125th Meeting Minutes

Minutes - February 15th

The National Advisory Council on Drug Abuse convened its 125^th meeting at 9:00 a.m. on February 15, 2017 in Conference Rooms C & D, 6001 Executive Boulevard, Bethesda, Maryland.  The closed portion of the meeting held on February 15^th was for the purpose of reviewing applications for Federal grant assistance and was open only to Council members and Federal employees.  The open portion, which was open to the public on February 15^th, began at 11:00 a.m. and was also webcast.  The Council adjourned on February 15, 2017 at 3:59 p.m.

Council Members Present
Anne Andorn, M.D.
Laura Bierut, M.D.
Julie Blendy, Ph.D.
John Carnevale, Ph.D.
Linda Chang, M.D.
H. Westley Clark, M.D., J.D.
Arthur Dean, M.A.
Karl Deissesroth, M.D., Ph.D.
Marie Gallo Dyak
Jay Giedd, M.D.
Kenneth Mackie, M.D.
Lisa Marsch, Ph.D.
Edward Nunes, M.D.
Robert Rancourt, J.D.
Steffanie Strathdee, Ph.D.

Council Members Absent
Judith Auerbach, Ph.D.
Eric Verdin, M.D.

Council Chair
Nora Volkow, M.D.

Executive Secretary
Susan Weiss, Ph.D.

Federal Employees Present

Members of the Public Present
Leslie Cohen–Addiction Technology Transfer Center (ATTC)
Anjali Jain–The Lewin Group
Estelle Ntowe–Kelly Services, Inc.
Dena Procaccini–Kelly Services, Inc.
Ann Rea–Kelly Services, Inc.
Juli Rose–A. Bright Idea, LLC
Jen Sizemore–A. Bright Idea, LLC
Albert Terrillon–Community Anti-Drug Coalitions of America (CADCA)
Roy Walker–Synergy Enterprises, Inc.
Patrick Zickler–The Palisades Group, LLC
Rita Valentino–Brain and Behavior Research Foundation

Closed Portion of the Meeting – February 15, 2017

1. Call to Order

   This portion of the meeting was closed to the public in accordance with sections 552b(c) (4) and 552b(c) (6), Title 5, U.S. Code and section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix 2).

   Dr. Nora Volkow, Director, NIDA, called the meeting to order and welcomed the Council and staff.  She reminded those present that the Federal Advisory Committee Act applies to Council meetings and that this portion of the meeting was closed to the public. 

   Dr. Susan Weiss, Executive Secretary, summarized relevant NIH policies, provided detailed instructions on Council review procedures, and reminded those present about NIH confidentiality and conflict of interest policies.  

2. Application Reviews

   In turn, the Director or a designee for the Division of Epidemiology, Services and Prevention Research, the Division of Neuroscience and Behavior, and the Division of Therapeutics and Medical Consequences presented their applications for consideration by the Council.  For each, Council provided concurrence with the initial scientific reviews en bloc.  Council also approved Administrative Supplements.   Relevant applications were presented to Council for Special Council Review, and Council agreed with program assessments. All Trans-NIH Initiatives, i.e., Common Fund applications and NIDA Secondary applications also received Council concurrence.

   Members must absent themselves from the Council meetings during discussion of, and voting on, individual applications from their own institutions or other applications in which there is a conflict of interest, real or apparent.  Conflicts of interest statements were signed by each member of the Council.  Members were not required to leave if an application in conflict with that member was acted upon en bloc.  

3. Tobacco Industry Funding
   
   A brief discussion was facilitated by Drs. Susan Weiss and Kevin Conway concerning conflicts of interest posed by tobacco industry funding of specific research applicants.  The discussion was tabled, but will be followed up at the next Council meeting. A Points to Consider Document that had previously been approved by Council, regarding these types of concerns served as the basis for the discussion.

Open Portion of the Meeting – February 15, 2017

1. Call to Order

   Dr. Nora Volkow, Director, NIDA, called the open portion of the meeting to order and welcomed all attendees.   She reminded the Council and audience that the meeting was open to the public in compliance with the Government in the Sunshine Act and indicated that time would be provided for public comment. Dr. Volkow introduced three new Council members: Drs. Linda Chang, Karl Deisseroth, and Kenneth Mackie.

   Linda Chang, M.D. is a Clinician-Researcher and Professor of Medicine (Neurology) at the University of Hawaii's John A. Burns School of Medicine. She received her M.S. and M.D. degrees from Georgetown University, and completed her Neurology Residency and Fellowship training at the University of California at Los Angeles (UCLA)., where she was appointed as a Faculty in the Department of Neurology (1992-2000).  She was recruited to be Chair of the Medical Department at Brookhaven National Laboratory 2000-2004.  Over the past 12 years, she directed the Neuroscience & MR Research Program, which she co-founded with Dr. Thomas Ernst, at the Queen’s Medical Center in Honolulu. She conducts clinical-translational research on brain injury associated with HIV-associated neurocognitive disorders, methamphetamine or marijuana use disorders and other co-morbid conditions, in the settings of brain aging and brain development.  Dr. Chang currently serves on three Editorial Boards, and has been a reviewer for numerous journals, grant review committees and advisory boards. She has published more than 200 scientific papers and 30 book Chapters and has many ongoing clinical research studies, including NIDA-sponsored clinical trials, and collaborates extensively with other investigators nationally and internationally.

   Karl Deisseroth, M.D., Ph.D. is the D.H. Chen Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford University, and Investigator of the Howard Hughes Medical Institute. He received his undergraduate degree from Harvard, his PhD from Stanford, and his MD from Stanford; he also completed postdoctoral training, medical internship, and adult psychiatry residency at Stanford, and he is board-certified by the American Board of Psychiatry and Neurology. He continues as a practicing psychiatrist at Stanford with specialization in affective disorders and autism-spectrum disease, employing medications along with neural stimulation. In the engineering school he developed and launched the undergraduate degree in Bioengineering at Stanford, and continues to serve as Director of Undergraduate Education in Bioengineering, while also teaching yearly medical physiology and optics courses. National-scale service has included the NIH BRAIN Initiative Working Group and nonprofit disease foundations including the Brain and Behavior Research Foundation (NARSAD) and the Michael J. Fox Foundation for Parkinson’s Research. He was selected a Howard Hughes Medical Institute Investigator in 2013, began serving as a foreign adjunct professor at the Karolinska Institute in 2013, and was elected to the US Institute of Medicine in 2010, to the US National Academy of Sciences in 2012, and to the German National Academy of Sciences (Leopoldina) in 2014.

