RFI Comments - Infrastructure

Infrastructure

• I am a NIDA-funded investigator working on noradrenergic contributions to cocaine addiction. I submit that part of the plan should be to develop strategies focused on changing the current FDA approval process for addiction pharmacotherapies. My understanding is that the FDA approval criteria for addiction treatments are essentially insurmountable. Thus, even in the event that we are able to develop safe medications that are better than current treatments and can significantly reduce substance abuse, the chances of these drugs actually gaining FDA approval are remote. If cancer drugs were held to the same standards, nearly all current medications would never have seen the light of day, and cancer mortality would be catastrophic. This discrepancy is unacceptable, and it is time to level the playing field so that all the hard work of addiction researchers actually has a chance to come to fruition and help people suffering from drug dependence.
• I agree with the priorities except that biologics like vaccines and enzymes for addictions is grossly neglected by industry and needs special support by NIDA for not only mechanism studies but also investigator initiated clinical trials.  Getting INDs for this work is difficult and expensive, some special funding mechanism needs to be in place besides Avant Gard for this pre-phase 1 testing requirements to get an IND for these products.  The Grand Challenge RFA works OK for small molecules and re-purposing of existing medicines, but it is inadequate for biologicals.  In particular, the process for IND approval needs better NIDA support for filing and getting the necessary toxicology and safety data in animals with these biologics, since these requirements are quite different from small molecules.  These IND related types of peer reviewed proposals for IND enabling support do very poorly in peer review, because they are not innovative and cannot be.  This process merits more thought from NIDA in their strategic plan.  Finally, I particularly hope that NIDA does not imitate NIMH in reducing support for clinical trials of innovative and perhaps not so innovative biologics as treatments.  Clinical investigators are leaving the field in larger and larger numbers, and we are not recruiting new ones.  We are headed for disaster in developing the medications for tomorrow without new leaders being developed.  This type of strategic planning may require some significant re-engineering of the NIDA medications development program such that does not rely on the CTN for definitive studies of tired old medications in simple minded and tired old research designs of placebo vs one dose of medication (a dose that is often picked at random rather than with good phase 1 and 2 information including neuroimaging for receptor binding and reduction of relevant brain activation by the abused drug and its related cues).  I realize that this is not a lecture for Nora V, but it might be for some others in the medication development leadership and implementation.  Resources are not being well deployed at a time when economy should be a top priority of investments.Thank you for your consideration, and I am delighted to elaborate or address any questions that this short list of suggestions might provoke...
• Genetic, genomic and informatics strategies have emerged from decades of technical developments as powerful and precise means for identifying the basis of addiction susceptibility, chronic drug exposure effects, and mechanisms of behavioral change. Model organism genetics are a particularly precise and cost effective means of discovery of the mechanisms underlying addiction related processes, and the precision of cross species extrapolation and translation of these findings is now more readily performed. Many of these technical accomplishments have been made possible through NIDA’s historical investments in bioinformatics, functional genomics and epigenetics, including substantial involvement in the development of resources for mouse and other model organisms. These investments are now paying off with high precision, high diversity genetic resources including the Collaborative Cross and Diversity Outbred mouse populations, which exhibit expanded behavioral variation, genetic variation and mapping precision. Informatics resources including the Mouse Phenome Database, GeneNetwork, Neuroinformatics Framework and Geneweaver enable integration of data across populations and species and have become critical resources for understanding rodent behavioral variation and its relation to human behavior, ultimately leading to the discovery of new addiction related genes. Advances in data integration support genetic analysis by providing a means to make use of historical data sets, now augmented with deeper information from modern genomic methods. By making these data computable, it is now possible to reanalyze and refine old genetic analysis results, further leading to the synthesis and discovery of new genetic loci underlying addiction related behavior. Significant investments in the deployment of these technologies in addiction research are now required. Support for the continued maintenance, population and integration of informatics resources with BD2K initiatives will be required to ensure continued utility of these valuable resources to the addiction community. Continued support for education of researchers in the genetics of addiction will ensure that these resources are used by the research community. Centers of excellence that perform large scale research efforts and engage community investigators and develop core facilities to disseminate research resources are also required.
• I believe NIDA has done an absolutely outstanding job of creating innovation in the HIV funding area- the Avant Garde Awards.  I would suggest consideration for expanding this model to other areas of interest within the Institute. This program allows the science of the institute to broaden, an effort that I applaud.  
• I am a NIDA-funded investigator working on the neurobiology underlying, and novel treatments for, cocaine dependence. One important aspect of drug addiction research that I did not see outlined specifically in the strategic plan is changing the way that addiction treatments are evaluated and approved by the FDA. My understanding is that the current FDA approval criteria for new addiction pharmacotherapies are unrealistic and nearly unobtainable. If the same criteria were applied to approval of new cancer treatments, millions of lives would be lost. It is frustrating to know that even if NIDA investigators developed an addiction pharmacotherapy that was safe and more effective than anything currently available, its chances of winning FDA approval would be virtually non-existant. Thus, I believe that one of NIDA’s missions over the next several years should be to educate and lobby the FDA to change their criteria for approving new addiction medications.
• The priorities are well written. I do not think I can add much except to perhaps emphasize the importance of involving researchers from other disciples to be engaged into NIDA research. It is often the technology or conceptual breakthroughs that lead to advances in biology. I feel the ability to measure chemical composition changes (1. epigenetic changes in DNA, RNA and histones; histones will be very hard because the sensitivity of mass spec is still orders of magnitudes away; 2. signaling molecules) within homogeneous neuron cells or even a single cells is critical to potentially correlate with the behavior or phenotype. This presents a technology bottleneck at the moment. Organization of multidisciplinary teams may help PIs like me to know the problems and where impact can be generated.
• This note addresses an important emerging research need and opportunity in basic neuroscience, clinical and translational science, and science infrastructure, that is directly related to advancing the mission ofNIDA: bringing the power of science to bear on drug abuse and addiction.When one examines the scientific literature on neuroscience in general, and on drug abuse and addiction in particular, two trends stand out:the increasingly multidisciplinary nature of this research, and the growing number of studies that involve large data sets and/or computationally intensive approaches such as analysis of fMRI and EEG data, or computational modeling of biological neural systems that are closely tied to experimental data e.g. for design of and assessment of electrical or optogenetic methods for neuromodulation.These trends, which are natural consequences of recent scientific advances, offer great promise for breakthroughs in basic and clinical science, but they also pose significant challenges. In particular, the very diversity of backgrounds and experience, which is necessary if the members of a collaboration are to bring a wide range of expertise to focus on a problem, is a potential barrier to the cross-disciplinary exchange of ideas that is essential for knowledge integration. Put simply, the success of a collaboration depends on the effective exchange of information within the research team. This may be difficult to achieve within a diverse team because of the inherent complexity of biological neural systems, the multiplicity of experimental, theoretical, and computational approaches that are used to study them, and the sheer volume of experimental and computational data generated by those approaches.One way to meet this challenge is through the development of cyberinfrastructure environments that foster collaborative data- and computation-intensive neuroscience research. Such an environment would make it easy for a team of experimentalists, theoreticians, and modelers to share their data and software tools with each other. It would provide a single resource within which all participants in a project--even those with modest local computational resources--can have convenient and secure access to that project's shared data, software, and documentation, all in the context of a high performance computing environment. This would facilitate the kind of interactions within a diverse team that are required in order to synthesize an integrated understanding of complex phenomena. Much of the basic infrastructure for constructing such a resource has already been developed in projects supported by NSF and NIH, so creating a collaborative environment would not require developing everything from scratch
• As Program Director for a NIDA T32 Postdoctoral Research Training Program in Substance Abuse Prevention at [PII Redacted], I am pleased to have an opportunity to respond to this RFI concerning NIDA’s proposed FY2016-2020 Strategic Plan. I write in support of the plan’s strategic priorities: 1) basic neuroscience; 2) clinical and translational science; 3) public health; and 4) science infrastructure, as well as the unifying themes described. However, the focus of this response is on priority #4 - Science Infrastructure: Enhance the national research infrastructure to support advancements in science. The views expressed represent discussions among our training program faculty regarding this RFI.We are grateful for NIDA’s continuous support for the program these past nine years, during which we have successfully trained 21 prevention scientists (6 fellows are currently enrolled). Of those trained, over three-quarters are now faculty in various academic schools or departments, such as psychology, psychiatry, public health, social welfare, and health sciences, and the rest are employed as prevention scientists in interdisciplinary research organizations. Over the years, our renewal applications have received very favorable reviews by two successive scientific review panels, and our program has consistently received high endorsements from fellows trained. Drawing on these experiences, below is our response to select elements of the Science Infrastructure strategic priority in the proposed FY2016-2020 NIDA Strategic Plan.From FY2016-2020 Strategic Plan: Improve training for the next generation of scientists & Improve mentoring of young scientistsWe strongly support the need for improved training and mentoring for the next generation of scientists, particularly prevention scientists. Nearly 24 million Americans use illicit drugs, over 135 million use alcohol, and nearly 70 million use tobacco (SAMHSA, 2013). Drug abuse and misuse are also directly responsible for a wide range of health and psychosocial problems; are risk factors for other individual, family, and social challenges; and incur significant financial costs to society (NIDA, 2009a).  