cornell Medical College explained.

Crystal's lab is working to develop a cocaine vaccine using a replication-deficient adenovirus, which is highly immunogenic, as a delivery system. An analog of cocaine, either GNC or GNE, is coupled to the viral capsid protein to produce dAd5GNC or dAd5GNE, respectively. Studies in rhesus macaques found that vaccinated animals developed antibodies against the compounds, but these antibodies had short half-lives, so the animals had to be injected every month to maintain immunity. In both vaccinated mice and monkeys, there was a shift in distribution of cocaine following injection of the drug from the brain to the blood stream.

Vaccination with dAd5GNE correlated with reduced drug seeking behavior in rats and monkeys, supporting the vaccine's effectiveness. The Food and Drug Administration has approved dAd5GNE for clinical testing and Crystal's group will begin studying it in a cohort of people who use cocaine.

The other strategy to develop a cocaine vaccine, so far only tested in rodents, is to use an adeno-associated virus to deliver genes expressing anti-cocaine antibodies to the liver. One advantage of this strategy is that the expression could persist for many years so a single dose of vaccine might suffice.

Two strategies to develop cocaine vaccines that are being pursued involve adenoviruses (left) and adeno-associated viruses (right).

Using what we have

Treating opioid addiction involves managing withdrawal symptoms and cravings as well as normalizing the stress response. "The problem is when we only detoxify an individual, which is the actual dominant mode in this country, we are not really providing adequate care," said David R. Gastfriend, of the Treatment Research Institute at the American Society of Addiction Medicine. He outlined the role of the three existing treatments for opioid addiction: methadone, buprenorphine, and extended-release naltrexone.

Opioids bind the mu-opioid receptor, and methadone and buprenorphine work as full or partial agonists of this system, respectively, while naltrexoneis an antagonist. All three reduce overdose and death rates compared with counseling alone, but there are important differences between the treatments that could make one more acceptable to a patient than another. Methadone, which has to be taken every day and requires daily clinic visits, has higher rates of retaining people in treatment than buprenorphine, which is longer lasting and does not require daily visits to a clinic. However access to both is inadequate; methadone is not available in many areas of the country, and many physicians do not have waivers to prescribe buprenorphine, a DEA Schedule C-III substance.

An injected extended-release naltrexone (XR-NTX) was developed because the oral form failed to increase abstinence rates among addicts compared with placebo. Individuals have to be opioid free before starting XR-NTX, Gastfriend said. Yet because naltrexone is not a controlled substance, it can be easier to access for those motivated to be opioid-free. Naltrexone therapy is more expensive per day of treatment than methadone or buprenorphine, but could be more cost-effective.

Drug addiction has a strong genetic component. Among cigarette smokers, genetic factors account for about 86% of the variation between individuals in amount of cigarette consumption and 60% of the variation in quitting rates. People who have variants of the nicotine metabolism gene CYP2A6 that confer slower metabolism are about 3.7 times more likely to quit smoking compared with fast metabolizers, explained Rachel F. Tyndale of the Centre for Addiction and Mental Health at the University of Toronto.

But there's still hope for people who are fast or normal nicotine metabolizers; in this group, nicotine has a half-life of about two hours instead of three hours. The nicotine patch is more effective among slow metabolizers, but fast and normal metabolizers respond well to bupropion and varenicline, respectively. Nicotine metabolism status also seems to affect the risk of side effects of smoking cessation therapy. Varenicline is associated with an increase in abnormal dreams among slow metabolizers compared with normal metabolizers, and a decrease in irritability and anxiety among normal metabolizers.

Tyndale and her colleagues are trying to understand the neural basis for these differences. "By two or three days of stopping smoking all that nicotine is essentially gone, so why are we having these really substantial[ly] different quit rates way out at six weeks or six months?" Tyndale asked. Two factors that could contribute are that fast metabolizers had stronger reactions to smoking cues, based on fMRI studies, whereas slow metabolizers had decreased availability of nicotinic receptors.

People with variants of the CYP2A6 gene that confer slow nicotine metabolism are nearly four times more likely to quit than fast metabolizers.

Speakers

Susan R. B. Weiss

National Institute on Drug Abuse, U.S. National Institutes of Health

P. Read Montague

Virginia Polytechnic Institute; University College London

Yasmin Hurd

Icahn School of Medicine at Mount Sinai Hospital

Mark A. R. Kleiman

New York University

Highlights

In March, the NIH convened a landmark conference to discuss neuroscience and policy research on marijuana.