   Over a period of less than twelve years, his laboratory created and developed both optogenetics (a technology for precisely controlling millisecond-scale activity patterns in specific cell types using microbial opsin genes and fiberoptic-based neural interfaces) and CLARITY (a technology for creating composites of biological molecules in tissue covalently linked to polymer hydrogels (typically acrylamide-related), allowing removal of unlinked tissue elements to create transparency and accessibility to macromolecular labels; the resulting new structure allows high-resolution optical access to structural and molecular detail within intact tissues without disassembly). He also has employed his technologies to discover the neural cell types and connections that cause adaptive and maladaptive behaviors, and has disseminated the technologies to thousands of laboratories around the world. For his discoveries, Deisseroth has received the NIH Director’s Pioneer Award (2005), the Zuelch Prize (2012), the Perl Prize (2012), the BRAIN prize (2013), the Pasarow Prize (2013), and among other honors, was the sole recipient for optogenetics of the 2010 Koetser Prize, the 2010 Nakasone Prize, the 2011 Alden Spencer Prize, the 2013 Richard Lounsbery Prize, the 2014 Dickson Prize in Science, the 2015 Keio Prize, the 2015 Lurie Prize, the 2015 Albany Prize, and the 2015 Dickson Prize in Medicine.

   She then called attention to future Council meetings:  May 2, 2017 (NACDA) and May 3, 2017 (CRAN Joint Meeting), and September 6, 2017.

   Kenneth P. Mackie, M.D. is a Professor of Psychological and Brain Sciences at Indiana University, Bloomington, IN (IUB) and an Adjunct Professor of Anesthesiology at Indiana University School of Medicine.  He is also the Linda and Jack Gill Chair of Neuroscience and the Director of the Gill Center for Biomolecular Science at IUB.  He received his MD from Yale University, and completed his Internal Medicine Internship in the Yale system and Anesthesiology Residency at the University of Washington.  He did post-doctoral work at Rockefeller University and the University of Washington.  For fifteen years he combined an active laboratory research program with clinical care in anesthesiology at the University of Washington.  In 2007 he was recruited to IUB as a Gill Chair.  Dr. Mackie’s research interests focus on understanding the relationships between cannabinoids (such as THC), endocannabinoids, and the pharmacological and physiological responses to both.  His lab takes diverse approaches (imaging, electrophysiological, behavioral, molecular, and biochemical) to address these questions.  He has served on numerous national and international review boards and has taken an active role in organizing cannabinoid-themed meetings.  Dr. Mackie is a member of several professional societies including the Society for Neuroscience, the British Pharmacological Society, the International Cannabinoid Research Society, and the American Society of Anesthesiologists.

   She then called attention to future Council meetings:  May 2, 2017 (NACDA) and May 3, 2017 (CRAN Joint Meeting), and September 6, 2017.

2. Consideration of the Minutes of Council

   The Minutes of the NIDA October 2016 meeting were unanimously approved as written. 

3. NIDA Director’s Report – Nora Volkow, M.D., Director, NIDA

   Dr. Volkow began by announcing the recent departure of Dr. Phil Skolnick, the Director of the Division of Therapeutics and Medical Consequences (DTMC) to the private sector.  Dr. Skolnick was with NIDA for seven years and during his tenure created relationships with pharmaceutical industry partners to move products forward.  He will continue as emeritus scientist and serve as a scientific advisor at NIDA.  Dr. Ivan Montoya has stepped up as the Acting Director of DTMC until the hiring freeze is lifted and a search committee can identify the ideal candidate; one who has expertise in pharmacology or neuroscience, as well as in medication development.

   The next topic was an update on the budget, which continues to be under Continuing Resolution until April 28, 2017.  NIDA’s fiscal year (FY) 2017 operating budget is the same as that for 2016 at a little over $1 billion, with the AIDS allocation at approximately one third of the total budget; however, due to reconfiguration of NIH’s Office of AIDS research priorities, there is a slight decrease in overall AIDS funding from previous fiscal year actuals. 

   She then provided NIDA’s program level in appropriated and constant 1998 dollars.  Even though the total appropriated dollar amount has been steadily increasing, NIDA’s purchasing capacity has been stable at 1998 levels.  A major consequence of such limited purchasing power is limited ability to fund and support the increasing number of scientific research applications.

   Turning to what is new at NIH, Dr. Volkow announced the recent release of the Surgeon General’s Report on Alcohol, Drugs, and Health: Facing Addiction in America.  NIDA and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) participated, with leadership from Tom McLellan, a NIDA grantee taking the lead in organizing the document.  While there have been several Surgeon General reports released focusing on tobacco and tobacco products, this is the first to focus on other drugs. The intent of this report is to accelerate the use of evidence-based prevention and treatment interventions, as well as promote a better understanding of substance use disorders. 

   Another important event, is the passing of the 21^st Century Cures Act, which proposes to fund the following four research initiatives: 1) The Moonshot Cancer Research Initiative, which will receive $1.8 billion over the next 7 years; 2) the Precision Medicine Initiative, which will get $1.45 billion over the next 10 years; 3) the BRAIN Initiative at $1.5 billion over the next 10 years; and 4) the Regenerative Medicine Initiative, that will be funded $30 million over the next 4 years.  The BRAIN Initiative began in April 2013 and in 2014, NIH awarded 58 projects at a cost of $46 million.  Since 2014, over 100 awards totaling over $150 million have been made to researchers from 13 countries.  This project has been very successful, and has allowed experts from areas not typically supported by NIH, such as engineering, to participate and interact with neuroscientists, chemists and geneticists.  The increased funding for the BRAIN Initiative, along with the diversity in scientific disciplines, has led to the following FY2017 Funding Opportunity Announcements (FOAs) focused on:  Cell census networks; next generation human brain imaging tools and technologies; training for postdocs and career enhancement; data informatics; ethical implications of advancements in neurotechnology, and integrated approaches across scales. 

   Dr. Volkow highlighted The National Academies of Sciences, Engineering and Medicine (NASEM, formerly the Institute of Medicine) report “The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research”, which was released on January 12, 2017.  She encouraged council members to participate in the follow up stakeholder engagement meeting scheduled for February 21, 2017.  This meeting is intended to give stakeholders an opportunity to discuss the report’s recommendations and proposed opportunities to advance the cannabis research agenda.  