Further, only 11% of the 22 million Americans who meet DSM criteria for drug dependence or abuse receive specialized substance use treatment (SAMHSA, 2013), and nearly three-quarters of individuals who do not receive treatment make no effort to do so (SAMHSA, 2008). The prevalence of drug abuse coupled with the low utilization of treatment indicates an urgent need for the development and rigorous evaluation of evidence-based preventive interventions, and for the continued training of prevention scientists.However, the implementation of evidence-based drug abuse preventive interventions remains insufficient to address this need. First, despite numerous recent advances in the identification of risk and protective factors for drug use and abuse, most of this science has not been translated into evidence-based preventive interventions (Sandler et al., 2014), particularly within diverse cultural and community contexts (Trickett et al., 2011). Second, there continues to be a significant gap between the translation of effective evidence-based interventions and their implementation in service systems, cities, and states (Flaspohler et al., 2012; Wandersman et al., 2008). Third, there remains a lack of trained prevention scientists who can integrate knowledge development and application across the various phases of prevention research –pre-intervention, implementation, and dissemination (Kellam & Langevin, 2003; Glasgow et al., 2012). Fourth, despite the widespread recognition that drug abuse prevention requires integration of scholarship from several disciplines, there remains a shortage of essential interdisciplinary research and limited opportunities for mentored interdisciplinary research training (Glasgow et al., 2012; NIDA, 2010). Fifth, despite considerable advances in identifying neurobiological models for drug abuse and addiction (McKee et al., 2012; Potenza, 2014), few models specify how individual neurobiological or gene-environment vulnerabilities interact with behavioral and social contexts so that preventive interventions can be developed (Bruce et al., 2013; Sinha, 2008). And finally, there are few interdisciplinary research training programs that blend use of mixed methods approaches, advanced data analytic strategies, and community partnerships essential to rigorous drug abuse prevention research, but exemplars are emerging (Brown et al., 2012; Tebes et al., 2014).Our own program addresses these challenges to our national science infrastructure by providing research training that emphasizes: a) understanding drug use/abuse and related behaviors within an ecological framework that emphasizes relevant developmental, family, social, cultural, and neurobiological contexts; b) translating that understanding into evidence-based  interventions to advance public health; c) developing and implementing culturally-grounded evidence-based preventive interventions in real-world settings; and, d) disseminating those interventions in large-scale trials to inform public policy. Finally, we incorporate addressing the above areas using rigorous methodologies and state-of-the-art data analytic approaches.These training objectives are emphasized in a two-year training program that combines required elements as well as individually-tailored research and training experiences based on each trainee’s individual development plan (IDP).  Our experience these past nine years in implementing these program components makes us recommend that they be adopted by other NIDA-funded research training programs to enhance our national science infrastructure. These components include:close mentoring with 1-2 scientific advisors in the fellow’s core research interests;development of an IDP by each trainee that is reviewed and updated quarterly with each mentor, and semi-annually with the Program Director;participation in required didactic seminars, which include: 1) Advanced Data Analytic and Research Methods for Substance Abuse Prevention Research; 2) Grant Development and Grant Writing; and 3) Professional Development;participation in regular writing groups that promote faculty and fellow peer review of scholarly manuscripts, grant applications, and scientific presentations, with specific numerical targets for peer-reviewed submissions as specified in the IDP;enhanced training in the ethical and responsible conduct of research, including research involving other disciplines and, as appropriate, public stakeholders as collaborators;participation in additional didactic training consistent with one’s IDP; and,completion of a NIH grant concept paper and extramural grant application by the end of the two-year program, in order to nurture grant development skills and kick-start NIH grant submissions early in one’s career as a scientist.We have found that these core components blend required and tailored elements to provide fellows with foundational knowledge for becoming successful scientists while also providing them sufficient freedom to develop and refine their own program of research. From 2016-2020 Strategic Plan: Increase effective engagement and training in multidisciplinary research & Increase effective collaborations in researchOver the past five decades, scientists have learned that they are better able to address complex biomedical and public health challenges when they work in collaboration across disciplines (Abrams, 2006; Kahn & Praeger, 1994), and increasingly, in interdisciplinary scientific teams (Stokols, Misra, Moser, Hall, & Taylor, 2008). As a result, training the next generation of scientists must include didactic and experiential education in readiness to understand scientific challenges from multiple disciplinary perspectives and in how to work effectively across disciplines and with public stakeholders who have different worldviews (Tebes, Thai, & Matlin, 2014). In our NIDA T32 postdoctoral research training program, we have an abiding  commitment to interdisciplinary research and training. All of our 23 faculty have participated in interdisciplinary consortia or scientific projects and all have engaged in collaborative research, including team science. Our diverse portfolio of active research projects provides fellows with exposure and training in a range of interdisciplinary research experiences as drug abuse prevention scientists.Training in interdisciplinary and collaborative research requires readiness by investigators, substantive didactic and experiential learning in these areas, and institutional support that promotes flexible disciplinary and institutional boundaries and provides incentives for faculty scientists (Domino, Bodurtha, Nagel, & the BIRCWH Program Leadership, 2011; Kessel, Rosenfield, & Anderson, 2008). Although the research concentrations for our training program are likely to be different in some respects from those at other programs, the approach we have used with success to train in interdisciplinary research and effective collaboration can be adopted by drug abuse research training programs because this subject matter is inherently interdisciplinary (Sinha, 2008). We have found that for interdisciplinary collaboration to be successful, it is essential for investigators to adopt shared cognitive schemas and effective partnerships across disciplinary, departmental, institutional, or geographic boundaries (Kessel et al., 2008), including partnerships with public or community stakeholders (Tebes et al., 2014). Making such training a priority in NIDA’s FY2016-2020 Strategic Plan would enhance the likelihood that future scientists that study drug abuse or addiction have essential interdisciplinary and collaborative skills to produce more innovative and ground-breaking science.From 2016-2020 Strategic Plan: Increase the number of well-trained underrepresented scientists in the drug abuse and addiction field at all career levelsIt is critical that drug abuse and addiction research have a sufficient number of scientists from underrepresented groups (racial, ethnic, disadvantaged) to meet the increasing need for culturally-grounded evidence-based interventions (Castro, Barrera, & Steiker, 2010; Hecht et al., 2003; Tebes, 2010). Research and interventions that have been grounded in local contexts and culture are more likely to be effective (Castro et al., 2010; Tebes, 2010; Trickett et al., 2011).To address this issue, a priority for our training program has been to train prevention scientists from underrepresented racial and ethnic groups in biomedical, behavioral, and clinical sciences.Thus far, 8 of the 27 fellows who have enrolled in our program (30%) self-identified as anunderrepresented racial or ethnic minority, and an additional 4 of 27 (15%) identified as other racial/ethnic minorities. In addition, 3 fellows (11%) identified as disadvantaged. Scientific review panels have praised our high rate of enrollment of racial/ethnic minorities, particularly individuals from underrepresented groups, and described us as a “model program” for minority recruitment and retention. We believe our success in recruiting and retaining individuals from underrepresented racial/ethnic groups is due to several factors that can be replicated by other programs: 1) a strong commitment to recruitment and successful retention of racial/ethnic minorities among related doctoral fellowship programs from which we routinely receive a portion of our applicant pool; 2) concerted efforts to recruit from underrepresented minority groups through widespread postings on websites, listservs, and newsletters of professional societies that have a higher concentration of underrepresented minority students and scholars; 3) an institutional commitment to support students and scholars from underrepresented groups through various programs once they are part of the academic community; and 4) strategic social networking at scientific meetings to ensure a strong pool of applicants from underrepresented groups. Each of these approaches can be replicated elsewhere, and we recommend that NIDA strongly encourage that they be adopted by other NIDA-funded training programs.We welcome information from other successful research training programs that we can use to further improve our own program, and appreciate the opportunity to respond to this RFI. References Abrams, D.B. (2006). Applying transdisciplinary research strategies to understanding and eliminating health disparities. Health Education & Behavior, 33(4), 515-531.Brown, C. H., Kellam, S. G., Kaupert, S., Muthen, B. O., Wang, W., Muthen, L. K., et al. (2012).Partnerships for the design, conduct, and analysis of effectiveness and implementation research: Experiences of the Prevention Science and Methodology Group. Administration and Policy in Mental Health, 39, 301-316.Bruce, J., Gunnar, M. R., Pears, K. C., & Fisher, P. A. (2013). Early adverse care, stress neurobiology, and prevention science: Lessons learned. Prevention Science, 14, 247-256.Castro, F. G., Barrera Jr, M., & Steiker, L. K. H. (2010). Issues and challenges in the design of culturally adapted evidence-based interventions. Annual Review of Clinical Psychology, 6, 213.Domino, S. E., Bodurtha, J., Nagel, J. D., & the BIRCWH Program Leadership (2011).Interdisciplinary research career development: Building interdisciplinary research careers in women’s health program best practices. Journal of Women’s Health, 20, 1587-1601.Flaspohler, P., Lesesne, C. A., Puddy, R. W., & Smith, E. (2012). Advances in bridging research and practice: Introduction to the second special issue on the Interactive Systems Framework fordissemination and implementation. American Journal of Community Psychology, 50, 271-281. Glasgow, R. E., Vinson, C., Chambers, D., Khoury, M J., Kaplan, R. M., & Hunter, C. (2012).National Institutes of Health Approaches to Dissemination and Implementation Science: Currentand Future Directions. American Journal of Public Health, 102, 1274-1281.Hecht, M. L., Marsiglia, F. F., Elek, E., Wagstaff, D. A., Kulis, S., Dustman, P., & Miller-Day, M. (2003). Culturally grounded substance use prevention: an evaluation of the keepin'it REALcurriculum. Prevention Science, 4(4), 233-248. Kahn, R. L., & Praeger, D. J. (1994). Interdisciplinary collaborations are a scientific and social imperative. The Scientist, 8, 12.Kellam, S.G., & Langevin, D.J. (2003). A framework for understanding “evidence” in prevention research and programs. Prevention Science, 4(3), 137-153.Kessel, F., Rosenfield, P. L., & Anderson, N. B. (Eds.). (2008). Interdisciplinary research: Case studies from health and social science. New York: Oxford Press.McKee, S. A., Weinberger, A. H., Shi, J., Tetrault, J., & Coppola, S. (2012). Developing andvalidating a human laboratory model to screen medications for smoking cessation. Nicotine & Tobacco Research, 14, 1362-1371.NIDA - National Institute on Drug Abuse. (September 2010). Strategic Plan 2010: National Institute on Drug Abuse (NIH Pub Number: 10-6119). Bethesda, MD: National Institutes of Health.Potenza MN (2014) Obesity, Food and Addiction: Emerging Neuroscience and Clinical and PublicHealth Implications. Neuropsychopharmacol 39, 249-50. PMCID: PMC3857648SAMHSA - Substance Abuse and Mental Health Services Administration (2013). Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings NSDUH SeriesH-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental HealthServices Administration.Sandler, I., Wolchik, S. A., Cruden, G., Mahrer, N. E., Ahn, S., Brincks, A., & Brown, C. H. (2014).Overview of Meta-Analyses of the Prevention of Mental Health, Substance Use, and Conduct Problems. Annual Review of Clinical Psychology. doi: DOI: 10.1146/annurev-clinpsy-050212-185524Sinha, R. (2008). Chronic stress, drug use and vulnerability to addiction. Annals of the New York Academy of Sciences: Addiction Reviews, 1141, 105-130.Stokols, D., Misra, S., Moser, R. P., Hall, K. L., & Taylor, B. K. (2008). The Ecology of teamscience: Understanding contextual influences on transdisciplinary collaboration.American Journal of Preventive Medicine, 35, S96–S115.Tebes, J. K. (2010). Community psychology, diversity, and the many forms of culture.American Psychologist, 65, 58-59.Tebes, JK, Thai, ND, & Matlin, SL (2014). 21st century science as a relational process: From Eureka! to team science and a place for community psychology. American Journal ofCommunity Psychology, 53, 475-490.Trickett, E. J., Beehler, S., Deutsch, C., Green, L. W., Hawe, P., McLeroy, K….Trimble, J.E. (2011). Advancing the science of community-level interventions.  American Journal of Public Health, 101 (8), 1410.Wandersman, A., Duffy, J., Flaspohler, P., Noonan, R., Lubell, K., Stillman, L….Saul, J. (2008).Bridging the gap between prevention research and practice: An interactive systems framework for building capacity to disseminate and implement innovations. AmericanJournal of Community Psychology, 41(3–4), 171–181.

