124th Meeting Minutes

Minutes - September 8, 2016

The National Advisory Council on Drug Abuse convened its 124^th meeting at 9:00 a.m. on September 8^th, 2016 in Conference Rooms C & D, 6001 Executive Boulevard, Bethesda, Maryland.  The closed portion of the meeting held on September 8^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 September 8^th, began at 11:00 a.m and was also webcast.  The Council adjourned on September 8^th, 2016 at 4:29 p.m.

Council Members Present
Anne Andorn, M.D.
Judith Auerbach, Ph.D.
Laura Bierut, M.D.
Julie Blendy, Ph.D.
Regina Carelli, Ph.D.
John Carnevale, Ph.D.
H. Westley Clark, M.D., J.D.
Jay Giedd, M.D.
Lisa Marsch, Ph.D.
Edward Nunes, M.D.
Steffanie Strathdee, Ph.D.
Eric Verdin, M.D.

Council Members Absent
Arthur Dean, M.A.
Marie Gallo Dyak
James Hildreth, M.D., Ph.D.
Robert Rancourt, J.D.

Council Chair
Nora Volkow, M.D.

Executive Secretary
Susan Weiss, Ph.D.

Federal Employees Present

Members of the Public Present
Renata Henry–National Network of Addiction Technology Transfer Center
Kathryn Kaplan–Ogilvy Public Relations
Melissa Mera–A. Bright Idea, LLC
Ann Rea–Kelly Services, Inc.
Juli Rose–A. Bright Idea, LLC
Jen Sizemore–A. Bright Idea, LLC
Roy Walker–Synergy Enterprises, Inc.
Patrick Zickler–The Palisades Group, LLC

Closed Portion of the Meeting – September 8, 2016

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 Therapeutics and Medical Consequences, the Division of Neuroscience and Behavior, and the Division of Epidemiology, Services and Prevention Research 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. 

Open Portion of the Meeting – September 8, 2016

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 acknowledged the work of two retiring Council members, Drs. Regina Carelli and James Hildreth, thanked them for their service to NIDA, and presented Dr. Carelli with a certificate of appreciation (Dr. James Hildreth was not present).  She then introduced a new Council member, Dr. Jay Giedd.

   Dr. Giedd is a Professor in the Department of Psychiatry at the University of California, San Diego, and Director of the Division of Child and Adolescent Psychiatry at the Rady Children’s Hospital-San Diego. In addition, he is an adjunct Professor at Johns Hopkins School of Public Health in the Department of Family and Reproductive Medicine. Over the past 25 years Dr. Giedd has combined brain imaging, genetics, and behavioral analysis to explore the path and influences of brain development in health and illness. As one of the most highly cited neuroscientists of his generation, his over 200 scientific publications have had a transformative impact on medicine, psychology, education, judicial, and public policy.

   She then called attention to future Council meetings:  February 15, 2017, 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 May 2016 meeting were unanimously approved as written.  

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

   Dr. Volkow began her presentation with an update on the budget.  NIDA’s fiscal year (FY) 2016 operating plan places NIDA’s total budget 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.  The FY 2017 proposed budget is the same as that for 2016. 

   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 dollars.  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 new Director of the National Institute of Mental Health (NIMH), Joshua Gordon, M.D., Ph.D.  He is Associate Professor of Psychiatry at Columbia University Medical Center and New York State Psychiatric Institute.  He is also the associate director of the Adult Psychiatry Residency Program. His research focus is on mice with relevant mutations to schizophrenia, anxiety and depression; along with the use of new technologies, most notably in neurophysiology and optogenetics, to investigate the role of various circuits and proteins that may be involved in these diseases.  He is highly qualified and has a reputation for being very collegial, collaborative, and visionary and was strongly endorsed by Dr. Volkow.  He is expected to begin his appointment at NIMH on September 15, 2016. 