   She then presented NIDA priorities, beginning with Prevention Research.  The first topic was 2016 Monitoring the Future Study, a NIDA sponsored grant to University of Michigan, that supports data collection from over 45,000 children in 8^th, 10^th and 12^th grades throughout the U.S. to assess the prevalence of drug use and attitudes about drug use.  Of note, Dr. Lloyd Johnston, the lead PI on this project for 42 years, has retired and Dr. Richard Miech will be taking over this lead role.  Overall the data were very positive, with drug use going down for most drugs, with the exception of marijuana—which remained stable among 12^th graders but decreased in 8^th graders.  Although 8^th graders reported decreases in all 3 measure of use of marijuana in the past year (lifetime, past year, past month), levels seem stable over the last 5 years.  Students are reporting the lowest rates since the start of the survey across all grades for past-year use of inhalants, methamphetamine, alcohol, cigarettes, and synthetic cannabinoids.  One concern has been the rise in use of e-cigarettes among teens; although the majority report using e-cigarettes for flavoring, 25 percent of 12^th graders surveyed think that the mist from the e-cigarettes may contain nicotine.  E-cigarette use also declined in 2016; however, this is an area that requires continuous monitoring to ensure that teenagers do not resume nicotine use via newer methods.

   Dr. Volkow then presented data from SAMHSA’s, National Survey on Drug Use and Health, 2016.  She showed a map of the U.S. highlighting which states have legalized marijuana for medical or recreational purposes, along with trends in regular marijuana use by age group.  Regular use was increasing overall, but highest in adults ages 18-25 years.  The rates among teenagers, ages 12-17 years were stable or decreasing, despite the changes in legalization statue in 28 states and the District of Columbia.  A Report from the Rock Mountain HIDTA from January, 2017 shows that Colorado is leading the country in the past month use of marijuana for ages 12 and older.  Since legalization, marijuana use in Colorado has steadily climbed, well outpacing the national average.  In addition, youth use has also steadily risen in Colorado since legalization, in contrast to the national average.  For 2014-2015, the percentage of population ages 12 to 17 who used marijuana in the past month dropped by 1.5%, where as it increased by 0.9% for Colorado.  NIDA launched a new Council Workgroup on Policy Research Related to Cannabis Legalization.  The purpose of this workgroup is to provide advice and guidance to NIDA on critical research questions/priority areas related to the changing legal landscape for cannabis.  It will be chaired by NIDA council member, John Carnevale, and includes other experts in the area of policy research, as well as Ken Mackie (also a NIDA council member), and several NIDA staff.

   She then provided an ABCD Study update.  Since September 2015, the ABCD Consortium has: received central IRB approval, with local IRB approval where needed; developed policies and procedures, data informatics, outreach materials, and school-based recruitment strategies; conducted multi-site pilot studies; refined the baseline protocol; certified 18 sites to launch; added 2 new sites (University of Wisconsin Milwaukee, and the Medical University of South Carolina); begun enrollment -- to date there are 1,169 children recruited; and conducted analyses of data collected so far to validate measures. 

   Dr. Volkow then discussed NIDA’s Treatment Research priority area, focusing on the prescription opioid epidemic.  During 2015, drug overdoses accounted for 52,404 U.S. deaths, of which 63.1% involved an opioid.  From 2014-2015, the death rate from heroin increased by 20.6%.  There are multiple HHS agencies aggressively involved in addressing the problem of opioid abuse and related fatalities.  Per the CDC National Vital Statistics System, the prescription opioid drug increase began in the year 2000, which led to addiction and transition to heroin.  Now, with the introduction of powerful synthetic opioids, the nation is faced with another round of increased overdoses and mortality rates.  According to the National Forensic Laboratory Information System (NFLIS), fentanyl seizures have been increasing particularly in the Northeast.  Another concern is the emergence of several analogues to fentanyl like acetylfentanyl, sufentanil, and carfentanil.  These products are 50 to 100 times more potent than heroin, which poses incredible challenges at all levels, including the high risk of overdoses. 

   The goal is to develop pain medications that are not addictive, and develop user-friendly nasal delivery systems for naloxone that are affordable.  NIDA is working on research to help expand capacity.  In 2015, Jones et al., reported in the AJPH that there is limited capacity for opioid agonist medication assisted treatment (MAT) in the USA.  The difference between the number of individuals with opioid use disorder and MAT capacity was approximately 914,000.  This results in long waiting lists and increased risk for drug relapse.  A study by Sigmon SC et al., published in the New England Journal of Medicine in 2016, showed that giving interim buprenorphine led to abstinence from illicit opioids over 12 weeks.   This could be a way of integrating the health system with opioid use reduction.

   Dr. Volkow spoke about the 21^st Century Cures Act that was enacted in December 2016, and provides funding for biomedical research and streamlines the FDA drug approval process.  The provisions related to mental health and substance use disorders include, increasing providers in underserved areas; pediatric mental health care; eating disorders awareness, training and parity; community resources; grants to address opioid abuse—the act authorizes $1 billion in federal grants to states for use in carrying out opioid abuse prevention and treatment programs.  NIDA is working closely with SAMHSA on identifying related research areas.

   Dr. Volkow then went on to NIDA’s last research priority area:  HIV and drugs.  Two new funding opportunity announcements (FOAs) have been issued recently that align with the OAR goals.  One is RFA-DA-17-024: Optimizing the HIV care continuum for substance abusing populations at high-risk and/or living with HIV (R01).  This FOA encourages research that examines the optimization of multiple components of the care continuum, such as HIV testing (identification) status, linkage and retention in care, and viral suppression for individuals with HIV or substance abusing populations at high-risk and/or living with HIV.  The second is RFA-DA-17-020: Nicotinic immune modulation in the presence of HIV-1 infection (R01).  It encourages the submission of research project applications to determine nicotine’s modulatory effects on peripheral and central immune system functions in the presence of HIV-1 infection.  In addition, several previously cleared concepts are being reissued as RFAs, all led by Dr. Jacques Normand, Director of the AIDS Research Program at NIDA:  Advancing exceptional research on HIV/AIDS and substance abuse (R01); NIDA Avant-Garde award program for HIV/AIDS and drug abuse research (DP1); and the Avenir award program for research on substance abuse and HIV/AIDS (DP2).