Basic Science, Clinical and Translational Science, Infrastructure

• I would like to recommend the followings related to drug abuse and neurological disorder diseases within NIDA mission:(Experiments)  1. GPCRs (e.g., Cannabinoid Receptors) Structural Biology and structure based drug design (Medicinal Chemistry biology and biophysics) 2. Druggable chemical probe and ligand development of promising targets to accelerate new drug discovery and mechanism study; 3. Accelerate the identification and development of natural products to discover novel therapeutic drugs.(Big data computing): 4.“Big data” type disease specific chemical genomics (or chemogenomics) databases for system pharmacology and pharmacometrics research 5. Advancing computational technologies  to manage the big data , data-mining and  derive hypothesis for basic and clinic research   6. Develop Systems pharmacology and personalize medicine for treatment neuro diseases. 7. Discover and develop new therapeutic uses for existing or new lead molecules (New Therapeutic Uses or drug synergy), using big data and cloud computer prediction, computer-aided drug design technologies and chemistry modification methods;Above include research grant and training education

Basic Science, Clinical and Translational Science, Public Health, Infrastructure

• NIDA Strategic Plan 2015Comments from the National Prevention Science Coalition to Improve Lives (NPSC)Translational Prevention Science SubcommitteeDr. Diana Fishbein, ChairThe question that the drug abuse prevention sciences seeks to address is “What works best (evidence-based practices premised on basic research), for who (moderation), why (mediation by malleable conditions) and under what circumstances (developmental, experiential and contextual factors). The following is geared toward this model.  Basic Prevention Research to Guide Intervention Development (T1) Apply animal models to elucidate underlying mechanisms in psychopathology that portends drug abuse, transitions to drug abuse, and/or mechanisms in differential orientations to physical and social environments that influence risk. Design human laboratory or experimental studies to investigate whether neurochemical, structural and functional neuroanatomical, psychophysiological or other mechanisms observed in preclinical science can serve as important targets for the prevention of drug abuse in humans. Are neural substrates of novelty or sensation seeking, decision making, impulsivity, etc. identified in primate models amenable to change in response to psychosocial or environmental manipulations?Identify neurobiological underpinnings for differential susceptibility to environmental stressors or, conversely, differential responsivity to prevention programming.Determine the mechanistic effects of programs and interventions which will provide an evidence-base to guide efforts to refine and improve program components;Explore basic, malleable conditions that promote or interfere with intervention effects; i.e., study of moderation and mediation that accounts for changes at the neurocognitive or psychophysiological level that occur commensurate with behavioral change.Examine how neurobiological indices are related to the impact of interventions at critical or transition periods, including consideration of changing social contexts; e.g., studies of changing patterns of activation in cortical and subcortical circuits underlying emotional and cognitive processes in response to prevention messages, or recruited in the context of peer presence during decision making, etc.Conduct studies to ascribe a functional role to an epigenetic and/or genetic variant with respect to a particular aspect of drug abuse propensity.  Identify epigenetic and/or genetic variant effects on behavioral responses to social inputs and interventions.If the genetic makeup sets the stage for responses to environmental input, can psychosocial interventions alter: a) genetic expression of activities in underlying substrates of risk traits and b) the behavioral phenotype?  Will the outcome of this impact be sufficiently measurable in these markers?Account for the profound effects of adversity and severe and/or chronic stress on child brain development which, in turn, influences prospects for successful outcomes.Studies to understand mechanisms underlying impact of stressors and stress adaptations (physiological stress reactivity, coping, psychological status) on processes related to drug use onset, escalation and trajectories. Interaction effects of stress, genetic, and contextual factors on drug abuse risk.     And does change in stress adaptations in part mediate intervention effects? If so, do interventions that effectively improve stress adaptations have potential to prevent drug abuse?Expand understanding of drug abuse to addictions, in general, and how each of these addictions might be related to each other and underlying processes.Explore interplay of implicit and explicit processes as determinants of drug misuse.Explore how deviant social networks might impact drug use decisions in real time.Explore the extent to which group identification is associated with drug abuse through reputation based collectives or actual peer group interactions. Intervention Implementation and Evaluation (T2)Integrate discoveries from the basic biological (e.g. neurobiological), psychological (e.g. emotional, behavioral, cognitive, and developmental), social (e.g. social learning, peer network, and communications), and environmental (geographical locations, access) sciences to develop and test innovative preventive interventions that specifically target underlying mechanisms in drug abuse risk. Integrated data sets account for more of the variability in intervention response than the use of one set of variables alone.How can the assessment of environmental-neurobiological relationships contribute to the design of interventions that impact at critical points in the developmental trajectory to alter risk status?  Determine the types of interventions and specific program components that normalize or improve neurodevelopment in ways that lead to desirable outcomes (e.g., reductions in psychopathology, school failure, psychiatric symptoms, drug abuse, etc.).Development and/or application of new-generation designs, technologies and methodologies to identify neural substrates amenable to prevention interventions and to assess change over time.Indicate those critical windows during childhood that may produce the greatest effects for specific types curricula and program components based on developmental appropriatenessWhat are the critical developmental or transition periods for change; e.g., changing patterns of activation in the HPA axis, cortical and subcortical circuits underlying emergent emotional and neurocognitive processes in response to interventions?What are the critical stages of development during which psychosocial stress and other external influences (e.g., peer presence) differentially exert their effects?Develop and evaluate the effects of innovative educational programs targeted to various learning needs of children on neurodevelopmental markers of successful outcomes.Explore a “personalized” approach that focuses upon individual or subgroup level conditions and characteristics that influence level of liability to drug abuse.  The frontier in prevention research is understanding the individual differences in liability to improve prediction and early risk identification. This tact will further lead to interventions with an appropriate level of intensity and quality that specifically target underlying mechanisms that trigger or exacerbate drug abuse liability and thereby maximize efficacies and cost/benefits.  Practice-oriented Phase (T3) Research to test the degree to which efficacy and effectiveness trial outcomes can be replicated under real world settings, focused on adoption, adaptation, and disseminationStudy the characteristics of implementers, organizations, and systems that maximized adoption and maintenance of prevention and cessation programming.Study the types of adaptations that can be made without losing program impacts (e.g., through understanding “active” ingredients of programming)  Scaling Up and Wide-Scale Implementation and Adaption (T4): Increase the public health impact of NIDA research and programsResearch has confirmed the limited extent to which evidence-based interventions have been broadly and effectively implemented and this indicates much progress is needed to achieve population-level impact. A substantial research agenda is needed on the complex processes through which evidence-based interventions are adopted, implemented, and sustained at the community level, with a strong orientation toward devising empirically-driven strategies for increasing their population impact.  This agenda fits with recommendations in the National Prevention Strategy including the dissemination of community-based interventions that address health inequities, especially in inner-city neighborhoods and rural areas, the development, testing, and implementation of effective strategies to engage underserved populations, and the organization of representative, multi-sector community partnerships.Strengthen focus on bi-directional (back and forward across the spectrum, not just T1 to T2) translational researchScience Infrastructure: Enhance the national research infrastructure to support advancements in scienceActively pursue the Institute of Medicine strategy (IOM, 2009) on prevention, which has had a marked impact on prevention science and policy. Develop a large-scale national research program based on the input of a transdisciplinary group of basic and prevention researchers, clinicians, and practitioners. While broad, this can be achieved by assembling a core group of experts from multiple disciplines and institutions to apply a wide range of perspectives and capabilities toward understanding and reducing the drug problem.Develop a strategy to build a strong infrastructure (building both manpower and organizational capacity) to support the dissemination, diffusion and quality implementation of evidence-based prevention practices that range from screening and assessment of vulnerable populations and communities to the appropriate recommendations for prevention programming and monitoring. “Institutionalizing” evidence-based practices in school systems and communities nationwide.Exploring ways in which primary care physicians and pediatricians can assess and attend to children or families exhibiting signs of liability, without stigma or official reporting (except in the presence of imminent harm).Implement comprehensive “menus” of evidence-based programs and services in high poverty neighborhoods, as directed by the community’s assessment of needs.  Programs and policies recommended by experts are well-established and evaluated and could be made available on a large-scale basis.  