   Dr. Volkow then spoke about the BRAIN Initiative.  President Obama announced this initiative in April 2013; since then many accomplishments can be sited, including three rounds for funding applications, with one in August 2016 being the most recent.  The BRAIN initiative’s budget has been steadily increasing, and was up to $196 million for 2016.  The recommended budget from the BRAIN work group is to achieve $500 million per year by FY 2021.  The National Science Foundation, along with other third party participants, such as the Department of Energy, the Allen Institute, and the Simons Foundation have also been playing very important roles.  The first three years of the initiative focused on neurotechnology development, and as it moves forward, projects will transition to applying these technologies and tools to neuroscience research questions.  There are more than 150 publications already related to the BRAIN initiative.  The NIH has decided to recruit for a new BRAIN Director, which will be a senior level scientist to lead the initiative.  The Director will be housed at the National Institute of Neurological Disorders and Stroke (NINDS). 

   Dr. Volkow went on to highlight NIDA priorities, beginning with Prevention Research.  The National Survey on Drug Use and Health (NSDUH), funded by the Substance Abuse and Mental Health Services Administration (SAMHSA), released results of their 2015 survey earlier this morning.  Past month use of cigarettes has decreased and is at the lowest level in over a decade. Four percent of teens, ages 12 to 17, 27% of young adults, ages 18 to 25, and 20% of adults, ages 26 or older, reported past month cigarette use in 2015. Trends of past month alcohol use are less dramatic but there was a significant decrease in reported use among teens and an overall downward trend over time.  Among young adults and adults, 2015 rates remained high at about 58% and 69%, respectively. Past month marijuana use among persons aged 12 or older did not increase from 2014 to 2015, however, the overall long term trends vary by age group. For example, among teens, ages 12 to 17, recent years have remained stable; however, a significant decline was seen in past month use compared to 2002: 7% of teens reporting use in 2015 vs. 8.2% in 2002. Past month marijuana use is highest among young adults, ages 18 to 25, with 19.8% reporting past month use in 2015, a significant increase from 17% in 2002. Finally, among adults, ages 26 or older, rates significantly increased from 40.8% in 2002 to 46% in 2015.  In addition to past month marijuana use, it is important to also look at the number of past year marijuana initiates to get a better sense of the overall picture of marijuana use. In 2015, there were over 2.2 million new initiates of marijuana use among teens and young adults, ages 12 to 25.  Also, patterns of regular use (also referred to as daily or near daily use) of marijuana are associated with a higher likelihood of addiction and adverse effects. The good news is that regular marijuana use among teens has been stable, with 2.4% and 2.8% reporting regular use in 2002 and 2015, respectively. This is the age group that is most vulnerable to the adverse effects. Unfortunately, among young adults, ages 18 to 25, there was an increase in the regular use of marijuana from 6.4% in 2002 to 8.8% in 2015. Similarly, among adults, ages 26 or older, there was an increase from 2.0% in 2011 to 2.8% in 2015.

   NIDA, in partnership with other NIH Institutes (NIAAA, NIMH, NINDS, and NCCIH) hosted a well-attended scientific meeting titled “Marijuana and Cannabinoids: A Neuroscience Research Summit” on March 22-23, 2016.  The presenters addressed the basic science of the endocannabinoid system, as well as the adverse and potential therapeutic effects of marijuana and other cannabinoids on neurological, psychiatric disorders, and pain.  The goal was to ensure evidence-based information is available to inform practice and policy, particularly relevant at this time given the shifting landscape regarding the recreational and medicinal use of marijuana.  One area that could lead to the FDA’s approval of a medication is that of cannabidiol (a component of the marijuana plant that does not make people high) as an anti-epileptic agent.  Dr. Volkow encouraged all Council members to read the meeting summary and provide feedback on areas that NIDA, and NIH as a whole, need to better address through research.