   She then presented a list of national and congressional activities, in which she and NIDA participated, including the National Drug and Alcohol Facts week that was held on January 23-29, 2017.  More than 2100 national and international events were held, including 125 events from Mexico alone.  Fifty two schools participated in chat day--nearly 10,000 questions were submitted; and more than 60 scientists and science writers answered almost 2500 questions in a 10 hour web chat with teens.   Dr. Volkow concluded her presentation by informing council and the audience that NIDA has been working with HBO on an hour long documentary that will air in the spring “Warning: This Drug May Kill You.”  It portrays an emotional description of the consequences of opioid addiction through the eyes of families who have lost loved ones, or who are still struggling to help family members.  HBO has asked NIDA to partner with them on building an online resource page to offer more information on MAT and evidenced based treatment. 

   Council thanked Dr. Volkow for her presentation and for NIDA’s continued efforts at studying ways to make treatments accessible.   One council member brought up the need for research on Naltrexone in pregnant women, as well as in the area of new technologies, such as neurostimulation for treatment of withdrawal symptoms of substance abuse.  Dr. Volkow assured them that NIDA is working closely with NIMH and NINDS on understanding the mechanisms by which direct electrical stimulation or transcranial magnetic stimulation influence the brain.  Council also applauded NIDA’s leadership in emergency room departments, and infectious disease clinics to engage persons with opioid use disorders in different settings.

4. Priorities for the NIMH – Joshua A. Gordon, M.D., Ph.D., Director, NIMH, NIH

   Dr. Gordon began with the National Institute of Mental Health’s (NIMH) vision of a world in which mental illnesses are prevented and cured.  The mission to achieve that vision is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure.  The NIMH is the lead federal agency for research on mental illnesses; it supports more than 3,000 research grants and contracts at universities and other institutions across the country and overseas; in addition, NIMH’s intramural program supports approximately 600 scientists working on the NIH campuses.

   Dr. Gordon stated that he has no immediate plans to launch rapid and dramatic changes in direction.  His first task will be to listen to the perspectives of the people around him who are invested in what NIMH does.  This includes NIMH staff, as well as large and varied communities outside of NIMH, including the membership of American College of Neuropsychopharmacology (ACNP), extramural scientists, caregivers, consumers and consumer advocates, practitioners, trainees, and policy makers.  Scientifically, NIMH, as well as NIDA, are in an era of extraordinary possibilities.  Noninvasive imaging techniques for identifying and interrogating risk genes, approaches to characterizing and observing the connection between circuits and behavior, all of which present unprecedented possibilities for understanding the brain and its disorders.

   In psychiatry, he continued, there are complex challenges that include limited knowledge base, diagnostic uncertainty, and limited treatment options.  He discussed his struggles in the clinic to teach residents about the neural underpinnings of mental illnesses while simultaneously acknowledging the uncertainty engendered by the limited knowledge base. 

   He suggested that in order to improve that situation, NIMH will work toward a balanced research portfolio based on diversity in many forms.  Importantly, research must have diversity in terms of time frames.  Research has the potential to improve clinical care over the short, medium, and long term.  For short-term, this includes disorders in the present that require research to help ensure broad access to the most effective currently available treatment.  For the medium- and long-term, research must build the knowledge base that will lead to transformative treatments in the future, and fully investigate new treatment targets and methods as they arise.  Dr. Gordon’s areas of particular interest include neural circuits, computation and theoretical approaches to psychiatry, and suicide prevention. 

   Suicide prevention is an example of Dr. Gordon’s vision for a short-term investment that can have immediate and appreciable impact.  He shared some statistics indicating that suicide rates in the U.S. have risen since 1999; it is the 10^th leading cause of death overall, and has not decreased over time. Suicide prevention is a top Institute priority, and NIMH is a member of the National Action Alliance for Suicide Prevention, whose Research Prioritization Task Force issued a Prioritized Research Agenda aimed at “Zero Suicide;” NIMH has a Suicide Research Consortium; partnerships in suicide prevention efforts, such as Army STARRS, Mental Health Research Network, among others; and funds projects and studies aimed at reducing suicide rates. 

   Understanding Neural Circuits, is an example of a medium-term investment, as circuit neuroscience is fundamental to improving the understanding of the neural circuitry underlying the devastating symptoms of mental illness.  The disabilities that patients with neuro/mental/substance abuse disorders suffer is a direct result of disordered brain circuits. He offered two potential routes on such a road map, first, circuit neuroscience technologies could be directly translated into therapeutic interventions in humans; second, circuit neuroscience might identify key neurobiological targets amenable to conventional therapies. 

   And finally, in the long term, computational psychiatry holds promise in providing insight into psychiatric illness via idealized simulations.  From this perspective, diagnostic categories are not causes of signs and symptoms, but are diagnostic consequences of psychopathology and pathophysiology.  He then added, the key advantages of a reformulated nosological formulation include:  The formal integration of diagnostic categories and latent psychopathological constructs, such as data driven approaches; hypothesis/model space that accommodates formal evidence-based hypothesis testing, such as using Bayesian model comparison; the ability to predict therapeutic responses as in precision medicine; and a framework that allows one to test hypotheses about the interactions between pharmacological and psychotherapeutic interventions.  These and other advantages are largely promissory at present.

   Dr. Gordon then continued with some of the challenges facing the NIMH, including maximizing the utility of the Research Domain Criteria (RDoC) Initiative and experimental therapeutics approaches, as well as weighing the relative contribution of consortia-driven “big science” vs. hypothesis driven “small science.”  As the Experimental Therapeutics approach realigns research with treatment development, RDoC aims to focus clinical research.  It represents NIMH’s first approach for better classifications of mental illnesses, to advance therapeutics by understanding mechanisms underlying mental illnesses, to focus on top-down and expert driven approach, and to consider bottom-up, data driven approaches.