Some of these programs and policies serve to build self-regulatory skills in individuals that increase resilience against drug-related problems, while others work more universally to shift norms in high risk areas to promote mental and physical health.  On a population-wide level, this strategy would include the establishment of programs for community-level investment (e.g. parks, painting and fixing dilapidated buildings, accessible mental health and academic services, etc.) that inculcates positive work, health and skills.  Ongoing research efforts to apply rigorous evaluation criteria to determine what works best, for whom and why so that programs and policies can be further refined to achieve optimal results for greater numbers.  This strategy would eventually lead to the institutionalization (nationalization) of these programs and policies in communities and schools, particularly those most in need.Create a website and dynamic listserv that enable people and organizations at the state and local levels to communicate and collaborate.  A website that enabled anyone to ask critical questions about prevention and to provide answers to those questions could create a large, “federation” of problem solvers who could exchange information about what is working in ways that would spread knowledge much more quickly than occurs through traditional methods.  Through a new generation of media campaigns, increase public understanding of the need for and consequences of nurturing families and schools.  These newly-designed campaigns should target (appeal to) areas and individual-level characteristics (e.g., sensation-seeking, impulsivity, etc.) that have been shown to be at particular risk for drug abuse.  Also, these ads may disseminate information on evidence-based preventive interventions to familiarize people with new school- and community-based approaches. Rather than messages focusing centrally on drug abuse, they should demonstrate ways in which reducing conflict and coercion in these environments, reinforcing prosocial behavior, and limiting opportunities for experimentation with problem behaviors will prevent substance use and most other problem behaviors. Several decades of ads and a host of other informational campaigns were needed to eventually significantly reduce cigarette smoking; the same strategy is needed here.  To move evidence-based interventions into practice, create opportunities to fund innovative methods grants in the area of implementation/translational science. Create mechanisms and concrete opportunities to translate research findings for policy-makers and the public.Support student and early career training programs in translational drug abuse prevention and intervention.Create opportunities for multiple organizations and institutions to collaboratively conduct cross-cutting, integrative research.Create opportunities for multiple federal agencies to collaborate in funding translational drug abuse prevention and treatment research; e.g., NIH, SAMSHA, ONDCP, OJJDP, etc.Require grantees to demonstrate practice and policy relevance in applications beyond just their obligatory “significance” sections.Unifying themes:Prevention – proactionDevelopmentalContextual TransdisciplinaryTranslational – from T1 to T5, leaving nothing outDisparities, adversity, inequalitySex differencesEarly intervention – starting prior to conception
• Thank you for the opportunity to comment on your upcoming NIDA 2016-2020 Strategic Plan. We wish to applaud your continued efforts to remain at the cutting edge of research and practice in the field of substance use disorders and treatment.  In particular, we support the following:Basic Neuroscience: Neurobiological  correlates of recovery and drug effects on neuroplasticity.   It is clear that repetitive behaviors and overlearning are a significant cause of the behavioral process of addiction.  Consequently, there is a need to better demonstrate the behavior and cognitive practice that is needed to establish long term recovery.  This is particularly relevant in the context of the recent push to expand opioid assisted treatments.  This expansion leads tothe perception that medication alone is addiction treatment (for example, physician office based buprenorphine without required behavioral treatment).  This is problematic in that medication cannot create the same neuroplastic changes as behavioral practice.Clinical and Translational Science: Accelerating neurobiological recovery.  With the expansion of opioid replacement approaches, there would be an expected delay in the establishment of baseline neurochemistry.   For example, as long as tolerance to external opioids is maintained, one would not expect to see changes in the volume of neurotransmitters or receptors.  With shrinking lengths of stay it is critical to increase the rate of neurobiological recovery, so that treatment gains may be maintained.Public Health: Response to emerging health priorities.  This is a critical area and should be expanded and broken into two key areas: expansion of marijuana and the opioid overdose epidemic.Marijuana: With the rapid movement to legalize marijuana, there has not been adequate time to develop research on the side effects of marijuana, proper dosage and delivery for any medicinal purposes, and development of research on medicinederivatives (Marino! etc.). Research on the effects in states where legalization has already occurred would be helpful to determine the role of legalization, if any, on the rates of addiction. This is particularly important since marijuana has a known role as a gateway drug, particularly if started in youth.Opioids: The opioid overdose epidemic requires immediate investigation to determine causes and tools needed to interrupt the cycle of addiction.  The proposed solutions have disproportionately focused on administrative and medicinal solutions. This is counterintuitive to suggest that we can prescribe our way out of a prescription opiate epidemic with prescription opiates.  The opioid epidemic is exacerbating at the same time the prescription opioid medications are proliferating, increasing availability via diversion and excess prescribing.  Research needs to consider the role of opioid treatments in this problem and solution.  Further, as psychosocial treatments have diminished over time, there has been an increase in rates of addiction and incarceration.Science Infrastructure: Increase the number of well-trained scientists in the addiction field. We agree that there is a need for increased availability of trained scientists with an interest in addictions.  The availability of funding for skilled research is important in the identification of evidence based practices which will yield the best effects.We also notice that there has been a significant change in the types of goals when comparing the prior strategic plan with the current strategic plan.  Specifically, the current strategic plan is almost exclusively medication and biology focused (neuroscience, medications, etc.).  This is in sharp contrast to the prior strategic plan which was primarily focused on behavioral interventions (prevention services, treating comorbid disorders, matching approach to motivation, addressing relapse triggers etc.).  This sharp change suggests the devaluation of psychosocial approaches in the context of a menu of treatment options.  While biologically focused interventions are valuable, it should not be addressed to the exclusion of psychosocial approaches.In this light, we would like to propose the following additional areas of research:Research on Client Medication Matching: Most research has focused on how treatment may be assisted by the addition of certain medications.  More research is needed on client matching criteria.   Specifically, guidance is needed on who is most appropriate for methadone, buprenorphine or naltrexone, as well as who is not appropriate.Prevention Services: Additional guidance is needed on the effective prevention practices, particularly surrounding the use of fear based approaches, which have been proliferating despite research indicating that it is not effective and can increase substance use, especially in youth.  As there are more overdoses, and loved ones who are motivated to help others, it is critical to have clear guidance available so that they can readily access effective evidence based approaches to prevent others from facing addictionResidential Treatment: In recent years there have been serious cuts to the funding, availability and length of stay for licensed residential treatment.  Epidemiological research is needed to examine the decline of availability of licensed residential treatment services as it relates to the increase in the rates of addiction and overdose deaths.  If the level of care that is designated for the most severe substance use disorders is reduced in availability or duration, it should not be surprising that there is an increase in the deaths which are associated with the most severe disorders.Implementation of Parity: Research is needed to examine the implementation of the Mental Health Parity and Addiction Equity Act.  Specifically, what actions are being taken onthe state level and local levels to ensure compliance with the federal law?  A compilation of tools and best practices to support implementation would be very valuable.Implementation of Medicaid Expansion:  Research is needed to examine the effects of the implementation of Medicaid expansion.  This would examine how states with Medicaid  expansion compare with states that do not have Medicaid expansion.  Specifically, it would be valuable to examine treatment availability (number of treatment beds available in each level of care) and length of stay in treatment (well known as the number one predictor of treatment outcome), as compared to overdose rates in states with or without Medicaid expansion.Screening Brief Intervention and Referral to Treatment (SBIRT): In addition to the need for trained scientists, the field is in need of proper tools for the training of physicians to screen and refer to treatment.  Research on the tools, best practices and outcomes for SBIRT would help to make these skills more widely utilized and implemented.  This is particularly important inlight of the increased utilization of prescription drug monitoring programs, which encourage the discussions surrounding substance use and the need for warm handoff to treatment.Workforce Development: The specialty field of substance use disorder treatment faces significant workforce challenges.  Research is needed in how to attract, develop and retain a skilled workforce in the treatment of substance use disorder.  This may include training materials as well as best practice guides containing the tools and procedures to expand the specialty treatment workforce.Again, we thank you for the opportunity to comment on the strategic plan and we are happy to be a part of the dialogue to continue to advance addiction science for the coming years. This work is lifesaving as well as desperately needed for the families for those whose loved ones are struggling with this disease.