   She then spoke about her recent and alarming observation of commercial advertisements encouraging pregnant women to use marijuana to alleviate severe nausea during pregnancy and also promoting it as a nutrient.  Research on the effects of marijuana during pregnancy is limited.  One recent study published in the Hawaii Journal of Medicine and Public Health. 2014 Sep; 73(9): 283-287 states that 6% of women in Hawaii reported using marijuana the month before pregnancy, and 2.6% during pregnancy.  According to an article in BMJ, women who used cannabis in pregnancy had an increased odds of anemia, and infants exposed to cannabis in utero had decreased birth weight and were more likely to need placements in the neonatal ICU.  Dr. Volkow emphasized the importance of more research in this area, considering results of other recently published studies:  Marcoita et al., looked at dose-dependent teratogenicity of the cannabinoid agonist CP-55940 in mice.   They found that the CP-5594-treated fetal mice showed abnormalities of the brain, eyes, palate and mandible.  Another study by Cone et al., measured the effects of secondhand cannabis smoke on non-smokers. Drug-free nonsmokers were placed in a closed chamber room with experienced cannabis users and exposed to smoke for 1 hour. Oral fluid, whole blood and subjective effects were measured prior to exposure and at several intervals after exposure to measure the levels of THC. Although THC concentrations were higher in smokers compared to non-smokers, exposure through passive inhalation resulted in substantial levels of THC in non-smokers that remained for nearly 3 hours. The data were plotted on a logarithmic scale because of the large difference in concentrations between the two groups after the first several hours. Exposure to secondhand cannabis smoke was also associated with subjective effects. The ratings of subjective effects correlated with the degree of exposure. Subjective effect measures and amounts of THC absorbed by nonsmokers (relative to smokers) indicated that extreme secondhand cannabis smoke exposure mimicked, though to a lesser extent, active cannabis smoking.  Dr. Volkow restated the importance of prioritizing research on fetal exposure to cannabis, and also the effects of second hand marijuana smoke exposure.

   She then spoke about a recent historic visit to the NIH by the Acting Administrator for the Drug Enforcement Administration (DEA), Chuck Rosenberg, on July 8, 2016.  He expressed interest in working with NIDA and NIH to maximize the likelihood of using marijuana in research, while protecting the public from harm.  On August 11, the DEA had a press release and reported on their decision regarding two petitions to reschedule marijuana from Schedule 1.  The DEA denied the petitions to reschedule marijuana under the Controlled Substances Act because “it does not meet the criteria for accepted medical use in the USA, there is a lack of accepted safety for its use under medical supervision, and it has a high potential for abuse.”  However, the DEA will allow for additional authorized marijuana manufacturers supplying researchers. This will provide researchers with a more varied supply of marijuana and should help expedite research on differing types and formulations of cannabis and cannabinoids.

   Dr. Volkow then provided an ABCD Study update.  NIDA has started new collaborations with the CDC Division of Adolescent and School Health, as well as with the National Institute of Justice.  Furthermore, a multi-site pilot study was completed to refine and test the protocol for acceptability; site initiation visits are underway.  The official launch of the ABCD study recruitment was on September 1, 2016.  A Congressional briefing is scheduled for September 19, 2016 to inform Congress on the value of this study.

   Dr. Volkow presented new NIDA Funding Opportunity Announcement (FOA) to solicit highly relevant and innovative research on the topics of genetics and epigenetics.  PAR-16-357: Avenir Award Program for Genetics or Epigenetics of Substance Use Disorders (DP1) with application due dates of October 19, 2016, October 19, 2017, and October 19, 2018.  This FOA is to support early stage investigators proposing highly innovative studies in genetics and epigenetics of addiction; including novel methods or approaches.  Investigators from outside the field of addiction are encouraged to apply; and although they might lack the preliminary data required to obtain an R01, they are able to propose high impact research, and show promise of being tomorrow’s scientific leaders in genetics and epigenetics of SUD.

   Dr. Volkow then discussed NIDA’s Treatment Research priority area, focusing on improving treatments for addiction, and was happy to share that the FDA approved the use of implanted buprenorphine on May 26, 2016.  This will help improve compliance, and also help reach populations that have limited access to facilities that dispense buprenorphine daily.  Another study recently published by Krupitsky et al. in the American Journal of Drug and Alcohol Abuse 2016, analyzed retention in treatment of patients who were given implantable naltrexone, oral naltrexone, or placebo.  Patients that received the implantable naltrexone had significantly higher rates of retention compared to patients given oral naltrexone (given daily) or placebo.  Another important area of research is the development of non-addictive pain medications with the same benefits of analgesia as morphine or other opioids. The negative effects of opioids are predominantly associated with the beta arrestin signaling pathway whereas the analgesic effects of opioids occur via the G-protein signaling pathway. Researchers have identified molecules that can selectively target specific signaling pathways, which have significant analgesic effects and reduced abuse liability.  A study in rodents demonstrated the feasibility of this approach with an opioid compound, PZM21. It had analgesic effects, with reduced side effects, and when compared to morphine, PZM21 has reduced effects on respiratory depression.