Marijuana use during pregnancy has been associated with expression changes in genes involved in drug use in babies.

Models of neuronal activity could help predict individual behavior and the effect of drug use.

More regulations are needed on the sale and use of alcohol and marijuana.

Collaborating on cannabis

On March 22, the National Institutes of Health convened five of its institutes in a two-day conference called "Marijuana and Cannabinoids: A Neuroscience Research Summit." "It is really a landmark event because NIDA for a long time has been trying to get other institutes interested in cannabis and cannabis research because not all of the questions are those that fall within our mission," said Susan R. B. Weiss of the National Institute on Drug Abuse (NIDA).

The summit covered the state of the science and areas where more research is needed on the endocannabinoid system, the developing brain, psychosis, and policy research. "We have come a long way in understanding the endocannabinoid system and in thinking about how it may have potential for a wide variety of therapeutic indications, but we have come much less far in looking at the therapeutic effects of cannabis the plant," Weiss said. One of the most exciting new directions in therapeutic development is tweaking the endocannabinoid system, such as by inhibiting enzymes that break down endogenous cannabinoids, Weiss said.

Weiss summarized conflicting research on marijuana's effects on cognitive impairments in adolescents. A study in a Dunedin, New Zealand, cohort linked marijuana use with decreases in IQ, but a recent twin study found no difference in IQ among teens that used marijuana. "The dose, the strain, the potency, all of these things may be giving us very different effects," Weiss said. Data are more consistent on psychosis, with several studies suggesting that early cannabis use could increase the risk of developing schizophrenia in people who have genetic risk factors for the disease.

The policy discussion at the summit was well received, Weiss said. Speakers discussed challenges in policy research due to differences between states, and some states have recently changed their marijuana policies.

Many studies have linked early cannabis use with increased risk of schizophrenia among those with genetic risk factors.

Baby's first dose

Yasmin Hurd of the Icahn School of Medicine at Mount Sinai Hospital discussed transcriptional and epigenetic profiles associated with drug use that could help elucidate the neurobiology of addiction and improve treatments.

In a study of post-mortem brain samples, Hurd and her colleagues have found stark differences between heroin users and control individuals in the transcriptional profile in the nucleus accumbens, particularly for glutamatergic genes, and in the epigenetic profile, such as histone acetylation at the GluA1 glutamate receptor subunit. Studies in rats found the same transcriptional and epigenetic changes occurred after animals started using heroin, suggesting drug use could be causing these changes. Inhibitors of bromodomain protein complexes, which are involved in transcription at acetylated histones, decreased heroin self-administration in rats.

Hurd's group is also studying the effects of marijuana on the developing fetal brain. Almost 20% of newborns in the U.S. have THC in their meconia. Hurd and her colleagues found reductions in expression levels of dopamine D2 receptor and other genes involved in substance use in babies born to mothers that reported smoking marijuana during pregnancy. The research also suggests there could be germline transmission of cannabis effects, as rats exposed to low doses of THC during adolescence had offspring that were more likely to self-administer heroin. "It is not only during your lifetime [but] there is indeed vulnerability both in humans and our animal models and this cuts across generations," Hurd said.

Babies born to mothers who smoked marijuana during pregnancy have lower levels of dopamine D2 receptors.

Great expectations

Can the behavior of neurons be modeled computationally to predict individual behavior and the influence of drug addiction? P. Read Montague of Virginia Polytechnic Institute and University College London hopes to answer that question. Focusing on midbrain dopamine neurons, his hypothesis was that neurons fire, releasing dopamine and serotonin, at rates that reflect the expectation of reward. The rate stays the same if the expectation does not change, but increases or decreases with the expectation. "They are always emitting information even when they are quiet," Montague said.

Montague's group has focused on the neural signature underlying reward-based errors that people make when they engage in betting tasks. They found that the signature associated with error was similar between smokers and nonsmokers, based on fMRI studies, but that "in smokers' brain[s], it is decoupled from having an impact on their behavior," Montague said.

The group also adapted a technique used in rats called fast-scan cyclic voltammetry to allow them to see sub-second fluctuations in dopamine and serotonin firing simultaneously from midbrain dopamine neurons. In a group of Parkinson's disease patients with electrodes implanted for deep brain stimulation, they showed that dopamine levels tracked very closely with the betting task, underscoring the role of dopamine in gambling addiction.

The expectation of reward is thought to lead to changes in spikes of dopamine release.