• This document is the Community Anti-Drug Coalitions of America's (CADCA) response to the National Institute on Drug Abuse's (NIDA) request for information regarding the 2016-2020 update oftheir Strategic Plan (RFI NOT-DA-15-005).CADCA has been successfully representing and promoting coalitions, community-based problem solving,and population-level substance abuse prevention efforts since 1992. As a member-based, not-for-profit, CADCA provides coalitions and their communities with support and services relating to all aspects of community-based substance abuse prevention. These services range from training, technical assistance, and the dissemination of best practices and research, (through its National Coalition Institute) to actively promoting and advocating for federal and state policies and practices that increase the effective use of community-based, universal prevention. CADCA currently serves over 5000 coalitions located in the United States and 18 countries around the world.The Draft Strategic Plan included in the RFI is a comprehensive and sound approach to the role thatNIDA should take in substance abuse prevention. Clearly NIDA recognizes the variety of substance abuse priorities across the Institute of Medicine's continuum of care model.CADCA's comments focus on the emphasis that Universal, Selective, and Indicated interventions should play in a comprehensive approach to prevention. CADCA's comments are organized by the Draft Strategic Priorities outlined in the RFI as follows:NIDA Priority: Basic Neuroscience: Improve our understanding of the basic science of drug use, addiction, vulnerability, to addiction, and recovery.NIDA Sub-priority: Increase our knowledge of biological, behavioral, environmental, and developmental factors involved in risk and resilience for drug use and addiction.The effectiveness of universal, selected and indicated interventions in a complete model of prevention is determined to a great extent by the science linking broad environmental conditions to large group, smaller group, and individual behaviors. A complete model of prevention requires a thorough understanding of how macro-level conditions interact with individual level processing as described inthe social-ecology model. While spending on environmentally-based approaches has been decreasing, there is a growing body of research clearly indicating that environmental approaches are highly effective. Environmentally-based approaches delay the initiation of substance use which decreases the likelihood of addiction. Focusing specifically on environmentally-based prevention also yields major economic dividends. The savings per dollar spent on substance abuse prevention can be substantial and range from $2.00 to $20.00 (Swisher, Scherer & Yin, 2004). Miller and Hendrie (2009) indicate that some prevention efforts result in cost-benefit ratios of more than 30:1. Investing in prevention yields savings and reduces economic and healthcare burdens (National Institute on Drug Abuse, 2007). NIDA and NIAAA have invested heavily in prevention science and have focused efforts to understand the factors at the school, family and community levels that make substance more or less likely for a given population. Based on both the significance of Prevention and the decreasing funds available for its implementation, CADCA recommends that a sub-priority be created that is dedicated solely to environmentally-based Prevention. This would help demonstrate and clarify NIDA's long standing commitment in this area.Recommendation: Increase our knowledge of how environmental factors relate to biological, behavioral, and developmental risk and resilience for drug use and addiction.NIDA Sub-priority: Drug effects on neuroplasticity, neural structure, and circuit function across the stages of addiction.Two behavior categories have gained increased significance over the past 5 years relating to this sub­ priority. The first is the growing issue of marijuana exposures. While exposures have increased and have serious consequences for all age groups, these exposures were particularly high for adolescents. According to the Rocky Mountain Poison Center and the American Association of Poison Control Centers, unwanted exposure to marijuana has increased for all age groups. However, the increase from 2006 to 2013 was 95% for adolescents between the ages of 13 and 17. For all age groups in Colorado, marijuana-related exposures increased 89%, while national marijuana-related exposure increased 32% during this same time (Rocky Mountain HIDTA, 2014). Furthermore, increased access to marijuana in certain states is strongly linked to the number of emergency admissions and illnesses. One primary areaof concern for emergency episodes involves edible marijuana. Currently there is a paucity of research on how increased medical emergencies related to marijuana correlates to addiction and how marijuana­ related exposure impacts biochemical and neurological functions (http://www.medicalnewstoday.com/articles/285202.php). Therefore it is important to better understand how second hand exposure as well as various drug ingestion behaviors impact the likelihood of addiction and other negative consequences.CADCA therefore recommends a research priority that specifically addresses both marijuana-related emergencies and marijuana-related exposures.Recommendation: Drug effects of both marijuana-related emergency episodes and marijuana-relatedexposures on neuroplasticity, neural structure, and circuit function  across the stages of addiction.NIDA Sub-Priority: Improve our understanding of the interaction between addiction and co-occurring conditions.Another important research area under this priority involves the impact of electronic nicotine delivery systems (ENDS) on human functions through both direct exposure and indirect exposure. While use of ENDS among youth has tripled from 2011 to 2013 (Bunnell, et al.; 2014), there is little scientific data regarding the impact of its use (Callahan-Lyon, 2014), including its interaction on addiction or co­ occurring conditions.Due to substantial increases in exposure and use of ENDS, combined with the paucity of research in these areas, CADCA recommends that the issue of addiction to co-occurring conditions focus on both marijuana (see above) and e-cigarettes.Recommendation: Improve  our understanding  of the interaction between addiction and co-occurringconditions particularly relating to marijuana and e-cigarettes.NIDA Pri.ority: Clinical and Translational Science: Support the development of new and better interventions and treatments that incorporate the diverse needs of individuals with Substance Abuse Disorders (SUDS).Complex community health problems, like substance use and abuse, require comprehensive,collaborative solutions in order to achieve benefit for the entire community.  "As the field of prevention has matured, it has been recognized that any single strategy is unlikely to succeed and a reinforcing set of strategies has the greatest potential to reduce use" (Johnson et al., 2007, p. 229). Substance use and abuse is influenced at multiple levels and as such interventions must be broad-based, comprehensive and seek change at multiple levels (Sorensen, Emmons, Hunt & Johnston, 1998). NIDA has long supported research on comprehensive, community-based approaches and should continue to do so. While research in the past 5 years has offered much to the field there are still two primary challenges. First, there is still a paucity of community-level, comprehensive approaches that have formally been declared as "best practices". This leads many well-meaning prevention specialists to over-rely on either post diagnosis approaches to substance abuse or indicated and selected approaches to prevention.Research support from NIDA would help solidify the scientific role that universal prevention can play in a population. In addition, research to guide practitioner use of these strategies and how to combine them in ways to achieve maximum benefit for the smallest cost are also needed. Additionally, while there is much focus on single interventions and their impact, more research is needed on the synergy thatoccurs when a comprehensive set of strategies working at multiple levels of influence are implemented. It is also important to support new and innovative approaches to universal prevention that may foster adoption of this approach. Local community members may not fully understand the intricacies of universal prevention, so they may have trouble implementing these approaches with fidelity. Implementing universal intervention strategies without fidelity is detrimental to the prevention movement because lack of fidelity decreases the potential impact of the strategies and may reflect poorly on the field.CADCA recommends that a sub-priority area focus on solidifying the scientific value of promisinguniversal approaches to prevention and increase the likelihood of successful implementation. Recommendation: Support the development of promising, evidence-based, universal prevention strategies, including practices relating to innovative implementation that enhance effectiveness.NIDA Priority: Public Health: Increase the public health impact of NIDA research and programs.Sub-priority: Increase readiness to respond to emerging public health priorities (opioid overdose epidemic, potential consequences of marijuana legalization, changing healthcare landscape, emerging drug trends, etc...)Research demonstrates that coalitions engaging in comprehensive, environmental strategies aresuccessful at bringing about community changes on a variety of issues (Sorensen, G., 1998; National Research Council, 2004; Hingson et al., 2005; Yang, E et al, 2012; Nargiso, J., 2013). Communities with active coalitions engaging in best practices are better prepared for changes in the substance abuse landscape. However, there are two primary challenges to a coalition's success. One is the relative paucity of research on evidence-based best practices for substance abuse prevention coalitionfunctioning. Another is the ability of coalitions to adapt existing best practices. Increasing the number of research projects on effective substance abuse prevention coalition processes would foster the development of best practices that can be integrated into everyday coalition work.Recommendation: Increase readiness to respond to emerging public health priorities by creating aseries of evidence-based best practices for coalition development and capacity. (opioid overdose epidemic, potential consequences of marijuana legalization, changing healthcare landscape, emerging drug trends, etc...)NIDA Sub-priority: Improve the understanding of factors that influence the integration of evidence­ based research findings into healthcare policy and practice.The relationship between substance abuse and other community health issues has long been recognized in the research. Substance abuse has been linked to child abuse, poor school performance, mental  health issues, violence, a range of personal health issues, etc... While these links are generally  understood by health professionals, there is a gap in practices to resolve these issues at the universal prevention level. Leveraging resources through the development of reliable and valid practices for nexus issues would enable coalitions and other groups to more effectively and efficiently manage social health issues at the community-level. There are two primary areas of research that would help coalitions manage these nexus issues. The first involves the best practices for disseminating information regardingthese nexus issues. Improving communication capacity between researchers and practitioners would greatly enhance how theory is implemented in the field. This involves at least some clarification regarding how communities should manage risk factors for nexus issues as opposed to individual issues. The next involves how to leverage resources at the community level to engage the community in developing and maintaining universal prevention for these nexus issues.Recommendation: Improve the understanding and communication of nexus-based risk factors  in order to improve the ability of healthcare professionals  to work with communities towards the full  integration of evidence-based research findings and strategies that result in healthcare policies and practices  that address multiple health issues simultaneously.NIDA Priority: Science Infrastructure: Enhance the national research infrastructure to support advancements in science.NIDA Sub-priority: Improve training for the next generation of scientistsAccording to the Bureau of Labor Statistics, the field of public health is expected to grow more than 20%, and epidemiology is expected to grow 10% over the next eight years( http://www.bls.gov/ooh/community -and-social-service/health-educators.htm#tab  -1).  Community­ based universal prevention has gained recognition as both an effective and efficient element in a complete prevention system (Yang, E et al, 2012). With this recognition is a growing need for researchers who specialize in developing community capacity to engage in universal prevention strategies.Recommendation: Improve training and mentoring opportunities for the next generation of scientists,including those who specialize in community-based, universal prevention.NIDA Sub-priority: Increase effective collaborations in research.Community-based participatory research (CBPR) is a collaborative approach to research that engages community members and researchers as equal partners in all phases of the research process (Israel, Schulz, Parker, & Becker, 1998; Foster-Fishman, 2009). CBPR more appropriately responds to the needs of communities because it engages community members in defining the problem, selecting the solutions, controlling the implementation and owning the knowledge generation process. An understanding of the community context is imperative in solving local problems and the strategies and methods selected by the community are more likely to fit the local context (Foster-Fishman, 2009; Katz, 2004). Additionally CBPR supports Type II Translational Research by making research and action more culturally competent, relevant, and useful (Foster-Fishman, 2009). This approach to research answers questions that fit practitioner needs and takes into consideration more of the factors and conditions in which interventions are implemented in real world setting; hence interventions that come out of CBPR studies are more likely to have buy-in and utility to the community.Recommendation: Increase the use of Community-based participatory  research and evaluation.NIDA Sub-Priority: Increase effective data and resource sharing (big data, biorepositories, transgenic/optogenetic tools, data standards, etc...)Accurate, timely information is the cornerstone of prevention efforts at all population levels, including national, state, county, or local community. Each population level has its own unique challenges and resources and there are three primary priority areas that would greatly enhance current prevention efforts.A complete prevention model requires a variety of approaches to addiction covering the entire spectrum of behavior and motivation. This is true regardless of which holistic prevention model is being used (for example 10M, or Health Pyramid). Within each model are various types of prevention serving different populations ranging from entire populations to individuals. While there is agreement that a complete prevention model addresses the entire spectrum of audiences, there is less agreement as to the appropriate balance of prevention types that are most effective. It is therefore important to better understand how current prevention efforts attempt to find this balance. An assessment of current approaches and levels of prevention will help the field better understand how to achieve an optimal balance of strategies. A monitoring system would delineate which aspects of prevention research are being funded and which areas could use more funding. For example, while research on preventioninterventions is well funded, more monitoring would help ensure that efforts to fund translational research to support practitioner adoption of these interventions occurs.Recommendation: Develop and maintain a prevention  research monitoring system in order to assessstrengths and gaps towards the development of a holistic national model for prevention.Another critical data piece for prevention is the ability of local communities to access local data on emerging trends. In fact, "readiness" described as a priority (see above) is directly related to the availability oftimely information that is presented in a useful format. Not only is local data critical as a tool for responding to emerging trends, it is also critical in tracking the effectiveness of selected strategies. Perhaps the biggest challenge to local coalitions and other local substance abuse efforts isthe availability of local data. While there is a plethora of archival data collected by various federal, state, and county agencies, all too often this data is relatively inaccessible for local communities seeking data directly addressing their smaller, local communities. There is a tendency to aggregate local data sources once it is in the data system or data reporting systems are not capable of disaggregating local data when it exists.Recommendation: Increase effective data and resource sharing applicable to all population  levels,including at the local community level.It is a pleasure and honor for CADCA to offer these recommendations on behalf of more than 5,000 coalitions nationwide. NIDA has always been a powerful force in community drug prevention and CADCA is proud to continue our special relationship with your organization that helps keep communities safer and drug free. We provide the above comments as a way to strengthen our collective understanding of the factors that make substance use and abuse less likely and less severe on a population-wide level in our communities.