   Dr. Volkow then went on to NIDA’s last research priority area:  HIV and drugs.  NIH’s overarching AIDS research priorities are reduced incidence, including vaccines; next generation of HIV therapies with better safety and ease of use; research toward a cure; and HIV-associated comorbidities and co-infections with the cross cutting areas being in basic research, health disparities, and training.  The Office of AIDS Research (OAR) reviewed 1207 extramural NIH grants eligible for 2016 renewal.  Out of those, 242 grants were low priority ($65.2M); $14.2M from NIDA.  OAR also reviewed 56 intramural projects, and 26 of them were determined to be low priority ($6.6M); $3.3M from NIDA.  These amounts are significant, especially the effects it might have on an already budget restricted intramural program.  Thus NIDA is making it a priority to ensure realignment of its priorities with OAR’s in HIV/AIDS and substance abuse disorders.  Two new funding opportunity announcements (FOAs) have been issued to reach that goal.  RFA-DA-17-013: Mechanisms of Immune Activation and Inflammation- HIV Infection, ART, and Drugs of Abuse (R01).  This is to help generate research on molecular mechanisms of HIV infection-induced immune activation and inflammation in the presence of antiretroviral therapy agents and drugs of abuse. The application due date for this FOA is on November 18, 2016.  In addition, RFA-AI-16-038: Silencing of HIV-1 Proviruses (R61/R33) is being developed along with the National Institute of Allergy and Infectious Diseases (NIAID) with a due date of December 7, 2016.  The goal of this FOA is to fund exploratory and developmental research on identification and optimization of small molecules or RNAs that interact with host epigenetic machinery to mediate long-term or permanent epigenetic silencing of HIV-1 proviruses.

   Another area that has proved to be challenging is that of the continued rise in the number of people diagnosed with the Hepatitis C infection.  A recent study analyzed Hepatitis C Virus (HCV) testing and treatment among persons receiving buprenorphine in an office-based program for opioid use disorders.  Among the 226 office based opioid treatment patients with chronic HCV infection, more than half received genotype testing (n = 132, 58.4%), while less than half were referred to an HCV-related specialist (n = 103, 45.6%). Only a very low number of patients ever initiated treatment (n = 5, 2.21%). Among the 5 patients who initiated treatment, 80% (n = 4, 1.17% of total sample) achieved an undetectable viral load.  NIDA has partnered with the Appalachian Regional Commission (ARC) to fund grants that address increased opioid intravenous drug use overdoses (IDU OD), HIV and HCV.  They are one-year planning grants to identify the scope of the problem, and the contributing health trends; and also identify resources and obstacles.  Four applications are expected to be funded by September 30, 2016.  There are plans to broaden the program in FY 2017 with ARC to include the Centers for Disease Control and Prevention (CDC), and the Substance Abuse and Mental Health Services Administration (SAMHSA).

   Dr. Volkow then moved on to the 2016 Addiction Science Award recipients.   In first place, is Kashfia Rahman from Brookings High School in Brookings, SD, for her research project “Making the Mind Matter: Stress Mindset Effects on Sleep Quality, Stress Response, Emotion and Cognition in the Developing Adolescent Brain and the Role of the Prefrontal-Amygdala Circuit”.  In second place, Lindsay Poulos from Episcopal School of Jacksonville in Jacksonville, FL.  Her winning project was the “Effects of E-Cigarette Vapor on Drosophila melanogaster”.  And in third place, Rachel Mashal from the John F. Kennedy High school in Bellmore, NY, looked at “Development of a Caffeine Addiction Paradigm to Examine How Dietary Restriction and Level of TOR Signaling Modulate the Effects of Drugs”.

   She then went on to present recent and upcoming congressional activities, and concluded her presentation by discussing the upcoming Society for Neuroscience annual conference, and the NIDA/NIAAA Frontiers in Addiction Research mini-convention on November 11, 2016 in San Diego, CA.  The mini-convention will focus on relapse and recovery: from mechanistic understanding to translational research.  A preliminary agenda was shared with Council members and the audience.