   NIMH requires an experimental therapeutics approach to the development and testing of interventions, in which interventions serve not only as potential treatments, but also to generate information about the mechanisms an underlying disorder:  This involves careful selection of treatment groups to test mechanisms, early stage trials to provide signs of failure or success, negative results to redirect attention and doses based on adequacy of target engagement.  An RDoC-like approach, which includes genetic analysis, may address gaps in knowledge of psychiatric diagnoses.  Genomics research will be crucial to such understanding, and NIMH efforts in this area include:  1) The Genomics workgroup that advises the National Advisory Mental Health Council (NAMHC) on future directions in psychiatric genetics and functional genomics, including how best to address the gap in knowledge between gene discovery and mechanistic models of disease that transcend categorical DSM disease classification; 2) Leveraging Electronic Medical Records for Psychiatric Genetic Research Workshop, to merge electronic medical records with genomic data and population-based registries for research on risk; and 3) Psychiatric Genomics Consortium (PGC) that uses the NIMH Repository and Genomics Resource to conduct meta-analyses of GWAS data. 

   Dr. Gordon concluded his presentation by reiterating the road ahead for NIMH, and his priorities for excellent science, and within the realm of excellent science, diversity.  Focus on learning and working closely with NIDA to gain insight that can help inform the future directions of research programs, address challenges facing NIMH, think more broadly about neuroscience, psychiatry, and public health; and help build momentum towards treatments that can change the lives of individuals, families, and communities affected by mental disorders.

   Dr. Volkow and Council members thanked Dr. Gordon for his presentation.  Council expressed their enthusiasm to have him lead NIMH and for the potential for great research with NIDA.  Dr. Gordon was encouraged to participate in the Collaborative Research on Addiction at NIH joint council activities, with NIDA, NIAAA and NCI.

5. NIDA’s Marijuana Policy Research Program: Understanding the Impact of a Rapidly Shifting Environment – Marsha Lopez, Ph.D., M.H.S., Chief, Epidemiology Research Branch, DESPR, NIDA

   Dr. Lopez began her presentation with a statement that under federal law marijuana is still considered illegal and doesn’t have any approved medical use; thus for the purposes of this presentation, the use of the terms medical or legal are based on the state definitions for ease of discussion.  For more than 40 years now the landscape of marijuana legalization has evolved to a point where nearly every state in the US has some form of law on the books.  28 states and the District of Columbia (DC) have what is termed “medical marijuana,” in addition, eight states and DC allow for recreational use of marijuana.  She showed a slide from a NIDA grantee, Rosalie Pacula at RAND, to highlight just one of the complexities in talking about marijuana legalization and what that means.  There is huge heterogeneity not only in what the law itself may be termed, but also from regulations on possession limits, home cultivation, patient registration, and residency requirements.  Also, there is the broad range of conditions that can be considered for the medical aspect.  Results from the Monitoring the Future data show that over the past 20 years, youth use of alcohol and cigarettes have been on the decline.  However, there is no indication of corresponding decreases in marijuana use.

   NIDA has provided multiple vehicles for the scientific community to respond.  In 2011, RFA-DA-11-008 “Medical Marijuana Policy Research: Exploring Trends and Impacts” awarded three research grants, then in 2013 eight applications that responded to PA-13-138 “Research on Marijuana Legalization in the U.S.” were funded , two of them to NIAAA funded projects.  And in the past two years, NIDA has had an open program announcement, PAS-14-020 “Public Health Impact of the Changing Policy/Legal Environment for Marijuana.”  To date, three grants have been funded.  Over time, NIDA has incorporated marijuana policy research into the broader funding opportunities, such as the epidemiology of drug abuse, among others.  More recently, PAR-16-055 “Mechanism for Time-Sensitive Drug Abuse Research”, and, in conjunction with NIAAA PA-17-132, 134, and 135 “Public Policy Effects on Alcohol-, Marijuana-, and other Substance-Related Behaviors and Outcomes” have been published.  These encourage use of certain policy surveillance resources.  One of the resources that NIDA supports is the Prescription Drug Abuse Policy System (PDAPS), which provides data on prescription drug abuse and medical marijuana laws.  Another one that is set to launch in the spring of 2017 is the Drug Abuse Policy System (DAPS), which offers longitudinal data on recreational marijuana, medication-assisted treatment with methadone, and drugged driving laws.  Also supported is LawAtlas, the Policy Surveillance Program, which is a national program of the Robert Wood Johnson Foundation at Temple University’s Center for Public Health Law Research.  It provides cross-sectional data on recreational marijuana (2015), local medical and recreational marijuana laws in Washington (2014), and more than 60 other health policies.

   Dr. Lopez moved on to policies thus far and how they have impacted marijuana use.  Among adolescents, marijuana use has mostly remained stable.  This has been shown by NIDA-funded researchers Drs. Hasin and Martins using data from the Monitoring the Future and the National Survey on Drug Use and Health.  In contrast, marijuana use among adults has increased.  In regards to dependence, NIDA grantees have shown that geographic areas that have higher density of dispensaries and local areas are associated with higher rates of abuse.  Silvia Martins et al., DAD, Vol 169, 2016: 26-32 “Prevalence of Past Month Marijuana Use by Age and State MML Status” points to the increased prevalence among adults aged 26 and older from 2004 to 2013. 

   Another issue affecting marijuana use and dependence is the many product types and methods available and being used.  Medical marijuana consumers use marijuana differently than recreational consumers, with smoking being the predominant method in youth; however, in medical marijuana states there is more likelihood to consume it in food or in other ways.  Also, social media is a source of information on novel forms of marijuana, such as YouTube videos of dabbing, as well as Tweets related to edibles and dabs are greater in states with medical and/or recreational marijuana laws.  

   Dr. Lopez showed the results of a study by Schmidt et al., AJPH August 2016: Vol. 106, No. 8:1498-1503 that looked at trends and attitudes about marijuana risk from 2004-2013.  Dr. Schmidt used 10 annual waves of the National Survey of Drug Use and Health, and showed that across all age groups there was less concern about risk, also a gradient in attitudes by age. Data from Monitoring the Future, shows the likelihood of wanting to try marijuana appears to be trending up among high school aged youth, especially if it is legalized in their state.

   Another concern, is the accessibility of marijuana given all the dispensaries.  Data indicate that medical marijuana patients themselves have great access to dispensaries, forms of use, more frequent and intensive use than non-patient marijuana users.  There appears to be a general lack of public understanding about age and possession limits.  Dr. Martins attempted to overlay principles of good manufacturing practices that are enforced by the FDA, and she discovered that there is great heterogeneity in practices that fall under “good medical practice” across dispensaries that are available.  It was noted that there was much higher enrollment in “less medicalized” programs, which is a concern.  The same paper looked at the perceived availability, and it was the highest among adults aged 26 and older.