Uncontrolled substances

Moving beyond the brain, Mark A. R. Kleiman of New York University discussed the myriad effects that drug addiction has at the individual and societal level. Kleiman disclosed that his firm works for the Washington State cannabis board, and he would probably profit personally from the legalization of cannabis.

Kleiman focused on three drugs of abuse in his talk: alcohol, nicotine, and cannabis. He called alcohol the "classic case" of inadequate control; since Prohibition, its availability has become virtually uncontrolled. Kleiman highlighted two effective strategies for reducing the harms of alcohol abuse: federal alcohol tax increases and the 24/7 Sobriety Project, which establishes zero tolerance for repeat drunk driving offenders. These strategies lead to substantial decreases in rates of homicide, mortality, and automobile crashes. For tobacco, Kleiman explained that big variations in state taxes have driven up the rates of smuggling in the last decade, and that market is expected to continue to grow.

Although cannabis use is lower than alcohol use, it has rapidly expanded in the past 20 years. More than 80% of cannabis use in the U.S. is only weekly or less often, and there is no evidence of harm with that infrequent use. However, the remaining 20% are heavy users, and are a rapidly growing group. "We are moving toward an alcohol model of essentially unregulated legalization: modest taxes, a rule against selling to minors, and not much else," Kleiman said. The policy goal should instead be to make cannabis legal for moderate use among adults, such as by allowing only government stores to sell it, he added.

Speaker

Patrick J. Kennedy

Former United States Representative for Rhode Island; co-founder of One Mind; founder of the Kennedy Forum

Highlights

The Kennedy Forum advocates improvements in five broad areas of mental health care, from parity to screening and diagnosis.

The main barriers to better mental health care are political disinterest and unwillingness of clinicians to work together.

Legalizing cannabis will disproportionately affect minority groups who have less access to health care.

Five pillars

Treatment for mental health and substance use disorders is separate and unequal from the rest of health care, declared Patrick J. Kennedy, Former United States Representative of Rhode Island, co-founder of One Mind and founder of the Kennedy Forum, in his closing keynote address.

Kennedy opened his talk with a video that the Kennedy Forum created to illustrate the five pillars needed to improve mental health and addiction treatment. One of the pillars is parity, which is addressed by the Mental Health Parity and Addiction Equity Act that Kennedy wrote when he was in Congress. It requires insurance providers to cover mental health treatments like they would other health conditions. The other pillars are early screening and diagnosis of mental health disorders, brain fitness and training, technology to help patients manage and find care, and coordinating health care providers.

The biggest challenges to achieving improvements in mental health care are politics, and bringing together disparate groups of clinicians, said Kennedy, who has struggled with addiction. No one in Washington is sounding the alarm about problems with mental health care, such as not having enough doctors, and poor reimbursement rates and prescribing restrictions for doctors that do provide care, he said. There is also not enough focus on insurance providers, especially for self-insured plans, measuring outcomes and not just following up when a person returns to a rehabilitation program.

Although Kennedy has led efforts in Congress for drug courts and does not support incarcerating people with addictions, he opposes the legalization and commercializing of cannabis. He argues it will disproportionately affect minorities and the poor, like alcohol does. "If you are a progressive liberal who cares about public health, you cannot stand by and watch a new industry like big tobacco take over and addict poor people who don't have access to the Mayo Clinic [and addiction psychiatrists] like I do, and they are going to be out there struggling," Kennedy said.

What are the differences in brain networks in adolescents that put them at higher risk of addiction?

How do stress and other environmental exposures influence the connectivity of the prefrontal cortex in adolescents?

Can neurotransmitters that mediate drug-evoked neuroplasticity serve as therapeutic targets?

What are the epigenetic and transcriptional changes that accompany drug-evoked neuroplasticity?

What are the long-term consequences of early use of alcohol, marijuana, and electronic cigarettes in adolescents?

Are the differences in brain structure and function associated with drug use in adolescents caused by drug use or risk factors that precede drug use?

Can stress-reduction interventions in children and adolescents change the trajectory of brain development?

Will vaccines be an effective strategy to prevent drug use?

How can we increase the uptake and retention of effective treatments among opioid users?

How can research on the effects of marijuana legalization better account for policy differences between and within states?

Could taxation and other strategies shown to be effective for reducing harms of alcohol use be applied to marijuana use?

How can policy makers, clinicians, and politicians improve access to and quality of care for mental health and substance use disorders?