   Council thanked Dr. Volkow for her presentation and for NIDA’s efforts to work with the FDA and the DEA to help increase access to marijuana for research.  Council members also congratulated NIDA on its efforts in developing and getting the buprenorphine implant approved, and encouraged continued efforts at studying ways to make treatments accessible, and to increase rates of retention in treatment programs to help alleviate with issues such as IDU OD and HCV.

4. Lessons from Marijuana Legalization in Colorado: State of Current and Future Research - Andrew Freedman, J.D., Director, Marijuana Coordination State of Colorado

   Mr. Freedman began his presentation by stating that his mission is to carry out the people’s will on marijuana legalization through effective and efficient regulation, policies, and initiatives that protect and promote public health, public safety, and to keep marijuana out of the hands of kids.  He went on to say that he is neither for nor against legalization of marijuana.  The policy priorities are 1) to decrease youth marijuana use and consumption through strong regulations, public education, and proven youth-prevention programs; 2) to maintain public safety by preventing marijuana-impaired driving and ensuring marijuana-related crimes are effectively policed; and 3) to promote public health by providing options for substance-use disorder treatment services, educating consumers on responsible, legal use, and creating stringent health and safety standards for industry.

   He presented the current state of data from a survey conducted in Colorado, focusing specifically on measures of social impact.  According to Mr. Freedman, from the perspective of the State of Colorado, this information is baseline data and conclusions cannot be drawn at this time about the legalization of marijuana.  He then showed a series of slides to demonstrate the data collected.  The first figure showed prevalence of Ever and Current Marijuana use for high school students in Colorado compared to national prevalence from 2005-2015.  In 2009, the prevalence rates were much higher for ever use (42.6% vs. 36.8%), and current use (24.8% vs. 20.8%).  However, the prevalence rates for both Colorado and nationally have been the same, if not slightly lower in Colorado, since 2011.  Another graphic indicated the most prevalent method of marijuana use among high school students that reported current use in Colorado was smoked at 86.8% for 2015, as compared to only 2.1% consumed in food, 5.1% vaped and 6% other.   Another slide compared high school student perceptions of moderate/great risk of harm from using marijuana regularly in the entire state of Colorado and two regions within the State (Northwest Colorado and Denver).  The results indicate that perception of moderate/great risk has declined significantly in all regions assessed, was lowest in Denver, and for the state of Colorado as a whole has gone down from 54% in 2013 to 47.7% in 2015.

   Another survey showed that access to marijuana in Colorado high schools overall (statewide) has not changed from 2013 to 2015 despite the increase in availability of recreational marijuana.  Mr. Freedman then showed a slide on school suspension rates.  Drug suspension rates, per 100,000 students increased significantly in 2009-2010 and have been at a steady rate since then, as compared to total suspension rate which has been declining.  Mr. Freedman stated that both suspension and expulsion rates are very specific to each school and its policies, thus making it difficult to draw any conclusions from these data. 

   He then moved to adult use results, and showed that prevalence of adult marijuana use in Colorado, 18 year and older, from 2014 to 2015 has remained the same.  The majority of adult users in Colorado are 18-25 year olds at 26.1%, followed by 26-34 year olds at 18.3%, then 35-64 year olds at 12.4%, and finally 65+ year olds at 4.4%.  Notably, the results from the Colorado survey differ from the NSDUH findings for Colorado, which indicate increases in past month use by 18-25 year olds with a steady rise from 2006-2014 (21.2% in 2006 vs. 31.2% in 2014).  The National rate for 2014 was 19.3%.  Increases in past month were also seen over this time period for adults 26 and older.

   A concerning trend that needs to be monitored is the rates of hospitalizations and emergency department (ED) visits with possible marijuana exposure in children under 9 years old.  Prior to legalization of medical marijuana, there were no reported ED visits and hospitalizations for children under 9 years old due to marijuana exposure; from 2001-2009 once medical marijuana was legalized, only one case of hospitalization was reported; from 2010-2013 once medical marijuana was commercialized, 41 cases of ED visits and 24 cases of hospitalizations; recently with retail marijuana being legalized from 2014 through June of 2015, 37 ED cases have been reported, as well as 15 hospitalizations.  Further hospitalization trend data indicate a significant difference in rates per 100,000 hospitalizations and ED visits with possible marijuana exposures, diagnoses, or billing codes. 