   Moving on to health outcomes, there have been consistent reports of increased hospital visits and increased calls to poison control centers in states that have medical marijuana laws.  In addition, persistent use is being associated with anxiety disorder, and other substance use disorders.  She presented Dr. Booth’s data from the State of Colorado.  Since the Odgen Memo of 2009, there was creation of large dispensaries in medical marijuana centers.  By 2013, there was more than 150 percent increase in calls to poison control centers for marijuana related reasons compared to 2009.  Furthermore, there is evidence of both substitution and complementary use of other drugs with marijuana.  A number of NIDA investigators have reported either anecdotally or more quantitatively trends towards less use of prescription opioids in a couple of different ways. Some investigators reported that medical marijuana patients are using marijuana to get off opioids.

   Dr. Lopez then moved on to the social outcomes, such as crime, education, child abuse, among other community impacts.  Dr. Freisthier’s work looked at the density of dispensaries, and found that it is related to crime, but not in the immediate area around the dispensaries but rather in communities adjacent to the dispensaries.  It was found that in the state of Washington, early adolescent use of marijuana is associated with lower levels of functioning in adulthood, such as lower education and socioeconomic status (SES).  Studies by Martins have shown that overall, in states that have medical marijuana policies, there has been a decrease over time in traffic fatalities especially in the age group of 25-44. 

   She then showed Council a list of questions that she had posed to them three years ago. Many of them remain unanswered, but with limited resources and the evidence that is being gathered, it makes sense to highlight some areas of focus moving forward: 1) How does the potency/composition of marijuana products impact behavior, health outcomes, and treatment needs? 2) How are marijuana policies, or specific aspects of marijuana policies, impacting use of other substances? 3) What are the prevention needs of youth who may have greater access and exposure to marijuana use in a family environment?  NIDA has launched a new Council Workgroup on Policy Research Related to Cannabis Legalization to provide advice and guidance to NIDA on critical research questions/priority areas related to the changing legal landscape for cannabis.  It will be chaired by NIDA Advisory Council member, Dr. John Carnevale.

   Dr. Lopez concluded by reiterating NIDA’s commitment to addressing the issues around marijuana and that there is now more research being done related to marijuana across the ICs. NIDA has specific initiatives targeted to the changing policies and she thanked Dr. Volkow and Council for their support in moving these forward to provide useful scientific evidence to guide the policies in the future.

   Dr. Volkow and Council members thanked Dr. Lopez for her presentation. Many council members expressed enthusiasm for the research focus areas moving forward, and encouraged studies to look at synthetic cannabinoid use and drug substitution, as well as the impact of the illicit marijuana market on policies, as examples.

6. Concept Clearances – NIDA Staff

   Ten total concepts received Council clearance.  Three were presented by the Small Business Innovation Research (SBIR) program.

   David Thomas, Ph.D., Program Official, Services Research Branch, DESPR, NIDA presented on the Development of clinical research tools to accurately and objectively measure pain.  Between 1999 and 2011, the number of people in pain in the US doubled. Now, nearly one in three Americans suffers from persistent pain.  We have a crisis.   Partly in an effort to curb this pain, opioid prescribing over has drastically increased.   Now we have another crisis, prescription opioid abuse.  Over 19,000 Americans died from prescription opioid abuse in 2014.  Opioids have too often been used as a replacement for comprehensive pain treatments.  Solely relying on opioids for pain is not the answer for people in pain.  We need better treatment options for people in pain that is personalized and includes objective measures.  Just as we do not rely on a patient’s subjective estimations of core body temperature, blood pressure or heart rate, we should not rely on only subjective measures of pain. This purpose of this RFA is to develop a tool to objectively measure pain for research and treatment purposes. This tool would allow for improve basic and clinical pain research, allow better understanding of biological changes associate with the transition to chronic pain and be used to personalize pain treatment approaches. 

   Samia Noursi, Ph.D., Program Officer, Services Research Branch (SRB), DESPR presented her concept: Wearable to track recovery and relapse factors for people with addiction.  Currently there are few cost effective tools that enable researchers to study drug addiction relapse and its biological factors in real time. The gold standard in treatment and research settings remains urine analysis (UA) or self-report. Unfortunately urine analysis can only detect recent drug use (depending on the type of drug) in the previous 24 to 72h. Many synthetics are not detectable at all.  The proposed SBIR concept will support small business efforts that will address the above mentioned gaps by developing a recovery wearable and supporting mobile applications. Technology feasibility is now possible because of miniaturization and cost reduction of sensors necessary to capture digital biomarkers associated with relapse.  However, previous studies included limitations such as lack of ability to capture data in natural environments, the use of proper method of analysis, and data validation. Our proposed wearable will demonstrate that these gaps are addressed. Ultimately, researchers will be able to: Integrate this research tool into substance use disorder treatment services; collect digital biosensor data: breathing patterns, galvanic skin response, and heart rate variability and sleep monitoring; compare bio data to qualitative assessments and patient self-report; and create a model for just-in-time interventions.

   Rao Rapaka, Ph.D., Chief, Chemistry and Pharmacology Branch, DNB, NIDA presented on the Development of novel intranasal formulations for improved therapeutic delivery.  Intranasal drug delivery is recognized as a useful drug delivery method and has good potential for delivering therapeutics for drugs such as high-molecular-weight substances like peptides for the treatment of neurological disorders. Less than 5% of developed pharmacotherapeutic drugs are able to penetrate the blood-brain barrier. In addition, in many cases therapeutics need to be delivered to the CNS acutely to treat life-threating conditions (e.g., opioid overdoses) or reduce toxicity/degradation or for delivery of labile/large molecular weight compounds. Narcan, is a good example of an antidote for emergency treatment. This drug formulation, developed in conjunction with NIDA, can deliver naloxone intranasally to treat acute opiate toxicity/overdose by emergency care individuals as well as by untrained individuals. After success in preclinical studies, insulin, vasopressin, CCK-8 and oxytocin have been used to treat some neurological disorders via intranasal delivery in human beings. Utilizing nanotechnological methods, recent discoveries of safe and effective mucosal adsorbents, permeation enhancers, along with other innovative delivery systems, have made intranasal delivery even more attractive. Many important neurohormones and neurotransmitters are peptides that may be labile and/or cannot cross the BBB. Many lipid signaling molecules also suffer from similar drawbacks. In such cases, information is usually obtained from other stable synthetic analogs, however, the information obtained on the analogs may not truly represent the biological properties of the original and/or endogenous compounds, especially results involving PK/PD studies. There is a great need for delivering peptide drugs such as oxytocin, neurotensin, orexin, lipid signaling molecules such as anandamide or 2-AG analogs, or other nano-encapsulated therapeutics to broaden the possibilities of devising/developing novel treatments for addiction.  This SBIR solicitation seeks research proposals aimed at the development of formulations for the treatment of SUDs. The therapeutic formulation must be safe, effective, nontoxic and should have no long-range side effects. The PK/PD information, CNS bioavailability and analytical methods for quantitation should be provided. In addition to enhanced therapeutics, the small business may develop a formulation that delivers novel probes to the brain, which might be used to better understand the pharmacological role of endogenous compounds, especially labile compounds.