Basic Science, Infrastructure

• In the strategic priorities for basic research I would add:  *   Improve understanding of how addiction depends on neuroplasticity and especially the late phase of plasticity.Under infrastructure I would change the item:Accelerate the development and utilization of advanced technologies (e.g. the President’s BRAIN Initiative), data repositories (e.g. Big Data to Knowledge (BD2K) initiative, and statistical models to spur innovative research
• Alternative approaches to treating conditions should be a priority, where the drugs of abuse are recommended. For example, for painful conditions, research involving identifications of novel targets and endogenous or exogenous ligands that interact with the targets as an agonist or antagonist should be encouraged and promoted.Co-morbid conditions and the possibility of drug interactions that could exacerbate the addictive potential should be discouraged.Dangerous chemical moieties synthesized overseas with strong potential for addiction must be quickly identified (in collaboration with DEA) and must be made available to scientists intramurally and extramurally to promptly identify the dangers associated with. Furthermore, the potential of these drugs to cause excessive respiratory depression, when combined with alcohol has to be tested with appropriate animal models so as to quickly make the public aware of the dangers associated via the mass media.There are very useful compounds derived or isolated from addictive chemicals or substances without psychoactive properties have to be identified, so that these compounds can be made available for researches to evaluate for potentials use in other disease conditions. For example, cannabidiol, a non- psychoactive chemical obtained from cannabis has been found to be useful in refractory childhood epilepsies.The non-psychoactive compounds have to made available for scientists without going through the rigmarole to conduct scientific research by changing the schedule under which they are currently classified.Most, if not all of the grants must be recommended for modular budget (not to exceed 250k for 4 to 5 years, unless in extraordinary circumstances), so that talented young researchers have an opportunity to test their ideas
• I am writing to address and request your support for two items on the list of subjects in the RFI: (1). Accelerate the identification of promising targets and ligands to accelerate new drug discovery and development, and (2). Improve training for the next generation of scientists. I chose these two areas of focus because after many positive and very appreciative years of NIDA funded experience in these two areas, I still feel they are the two critical needs that would advance the goals of NIDA significantly and should be highlighted in your Strategic Plan.As I complete my 20th year as a chartered member of NIH study sections and start my 18th continuous year as a NIDA researcher, I thank the NIH and NIDA for their continuous support of me and my students whom make this job a joy and an honor. However, I continue to be amazed at the significant number of grant submissions and manuscripts that I review from colleagues and new investigators that seek to identify targets and ligands for new drug development without adequate training or appreciation by the PI or the co-investigators of basic pharmacokinetics, bio-distribution, drug stability and the translational challenges of crossing barriers of the human central nervous system such as the blood brain barrier (BBB), blood retinal barrier and blood csf barrier. I answer this RFI with a passionate request that we focus our energy and funding in this Strategic Plan on improving the identified needs in our training of the next generation of scientists in basic pharmacokinetic (PK) and bio distribution drug delivery so that we can truly accelerate the identification of promising targets and ligands to accelerate new drug discovery and development.  There are many good ideas and newly formulated synthetic chemical designs for new drugs in many potentially exciting applications and manuscripts published, but the lack of understanding in what is required to actually deliver the ligand to the human brain dampens any and all enthusiasm for success. In many cases this paucity of training is a main reason for the lack of advancement in new drug discovery. This is our challenge.In 2002, leaders at the National Institute of Neurological Disorders and Stroke formed a Stroke Progress Review Group (SPRG) that recognized the urgency to determine the role of the BBB in stroke. This SPRG identified the priority to “better define the molecular influences and cell-signaling mechanisms that characterize the interaction between circulating blood elements and the blood vessel wall, the extracellular matrix, glia and neurons (together, the neurovascular unit) . . ..”(NVU). The BBB and NVU remain the most significant challenge to central nervous system (CNS) drug development from the past century. This fact drives the passion of my students and colleagues. We understand that progressing preventing, diagnosing, or treating diseases of the CNS depends upon understanding the BBB and NVU. It is often stated, “if we cannot get the drug into the brain we cannot treat a disease of the brain.”Over the past 35 years at the University of Arizona I have had the honor of training 13 PHD students, 2 MD/PHD students, 3 masters students, and 20 post-doctoral fellows in drug delivery. Each of my trainees has contributed to improving and advancing the field, but we need more. I need to do more and we all need to do more, so I respectfully request this Strategic Plan to focus on these two Goals and I thank you very much for your service and your kind request for this
• Responses to RFI: FY 2016-2020 Strategic Plan for the National Institute on Drug Abuse.These responses briefly address several draft strategic priorities in Basic Neuroscience. We divide the responses into those most germane to human research and those most addressing animal model research, and then comment on integration of these two approaches.Human Research.Priority: Increase our knowledge of biological, environmental, and developmental factors in risk and resilience for drug use and addiction.Comment: Among these factors, genetics contributes something like half of the variation between individuals in vulnerability to addiction. However, as with all complex diseases, identifying individual polymorphisms is challenging because of the large sample sizes required to resolve highly polygenic causal pathways. Therefore, there should be a continuing effort to create adequate sample sizes through aggregation of existing samples. NIDA has made considerable investments in detailed phenotyping of clinical and epidemiological samples. A modest additional investment in whole genome genotyping (GWAS) and/or sequencing would leverage the power of these existing samples, both within and outside the NIDA repository. Experience with other complex disease traits (e.g. schizophrenia, Type 2 diabetes, lung cancer/smoking) has shown that once sample sizes are adequate, then discovery of specific genetic polymorphisms will be successful. Experience also suggests that large samples with broadly defined phenotypes (e.g. polysubstance dependence) can be informative about general mechanisms vulnerability.Aggregation of existing samples (e.g., GWAS meta-analysis) is a critical step to identify many additional genetic loci that affect risk for substance use initiation, addiction, and cessation. Aggregation approaches have proven powerful, but they are necessarily limited by the measures, outcomes, and genotyping technology each study happened to gather at the time of data collection, which can be decades in the past. To move the field forward, and anticipate the success of aggregation efforts for the narrow array of previously collected phenotypes from existing samples, we propose the following: *  New participant recruitment to obtain a wide array of drug use phenotypes that have not been routinely collected on large scales, including marijuana, cocaine, prescription opioids, stimulants, psychosocial environment, and relevant biomarkers, all of which must scale to sample sizes large enough to provide statistically powerful tests of genetic associations and interactions. *  Size of this new ascertainment must approach hundreds of thousands of participants. which is now financially feasible using novel phenotyping strategies (online surveys, wireless monitoring, etc.). It has been demonstrated now for the vast majority of complex diseases and traits, including complex psychiatric disease such as schizophrenia, that such large samples will be required to achieve the promise of genetics in biological insight, environmental etiology, and clinical translation. *  There are substantial long-term benefits to conduct whole genome sequencing on this sample, including the continued dropping costs of sequencing, the clinical translational potential of rare mutations, and the ability to continuously increase sequence depth at later dates. This has been recognized, for example, in recent NHGRI initiatives to sequence tens of thousands of samples to further develop and refine sequencing techniques. *  Biomarkers should be collected to potentially improve the accuracy of substance use histories. Hair samples may prove particularly useful for providing objective, quantifiable, histories of substance use and these more accurate phenotypes may prove to be crucial for identifying quantitative trait loci. *  Any large study should serve as a research platform to serve the entire substance use research community and beyond. Collected data must be immediately and widely shared with qualified investigators (and a subset  with the public at large). Participants must consent to be recontacted, and contact information will be updated regularly and shared with outside investigators to propose follow-up research on selected subsets of genetically or phenotypically interesting research participants (e.g., individuals harboring loss of function mutations).Priority: Understand the developmental trajectory of addiction and individual heterogeneity.Priority: Normal development and function across the lifespan including mechanisms of reward, self-control, and conditioning.Priority: Improve our understanding of the interaction between addiction and co-occurring conditions.Comment: Among the most successful approaches to understanding development and heterogeneity, co-occurring conditions, and executive control are longitudinal twin and family studies that permit an assessment of both genetic and environmental contributions to these phenomena and, importantly, their interrelationships. Behavior genetic studies of twins and families should be a continuing priority for addiction research. The coordination of normal twin studies with studies of high risk families provides an especially powerful approach to normal development and its relationship to clinical problems of addiction and co-occurring conditions.Priority: Improve our understanding of brain circuits related to drug abuse and addiction.Comment: As with other phenotypes associated with addiction, it is critical to be able to distinguish between genetic pleiotropy (genetic correlation) and causal relationships. The most powerful methods available to us in human populations are genetically informative twin and family studies; a particularly powerful research design for parsing causal relationships would include the longitudinal study of monozygotic twins discordant for substance use.Summary. Genetic variation accounts for a substantial proportion of individual variation in vulnerability to addiction. We now know that very large sample sizes, achieved through aggregation across studies and phenotype, will yield significant new knowledge about specific genetic mechanisms. Leveraging existing investments in samples and phenotypes through genotyping and sequencing of existing samples should be a high priority. Collecting additional large samples with a broad range of phenotypes, whole genome sequencing, and wide data sharing should be a high priority. Equally important are genetically informative twin and family studies of phenotypic development, comorbidity, heterogeneity, and underlying brain mechanisms. These approaches are complementary and likely to yield real advances in knowledge during the next five year period.Animal Model Research.Priority: Integrating animal models, behavior, genetics, epigenetics, and other molecular biomarkers for drug abuse and addiction.  Comment 1: One of the long-term goals of human genetics, be it addiction genetics or genetics of other diseases is to identify targets for intervention and improved therapies.  Now that some genes have been identified that clearly impact risk for drug dependence, researchers need to use molecular methods, animal models, and human studies, when feasible, to fully characterize the effect of specific genes and alleles. This includes the use of molecular approaches to identify functional variants that cannot be separated using human studies because of high linkage disequilibrium.  