   On a positive note, from 2012 to 2015 arrests for those 21 and over decreased by 82%, those 18 to 20 decreased 50%; and those under 18 decreased 28%.  These rates reflect both custodial arrests and citations issued by law enforcement.  In addition, at this time, less than 10% of driving under the influence citations by the Colorado State Patrol are related to marijuana only, compared with 78% alcohol only.  Unfortunately, roadway fatalities with cannabinoid positive drivers has been on the rise.  Note that a positive test for cannabinoids does not necessarily indicate impairment, since people can test positive hours or days after their last use. There were 55 fatalities in 2013, and 99 deaths in 2015, in which cannabinoids were detected.

   Mr. Freedman then went on to report on data from the Colorado Department of Revenue, the Marijuana Enforcement Division.  Total sales and excise taxes in fiscal year 2015 was $93 million, and for fiscal year 2016, $147 million.  The revenue gained from the sale of marijuana is used to fund public education campaigns to ensure the safety of the public, especially school aged children.  In addition, some state funding has helped stand the Institute of Cannabis Research (ICR) at Colorado State University in Pueblo.  ICR’s mission is to advance knowledge and support and promote, through education and research, responsible development of applications for cannabis-related natural and derived products.  ICR will also promote the sound ethical/legal and socially-responsible utilization of cannabis by providing medical research, genetic development, analytical testing services, guidance for public policy making, conceptualization and planning of new sustainable businesses, assistance with advertising and marketing strategies, which will accurately inform the public and private sectors.  The Institute will comply with Colorado and Federal laws in its work with cannabis and components thereof.

   In Mr. Freedman’s conclusion, he spoke about future research needs, which include:  Jail and probation terms tied specifically to marijuana arrests; probation violations tied to marijuana usage; human services impacts, such as drug use impacts on parenting and on youth at risk; comprehensive DUI linked to toxicology results; crash data, including property and injury factors, linked to toxicology results; fatalities linked to comprehensive toxicology data that could indicate impairment; school discipline linked to marijuana specifically; and marijuana as a substitute or complement to alcohol, tobacco, opioid and other prescription drugs.

   NIDA Council members thanked Mr. Freedman for his presentation.  Dr. Volkow asked Mr. Freedman about any data they might have captured related to the use of marijuana among pregnant women.  Mr. Freedman reported increased rates of THC present in newborns that are screened in parts of Colorado.  The Governor’s office has begun educational poster campaigns to address this issue; however, there are no data at this time reflecting its success.  Council members suggested a few items for tracking, such as various levels of toxicology screening to determine mere presence versus impaired presence; the impact of legalization on the illegal or illicit market; and also product safety, including the use of pesticides.

5. Studies with an Engineered Cocaine Hydrolase (TV-1380)  - Phil Skolnick, Ph.D., D.Sc. (hon.) Director, DTMC, NIDA​

   Dr. Skolnick began by stating that not all research projects result in success.  One of those studies was with an engineered cocaine hydrolase, TV-1380.  By way of background, cocaine is a diester that is hydrolyzed in the liver to benzoylecgonine; which is a metabolite in the urine.  Another way that cocaine can be hydrolyzed is by butyrylcholinesterase, which is an enzyme located in the blood and the brain.  The result is ecgonine methyl ester and benzoic acid.

   This particular study, was a small business grant to a company called CoGenesys which was eventually bought out by Teva, where they were trying to model the tertiary structure of butyrylcholinesterase with the objective of point-mutating amino acids around the active site to change the catalytic activity.  They were successful and that was the antecedent of TV-1380.  A study published in Neuropsychopharmacology in 2008 showed that a cocaine hydrolase engineered from human butyrylcholinesterase selectively blocks cocaine toxicity and reinstatement of drug seeking in rats.  The compound was also tested in non-human primates, and the results were similar.  Once TV-1380 is administered intramuscularly, a remarkable reduction in self-administration of cocaine was observed in the primates as well.  The TV-1380 is then degraded in the bloodstream, and there are no lasting effects.