   The Division of Neuroscience and Behavior (DNB) presented the following FOA concepts:

   Vishnudutt Purohit, Ph.D., Program Officer, Integrative Neuroscience Branch presented on his concept:  HIV-Associated Neuropathic Pain and Opioid Interaction.  With increased survival of HIV-infected patients due to antiretroviral therapy (ART) there is an increase in those living with neuropathic pain. Despite long-term ART, low levels of viral replication persists in CNS HIV reservoirs resulting in constant release of neurotoxic HIV proteins, including Tat and gp120. These toxic proteins have potential to contribute to neuropathic pain directly via inducing neuronal damage and indirectly via glia activation. In addition, HIV-infected opioid abusers appear to exhibit more severe neuropathy than HIV-infected non-drug users and repeated use of opioid analgesics promotes chronic pain in HIV patients. The purpose of this FOA is to promote research investigating the underlying cellular, molecular, genetic, and epigenetic mechanisms whereby opioids including prescription drugs exacerbate HIV-associated neuropathic pain. Some of the proposed mechanisms are upregulation of TLR4, CXCR4, and CCR5 receptors and increased transfer of intestinal bacteria to the peripheral circulation. The ultimate goal is to obtain information for developing safe and effective treatments of neuropathic pain for HIV-infected patients exposed to opioids.

   Dr. Jonathan D. Pollock, Branch Chief, Genetics, Epigenetics, and Developmental Neuroscience Branch

   Concept: Pharmacogenomics of Immune Recovery in People Who Inject Drugs (PWID).  Twenty percent of HIV infected individuals who successfully suppress plasma viremia below the limits of detection do not recover sufficient CD4+ T cell counts. The failure to recover normal CD4+T cells after anti-retroviral therapy is associated with intravenous drug use. Poor CD4+T cell recovery is associated with increased mortality and morbidity that has a genetic component. The goal of this funding opportunity is to identify genetic variants and epigenetic modifications affecting failure of recovery of CD4+T counts (<200) in PWID/HIV+ and PWID-/HIV whose viral load has been suppressed by ART for two years using existing resources or doing a prospective study. The resulting study will also provide information about gene by intravenous drug use interaction on recovery of CD4+ T cell count.

   Yu ‘Woody’ Lin, M.D., Ph.D., Program Official, Integrative Neuroscience Branch concept: Identification of Immune and CNS Biomarkers of HIV Infection and Substance Abuse Comorbidity.  The research objective of this FOA is to foster biomarker research to advance clinical assessment of damage and functional reservation of host defense mechanisms and comorbid complications at different phases of HIV-1 pathogenesis. Neuroimmunological profiling studies are encouraged for comprehensive evaluation of blood and CSF soluble and cellular proteins and other molecules that change during HIV infection and accompanying inflammatory and neurodegenerative alterations. These types of studies should enable identification of a set(s) of biomarkers that reflect the degree of damage and the functional resilience ability of the defense system, and facilitate establishment of standards, and the normal range of clinical lab tests that can detect early signs, and differentiate levels of functional and structural deterioration of the compromised immune and neural systems.

   John Satterlee, Ph.D., Acting Deputy Director of DNB presented his concept ‘Exploring Novel RNA Modifications in HIV/AIDS and Substance Abuse.’ Recent evidence suggests that certain RNA modifications have important biological and disease functions in mammals. Most covalent RNA modifications remain poorly characterized, although they are likely to influence RNA properties and functions such as RNA stability, trafficking, localization, activity, and patterns of interactions with other molecules. RNA modifications play a role in a variety of brain diseases including depression, schizophrenia, and addiction-relevant behaviors. For example, Fat Mass and Obesity (FTO), enzymatically demethylates m6A in RNA, an activity that alters dopamine function in mouse midbrain and striatum (Hess et al. 2013 Nature Neuroscience 16:1042-8).

   RNA modifications of the HIV RNA genome have been poorly characterized until recently. One research team has shown that depletion of enzymes that “write” the RNA modification m6A leads to decreased HIV replication as a result of decreased export of the m6A modified HIV RNA genome from the nucleus into the cytosol (Lichinchi et al. 2016 Nature Microbiology 1:article 16011). Furthermore they found significant changes to m6A levels on host mRNAs involved in the HIV-relevant processes. Meanwhile, another team has found that m6A reader proteins can inhibit HIV infection in cell lines and decrease HIV gag protein expression (Tirumuru et al. 2016 eLife 10.7554/eLife.15528). The mechanisms of m6A regulation in HIV/AIDS is very much under investigation. However there are at least three dozen additional RNA modifications in mammalian cells, and their role in HIV/AIDS and/or substance abuse is not known.   This FOA is designed to support exploration to see if any of the three dozen known mammalian RNA modifications also play roles in HIV infection, replication, or in HIV/AIDS disease progression. It will also support hypothesis-driven investigations to better understand how m6A and other better characterized RNA modifications function in HIV-relevant processes. Researchers will investigate the mechanisms by which HIV/AIDS-relevant RNA modifications may interact with chronic drug exposure and/or substance use disorders. The enzymes that read, write, and erase RNA modifications have evolved to bind to small molecules and are thus potentially druggable targets. Research in this area may lay the foundation for identifying novel HIV/AIDS therapeutic targets in the future.