Animal models also allow for in vivo validation of the contribution of genetic variants to drug related behaviors and alterations in brain function. Because investigators can carefully control the environment in animal studies in ways that cannot be achieved in human studies, variants that have a very modest effect on human phenotypes often have robust effects on related measures in animals.  Genome-wide association studies have revealed convincing evidence for several genes as associated with drug addiction (e.g. CHRN genes and CYP genes for nicotine dependence).  However, our understanding of the molecular mechanisms that underlie the risk associated with certain variants remains limited.  If we are to leverage the findings of human genetic studies to advance targeted treatments, it is necessary to follow through on the large human genetic studies by prioritizing studies aimed at understanding how such variants affect biology and subsequently risk for drug use and abuse. Comment 2: The use of animal models to identify novel genetic associations with drug abuse related measures should also be a priority. One limitation of human genetic studies is that only variants that are functional and impact a drug related phenotype can be detected. In other words, genes that contribute to physiology and brain function relevant for addiction will not be detected in human studies if there is no functional variant in the gene. Animal models certainly have distinct genetic variants from those found in humans and thus provide an opportunity to identify additional genes (and thus additional potential targets for pharmacotherapy) that contribute to drug related phenotypes that would not be detected in human genetic studies. Developing resources such as Diversity Outbred mice and the Collaborative Cross would be well suited for these types of studies.  Similarly, there is high co-morbidity for multiple drugs among individuals, so it is difficult to disentangle the specific genetic variants contributing to risk for use of certain drugs.  In animal models, researchers can examine individual drugs in carefully controlled experiments.  With continued interaction between basic scientists and human geneticists, these approaches have strong potential to move the field toward useful pharmacogenetic therapies.
• DBNBR RFI SUGGESTIONS1) Drug use is associated with a number of risk factors as well as different forms of plasticity resulting from exposure. Risk factors include impulsive risk-taking and oppositional behaviors in humans as well as exploration of novelty in animal models. Types of plasticity observed following the initiation of drug exposure include tolerance, sensitization and conditioning of drug effects. All are important to maintain drug use and to initiate relapse. While drug-induced plasticity has been studied in many different kinds of behavioral, systems, cellular, and molecular neurobiology based experiments, there has not been as much attention paid to the exploitation of the knowledge obtained to develop treatments aimed at reversing either risk factors or different types of plasticity supporting higher than normal levels of drug intake. Rescue experiments in animal models can be especially fruitful in this case. Pharmacological and especially genetically based interventions (e.g., delivery of WT or mutant proteins to select brain areas) need to be assessed for their ability to rescue animals by reversing their high levels of drug intake. No doubt, the behavioral, systems, cellular, and molecular neurobiological underpinnings of heightened drug use will continue to be elucidated with new knowledge and insights. The suggestion here is to encourage the direct exploration of methods based on available knowledge to reverse high (pathological) levels of drug intake. A focus on cellular and molecular targets I think will be especially fruitful. This approach would not only help further develop neurobiological models of drug abuse but importantly would inform and motivate the development of human based technologies.  2) We are witnessing the introduction of a number of wonderful new technological tools to the field of drug abuse research. Such developments sometimes occur rapidly and the dissemination of the different technologies to many researchers can be hampered by financial, training, and infrastructural factors. Even in those cases where a technological tool can be accessed by a researcher, its full exploitation may not be actualized because of isolation and lack of easily maintained exposure to technologically savvy colleagues. Conversely, investigators developing technological tools are often ill-equipped to adequately apply them to the study of complex behavioral systems and phenomena. Mechanisms need to be put in place that facilitate training in different technologies and promote interactions/collaborations in their use. Short-term, these could include funding mechanisms to support training courses or sabbaticals. More long-term mechanisms (e.g., funding for centers, intra- and inter-institutional partnerships) could provide incentives that encourage the formation of multidisciplinary groups that facilitate the bidirectional exchange of ideas between technological innovation and the proper assessment of complex behavioral systems. The latter I think is most important. There are some good examples in the country but there should be more.
• Submitted on behalf of the Collaborative Study on the Genetics of AlcoholismUnderstanding the complex addictive diseases is crucial for more effective prevention and treatment. Genetics offers a particularly valuable approach toward greater understanding of the biology that contributes to risk. Experience from other complex diseases, perhaps best exemplified by the recent successes in Schizophrenia, demonstrates that uncovering genetic variants that affect risk requires very large samples. Attention to both risk-increasing and protective variants is important. To date, the addictive disorders fall far short of those numbers. Also important is careful phenotypic characterization. Recent studies from our group and others underscore the value of multiple, carefully characterized outcome measures (e.g., diagnosis, as well as quantitative indices such as symptom counts and maxdrinks for alcohol), as well as the value of collecting relevant environmental data. Our suggestions emphasize the most productive ways NIDA can advance the field. 1. Greatly increased support for genotyping and sequencing of existing well-characterized samples to allow the identification of common and rare variants that affect the risk for addictions.Modern, cost-effective arrays allow efficient genotyping of common and even many uncommon variants. Existing repository samples that have careful phenotyping with respect to substance use disorders should be prioritized for genotyping. Among these, samples characterized in detail for use/abuse/dependence on alcohol, marijuana, cocaine and opiates (e.g. by SSAGA or SSADDA; or from the PhenX toolkit) should be given the highest priorities, as these will contribute proportionately more toward gene identification.Sequencing of samples that are particularly well characterized for substance use disorders and closely-related phenotypes (e.g., externalizing disorders) would allow exploration of rare variants that might have stronger effects. Family samples, including large pedigrees, trios and sib pairs, are particularly valuable for exploration of rare variants and should be prioritized. Sequencing of selected individuals within genotyped pedigrees is a particularly efficient way to explore the whole range of variant frequencies.2. Greatly increased support for collection and genotyping of additional samples, both case-control and family-based, is important. Despite the huge costs of substance use disorders to both the families involved and to society, the resources dedicated to identifying and carefully phenotyping individuals and families with SUDs has lagged behind many other complex diseases. Much larger numbers are needed for these complex disorders. We emphasize careful phenotyping of SUDs and related conditions, including psychiatric disorders, because there is much co-morbidity and evidence for shared genetic vulnerability. Studies of potential biomarkers, particularly transcriptomes, may prove very valuable both to help discover causative variants and to examine the pathways between genetic variants and phenotypes. New collections: It is important to collect new, well-characterized samples to greatly increase the number of subjects who can be analyzed, beyond those already in repositories. As noted above, alcohol, marijuana, cocaine and opiates should be the highest priorities, as these will contribute proportionately more toward gene identification. A range of different designs for sampling should be encouraged: large families are particularly valuable for studying variants in the uncommon to rare frequency range, and there are benefits to trio and sib-pair designs; these have been under-utilized in most studies of SUDs. Strategies that specifically recruit affected subjects and their families, particularly densely affected families, will be most valuable. The yield from population surveys will be lower, given the prevalence of many of the SUDs. Some collections with modest phenotyping, such as those obtained through clinical laboratories (e.g. methadone clinics) that allow secondary use of samples for research, may be helpful in further increasing sample size.Longitudinal studies that encompass the age ranges of peak risk (e.g. spanning early adolescence to the 30s) can be valuable, particularly in understanding the processes through which individuals acquire, sustain, and in some cases, recover from substance use problems. These include studies of treatment cohorts. Targeted studies of under-represented groups is important. Most existing studies primarily collect participants of European American background; other groups, such as African Americans, Hispanic-Americans (of different origins), Native Americans and Asian Americans, are still far too underrepresented. Sensitivity to differences in allele distribution, environment and socio-cultural contexts is required, so particularly careful environmental assessments are needed. Existing collections: There are many existing collections, including many which have already been genotyped or sequenced, in which re-contacting participants is permitted. It would be an efficient use of funds to carefully phenotype subjects in such studies (e.g. by SSAGA or SSADDA; or instruments drawn from the PhenX toolkit) to leverage the existing genetic data.Supporting analytical efforts to refine and harmonize phenotypes across existing studies in which different instruments have been used, and different amounts of data collected, is another way to increase sample sizes. 3. Studies of the genetic contributions to the comorbidity between addiction and other frequently observed co-morbid mental health outcomes is important, and a prime opportunity for collaboration among NIH institutes.Despite substantial clinical and epidemiological evidence that rates of substance use disorders are considerably elevated in individuals with other psychiatric illness, and support from twin studies that these phenotypes share partially overlapping genetic etiologies, systematic genomic studies of this comorbidity are limited. Large samples ascertained for other psychopathology, such as in the PGC, are likely to include substantial numbers of subjects with detailed clinical assessments of addiction. Support for additional characterizations of substance use/abuse/dependence in other samples, contributions to additional genotyping or sequencing if needed, and contributions for data analysis should be prioritized. Similar efforts at integrating results from recent brain functional studies, EEG/ERP, neurocognitive and neuroimaging efforts (e.g. ENIGMA, IMAGEN, NCANDA) with emerging GWAS findings and the development of targeted neurogenetic studies can facilitate gene-brain-behavior studies.4. Support for additional analysis of existing large repositories of samples with existing genetic data, and for development and implementation of methodological tools for genomic studies, is important. As noted above, supporting analytical efforts to refine and harmonize phenotypes across existing studies in which different instruments have been used, and different amounts of data collected, is a good way to increase sample sizes. The effort of extracting and harmonizing SUD phenotypes from these samples is substantial, and requires dedicated support. There is a strong need for further development of methodological tools that can be used to analyze data on SUDs and comorbid phenotypes, as well as gene-gene and gene-environment interactions. There is also need for tools for better integrating genetic, expression, epigenetic data, and to annotate results and deduce critical pathways.