   NIDA had fully integrated pharmaceutical companies interested in pursuing medication to treat cocaine use disorders.  Phase I studies were conducted to assess pharmacokinetic and pharmacodynamics interactions between albumin-fused mutated butyrylcholinesterase and intravenously (IV) administered cocaine in recreational cocaine users.  This was the first human study in which they were all provided an initial 40 mg push dose of IV cocaine, and three days later they were assigned to one of three different doses of TV-1380 (50 mg, 100 mg and 300 mg).  The participants were then re-challenged with 40 mg IV cocaine after 24 hours, four days and seven days.  The results showed dramatic reduction in plasma concentration of cocaine with the 300 mg TV-1380 cohort, and it persisted even through day 8.  In addition, a study by Jenkins et al., 2002; Journal of Analytical Toxicology, 26(7):382-392 showed that the concentration of cocaine in blood necessary to produce positive subjective effects is 150-200 ng/ml; thus if the enzyme can prevent cocaine from reaching those levels, the euphoric effect would be abolished or blunted.

   This lead to NIDA supporting a study by Teva under the Cooperative Research and Development Agreement (CRADA) program to bring this product into a Phase II 12-week, multicenter, randomized, double-blind, placebo-controlled parallel-group study to evaluate the efficacy and safety of once-weekly intra-muscular injections of TV-1380 (150 mg/week or 300 mg/week) as treatment for facilitation of abstinence in cocaine-dependent subjects. The primary outcome measure was abstinence based on FDA requirements.  208 participants were randomized to one of three groups with an average of 80% completion.  The data showed statistical difference for reaching the primary endpoint of abstinence, and secondary endpoint of negative urine samples; however, it was for the 300 mg dose of TV-1380, which is not a good option for this product and thus Teva did not pursue the development of TV-1380 for FDA approval. 

   He concluded his presentation by stating that although there are other studies now pursuing a path for cocaine-degrading enzymes, the question given the failure of the TV-1380 phase II trial, is will NIDA be able to partner with pharma to pursue one or more of these avenues in research?

   Dr. Volkow and Council members thanked Dr. Skolnick for his presentation.  Council questioned a reduction in harm as a possible outcome of future studies, but until the FDA makes changes to its requirements in drug abuse research for pharmaceutical research, it will be difficult to find companies willing to spend resources on such trials.

6. The National Pain Strategy and the Federal Pain Research Agenda - Linda L. Porter, Ph.D., Director, Office of Pain Policy, NINDS, NIH

   Dr. Porter began her presentation by describing the public health significance of pain.  According to the Institute of Medicine (IOM) there are currently 100 million American adults that report chronic pain; 40 million people have severe pain; 25 million people report daily pain; and 8 million people have pain that interferes with their lifestyles.  The issues that are standing in the way of helping these individuals include the lack of access to good pain management care; lack of insurance coverage to fully manage their pain; providers that are not well educated on pain management; the stigma associated with pain and the use of opioids as a treatment for chronic pain; as well as the NIH’s lack of strong evidence based effective treatments for individuals, along with the risks associated with the treatment options.

   The National Pain Strategy evolved from the intersection of two provisions that were in the Patient Protection and Affordable Care Act of 2010; Section 4305: Advancing Research and Treatment for Pain Care Management.  This called for the Secretary of HHS to convene an IOM Conference on Pain to recognize pain as a significant public health problem, evaluate care, identify barriers to care, and establish action plans to reduce barriers and improve pain research, education, and care.  It also called for the establishment of an Interagency Pain Research Coordinating Committee (IPRCC) to coordinate all efforts across Federal agencies and other departments that support research related to pain. The core set of recommendations from the IOM report led to the development of the National Pain Strategy (NPS).  The NPS is a comprehensive population health level strategy for pain, and it is the government’s first broad-ranging effort to improve how pain is perceived, assessed, and treated: a significant step toward the ideal state of pain care. 