   Dr. Jag Khalsa, MS, Ph.D., Chief, Medical Consequences of Drug Abuse and Co-occurring Infections Branch

   Division of Therapeutics and Medical Consequences (DTMC) presented the following two concepts:

   HIV/HCV Co-infections in Substance Abusers.  Currently an estimated 33 million people worldwide are living with HIV infection and 135 million people are living with HCV infection. In the US, the corresponding number of people with HIV and HCV infection are 1 and 3-4 million, respectively. An estimated 50,000 new cases of HIV and 30,500 newly diagnosed or incident cases of HCV infection in the US are diagnosed. Substance abuse plays a major role in acquisition and transmission of HIV/HCV co-infection with the highest incidence in persons with substance use disorders (SUDs). As many as 45-60% people with SUD are infected with HIV or HCV infection; an estimated 90% of HIV-infected IDUs are co-infected with HCV.  HIV/HCV co-infection in the context of substance abuse is associated with significant morbidity and mortality where pathogenesis of both infections is worsened by the presence of the other. An estimated 1 million people globally and 20,000 in the US die each year from HCV-related cirrhosis and hepatocellular carcinoma. Mortality due to HCV, particularly among those aged 55-64 years, has also been increasing, surpassing that due to HIV for the first time in the US in 2007 (confirmed in 2014). Populations most vulnerable to HIV/HCV co- infection and poor disease outcome are: young (15-24 yr olds) non-urban injectors (started with oxycodone), MSM (1.6/100 person/yrs, [6x more likely]); substance users with long-term chronic co-infection and those in incarceration settings. Some of the medical consequences associated with HIV/HCV co-infection of concern are: neuroAIDS, neuropsychiatric complications, cardiomyopathy, HIV-nephropathy, and HCV-renal disease, cardiac and hepatic steatosis, and antiretroviral therapy associated hepatic and cardiac steatosis. Substance abuse itself can exacerbate many of these comorbidities. Although there are several highly effective antiretrovirals (ARTs) available for the treatment of HIV/AIDS and recently approved highly effective direct acting antivirals (DAAs) for HCV cure, access to and successful engagement in treatment for persons with substance use disorders such as IDU and MSM remain critical issues. Therefore, eradication and cessation of viral transmission of infections in dually (HIV/HCV) infected opiate and other drug using populations, IDUs, MSMs, and the incarcerated is of paramount importance. Research is needed to develop improved strategies for prevention, screening, linkage to testing and care, and treatment and clinical management of HIV/HCV infection in persons with substance use disorders.

   The proposed FOA will support studies to (i) show whether  HIV/AIDS/HCV  disease is negatively impacted by  substance abuse and antiretroviral (HIV)  and/or drug treatment; (ii)  study the impact of HIV and substance use on health disparities in accessing care by HIV-infected substance abusing populations; (iii) determine whether drug abuse treatment or reduction in drug use can improve HIV/HCV, and other opportunistic infections (OIs) related health outcomes and/or disease progression; (iv) test the efficacy of antiretroviral medications and new HCV DAAs in HIV/HCV co-infected substance abusers; (v) develop new strategies such as telemedicine for integration of addiction MDs and IDs; (vi) implement adaptations of the STTR strategy to assess impact on care continuum; (vii) assess and prevent re-infections; and (viii) study drug-drug interactions between new ARVs, HAART and addiction medications.

   The second concept presented was Limited Competition Cohorts of HIV/AIDS and Substance Abuse Populations.  Through PAR12-222, NIDA supported a number of cohorts of HIV/AIDS and substance abusing populations to address emerging and high priority research on HIV/AIDS and other opportunistic infections. These cohorts continue to serve as a strong resource platform for current and future collaborative efforts with other investigators to address emerging questions related to HIV infection, prevention, and treatment in the context of substance abuse, as well as to foster the creativity and efficiency of investigator-initiated research. The purpose of this Limited Competition Funding Opportunity Announcement (FOA) is to support: (i) the maintenance of NIDA-funded existing cohorts to continue to address new emerging and/or high priority research on multidisciplinary aspects of HIV/AIDS and substance abuse, (ii) provide support for retaining HIV/AIDS infected substance abusing populations into the cohort(s) to provide insight into the demographics of the HIV epidemic among this high risk population in the US; (iii) encourage applications from:  current cohort investigators  This FOA will continue to provide a strong resource platform for current and future collaborative efforts with other investigators to address new and emerging questions related to HIV infection, prevention, and treatment in the context of substance abuse, as well as to foster the creativity and efficiency of investigator–initiated research goals.  The proposed FOA will support multi-disciplinary multi-component basic, behavioral, and clinical research to cover multiple areas of research including but not limited to: (i) impact of community or individual level treatment and prevention modalities related to substance abuse and HIV/AIDS, (ii) engagement and retention in care, adherence to treatment regimens, (iii) study HIV and OI-disease progression and outcomes, (iv) impact of long-term drug use on progression of HIV/AIDS and other OI-related disease; (v) immunologic and virologic responses to HIV therapy, (vi) progression of HIV, HIV/HCV disease, (viii) infections-associated medical and health consequences (neuro AIDS, cardiac, hepatic, renal, drug-drug interactions etc.) in drug abusing populations; and (ix) study the impact/role of the microbiome in HIV and HIV/HCV infections in substance abusing populations.   

   Dr. Sarah Duffy, Ph.D., Associate Director for Economics Research, and Acting Deputy Branch Chief, Services Research Branch, DESPR presented the last FOA concept:  Research on Responses to the Opioid Crisis.

   The 21^st Century Cures act authorized $1 billion in funding to the Substance Abuse and Mental Health Services Administration to target the opioid crisis. Almost $500 million has been appropriated this year, and Single State Agencies will apply for the funds through FOA TI-17-014. The amount states will receive is being determined by a formula. This sudden influx of funding represents an excellent opportunity for rigorous analysis of some important health services research and implementation science questions that could advance our understanding of how to best address this crisis. Specific research questions will come into focus only after information about States’ plans become available. The vast majority of funds are intended to be dedicated in some way to expanding access to treatment.  Thus, it is expected that many research questions will focus on issues related to efficient strategies for expanding access. Investigators would be encouraged to work with Single State Agencies to develop applications and implement funded projects. 

7. Public Comments
   None.

8. Adjourn
   The 125^th meeting of the National Advisory Council on Drug Abuse was adjourned at 3:59 p.m. 

Certification

I hereby certify that the foregoing minutes are accurate and complete.

Note: Informational materials provided to the public at the open session of the meeting may be obtained from the Executive Secretary.