   Six thematic groups of experts were established:  1) Population Research, whose objectives are to estimate the prevalence of chronic pain and high-impact chronic pain; refine and employ standardized electronic health care data methods to determine use and costs of care; and to develop a system of metrics to track changes in prevalence, impact, treatment, and costs.  2) Disparities as vulnerable populations receive inadequate and inappropriate care, the objectives were to reduce bias and its impact on care; improve access to high-quality care for vulnerable groups; facilitate communication among patients and providers; and to enhance data on the impact of pain on high risk population groups, their access to care, and costs of disparities in patient care.  3) Prevention and Care, to develop nation-wide pain self-management programs and determine cost and benefit; and to develop standardized, consistent, and comprehensive pain assessments and outcome measures across the continuum of pain.  4) Services and Payment, to define and evaluate integrated, multimodal, and interdisciplinary pain care; to enhance evidence for care; and to incentivize payments for quality care based on biopsychosocial model of pain: integrated, cost-effective, and comprehensive.  5) Professional Education and Training, to develop, promulgate, and update core competencies for pain care education, licensure and certification at the undergraduate and graduate levels; and to develop a pain education portal that contains a comprehensive set of materials to enhance curricula.  And 6) Public Education and Communication, to develop and implement a public awareness campaign about the impact of chronic pain to counter stigma and misperceptions; and to develop and implement and educational campaign encouraging safer medication use, especially opioid use for patients with pain.

   The NPS has already made progress despite formal implementation just getting underway, including the development of a validated self-reported screening tool.  This tool has been helpful in driving the inclusion of two high-impact chronic pain related questions into the National Health Interview survey.  This has also lead to changes in the objectives of Healthy People 2020, which is an initiative by the HHS Secretary to assess the health of the nation and set objectives for specific diseases and disorders to help improve them.  There are now 4 developmental objectives for pain within it.

   Progress has also been made in the theme of education.  A summit was established in 2012 by Scott Fishman and included 30 professions to develop a set of pain management core competencies across four domains: biopsychosocial mechanisms, assessment, management and context of pain for pre-licensure across clinical disciplines.  They are now planning an upcoming meeting in Japan to develop case based pain care modules at Centers of Excellence, and develop the core competencies further.  In addition, the Office of the Assistant Secretary’s Office of Disease Prevention and Health Promotion (ODPHP) has developed a training interactive video on pathways to safer opioid use. 

   Dr. Porter then moved on to the NPS’ implementation steering committee.  The goal is to have deliverables within five years.  The Federal Pain Research Strategy (FPRS) will fulfill the IPRCC’s mandate to coordinate research across the government to identify critical gaps in basic and clinical research on the symptoms and causes of pain; and make recommendations to ensure that the activities of the NIH and other Federal agencies are free of unnecessary duplication of effort.  It also will complete one of the missing key recommendations from the IOM report, to include an agenda for developing physiological, clinical, behavioral, psychological, outcomes, and health services research and appropriate links across these domains that aligns with the NPS.  She then provided a schematic of the organizational structure, including the co-chairs involved in the FPRS.  Representatives from the NIH Pain Consortium are involved in each of the groups to ensure NIH involvement.  She then provided examples of FPRS Work Group progress and the set of overarching priorities that have been developed.  Each group’s priorities will be weighed against all priorities of the other groups to end up with a shorter list of the highest priorities considered by all of the working groups together.   All work group recommendations are expected to be submitted to the IPRCC in early 2017.

   Dr. Volkow and Council members thanked Dr. Porter for her presentation.   A member of Council wanted to know if the definition for pain included those related to mental (psychic) pain, including people with depression and anxiety.  Dr. Porter stated that the definitions are more related to physical pain; however, the NPS does clearly include assessment and treatment of depression, anxiety and stress.  Council commended the NPS on studying the costs of non-opioid medications and other alternative treatments to manage pain, and to help set up systems that can support such treatments.  They also applauded efforts at integrating SAMHSA and HRSA into the work groups.

7. Public Comments
   Renata Henry from the National Network of Addiction Technology Transfer Center (ATTC) spoke about how the ATTC, which is funded by SAMHSA and NIDA, helps to accelerate the adoption and implementation of evidence-based practices to the substance use disorder workforce.  She wanted to thank NIDA for its support and to share with the audience the work that the ATTC has been able to accomplish.

8. Adjourn
   The 124^th meeting of the National Advisory Council on Drug Abuse was adjourned at 4:29 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.