• FY 2016-2020 Strategic Plan for NIDAResearch AreasTherapeutic benefits of cannabinoids:Investigate potential of non-psychoactive cannabinoids, natural and synthetic, with anti-inflammatory and anti-nociception propertiesselective CB2 receptor agonists (synthetic)Basic research on cannabinoids led to the discovery that cells of the immune system express the CB2 receptor. Medicinal pharmacologists have synthesized compounds that are highly selective for CB2 receptors. These compounds have been shown in a variety of conditions involving activated immune function to be ameliorative because of their anti-inflammatory effects on cells of the immune system. Similar suppressive effects of these compounds have been demonstrated for glia. Thus, CB2 receptor agonists may be useful in a number of models of CNS injury. Further, CB2 agonists have been shown to tighten the blood-brain barrier, which has relevance to neuro-AIDs, and to decreased replication of HIV as a result of decreasing activated T-cells. Further, CB2 agonists have potential for anti-nociception in conditions where pain results from concomitant inflammation. All of these areas indicate that the putative benefit of marijuana for a number of diseases can be obtained by cannabinoids with less inherent risk for dependence or other marijuana-associated side effects.CannabidiolCannabidiol is a natural phytocannabinoid that has established potential for anti-nociception. Its mechanism of action is not established.GPR55 antagonistsGPR55 is a lysophosphatidyl inositol receptor that also recognizes certain cannabinoids.  Recent work has identified agonists and antagonists that bind to this receptor. Data support the potential of GPR55 antagonists as having significant anti-nociceptive activity, and these compounds as well as GPR55 should be investigated further.Adverse health effects of marijuanaWith the growing public perception that marijuana is ‘safe’, understanding and educating the public on the adverse health effects of marijuana, as well as its addiction liability, needs to remain a priority for NIDA. Likewise, although synthetic cannabinoids were initially developed as research tools, some have become drugs of abuse due to their ability to activate CB1 receptors, and their illicit abuse has been associated with serious adverse effects. These compounds have numerous actions that are not due to actions at CB1 or CB2 receptors.Therefore, identifying their cellular targets remains a priority, along with investigation of their abuse liability and toxicities.Co-morbidity of addiction and stressDissect in greater detail the relationship between stress and multiple parameters of drug addiction.Stress impacts multiple phases of drug addiction. In humans, stress is associated with greater vulnerability to initiation of drug taking, more rapid transition from drug use to abuse, and higher rates of drug relapse. In rodent models, stressors can sensitize subjects to drug reinforcement, eliciting acquisition of self-administration at lower drug doses and with a faster time- course, promoting higher rates of self-administration that are more resistant to extinction, and triggering reinstatement of previously extinguished drug self- administration. The mechanisms and neural circuitry whereby stress produces such complex effects throughout the addiction cycle are largely unknown. Areas worthy of further investigation are:Neural mechanisms underlying active versus passive stress coping strategies and their impact on addiction.Common neurobiological substrates of stress-related psychiatric diseases (PTSD, anxiety, depression) that are co-morbid with addiction.Similarities and differences in the neurobiological basis of stress effects on addiction to natural vs. drug rewards.Intersections of stress and drug reward circuitry as targets for addiction treatment and prevention.Individual differences underlying vulnerability or resistance to stress effects on addiction, including but not limited to sex differences.Designer drugs: Synthetic cathinonesEffects of cathinone compounds on brain reward circuits and their mechanisms of action.Synthetic cathinones (e.g. MDPV, mephedrone, naphyrone, butylone, methylone) are an addictive, and sometimes lethal, group of understudiedpsychoactive compounds contained in a street drug called ‘bath salts’. The abuseliability and potential lethality of this particular class of drugs underscores the importance of developing neuropharmacological profiles of representative cathinones for comparison to established drugs of abuse including cocaine and methamphetamine. Most of what we know about the hazards of synthetic cathinones has been derived anecdotally; indeed, experimental evidence remains sparse, even for the parent compound cathinone. Areas worthy of further investigation are:Examine the mechanism of action of cathinones.Explore further how designer cathinones impact monoamine systems as nonselective monoamine transporter releasers or blockers. Determine if pharmacological manipulation of glutamate and GABA systems affects reinforcing, motivational, and drug-seeking effects of cathinones.Compare acute versus chronic exposure to cathinone compounds on brain reward circuits.Investigate effects of cathinones on neuroimmune function, including migroglial and astrocytic activation status, cytokine and chemokine profiling, and measures of toxicity, monoamine depletion, reactive oxygen species (e.g. superoxide, hydrogen peroxide, and hydroxyl ion), nitric oxide synthase function, and glutathione production (regulated in part by cystine-glutamate antiport systems).Polydrug useTest the effects of polydrug abuse on behavior, neuroplasticity, and neuroimmune circuits.Polydrug use is common amongst substance abusers. Along with illicit drugs, tobacco and alcohol use is common. In many cases studies have not adequately considered the possible occult effects of ingestion of multiple substances. Newer methods have been developed to mathematically examine drug interactions to determine if the effects of two or more drugs are additive, sub-additive, or synergistic. A variety of end-points are of interest including:Effects of polydrug exposure on tolerance, dependence, drug-seeking behaviors, and cognitive function.-Effects of polydrug use on neuroplasticity in brain circuits mediating reward processes and cognitive functions.Effects on polydrug use on neuroimmune circuits, glial activation, and HIV infectivity.Neuroimmune interactionsElucidate the impact of central (microglia) and peripheral immune function on parameters of addiction, extinction and craving.Recent advances in the appreciation of the crucial role of glial-neuronal cross-talk in key neuronal functions such as synaptic plasticity, neurogenesis and ultimately behavior underscore the importance of elucidating the role of glia in drug addiction. Given the recent evidence that drugs of abuse affect glial activity and vice versa, additional research is needed to understand these interactions and fully evaluate glia as novel therapeutic targets for treatment of psychostimulant addiction.Determine how drugs of abuse impact immune cell function and the role this plays in addiction.Substantial literature shows that cells of the immune system express opioid and cannabinoid receptors, and that drugs acting on these receptors have robust functional effects on cells of the immune system. Nicotine and alcohol also have been shown to be immunomodulatory. In aggregate, the majority of the literature reports that opioids, cannabinoids, nicotine and alcohol areimmunosuppessive. However, recently several prominent papers have been published suggesting that addiction is mediated by inflammation, and that opioids, in particular, cause inflammation. These recent reports go against most of the literature in the field. This new hypothesis needs to be thoroughly investigated and either definitively proven or disproven.Potential therapeutic effects of kappa opioid receptor compoundsDevelop kappa opioid receptor agonists without dysphoric effects as therapeutics for chronic pain and itch.The utility of kappa opioid receptor compounds as therapeutics has been limited by their central nervous system dysphoric effects. One avenue of investigation that is still open to pursuit is to develop peripherally acting kappa opioid receptor agonists. Such compounds would have utility in treating itch and potentially treating chronic pain.-Chronic itch is associated with many disease states and greatly affects the quality of life of affected individuals. It is an area of unmet medical needs. Kappa opioid receptor agonists have been shown to have anti-pruritic effects. Nalfurafine, a selective kappa opioid receptor agonist, has been used to treat uremic pruritis in hemodialysis patients in Japan. Surprisingly, at therapeutic doses, nalfurafine does not produce dysphoria.In the basic science area, understanding the mechanisms underlying kappa opioid receptor-induced dysphoria and why some kappa opioid receptor agonists do not produce this effect is an important goal.In the translational area, it is desirable to develop kappa opioid receptor agonists devoid of dysphoric effects for anti-itch medications, and potentially for the treatment of chronic pain.Clinical and Translational ScienceAccelerate drug discovery for treatment of SUDs.Several years ago NIH began funding academic research centers in pharmaceutical development with the Molecular Libraries Probe Development Grants and other NIH Roadmap Initiatives (e.g., U54/X01). As NIDA has recognized, this division of labor and complementarity can potentially extend to small academic labs that may have expertise in the kind of small scale assays, molecular modeling, and phenotypes that can characterize a putative disease mechanism and identify relevant molecular targets.  Improved access of individual investigators to big data sets, molecular libraries, and modeling programs could help to fast track discoveries of new targets and drugs for the treatment of SUDs. Likewise, increased access of small academic laboratories into partnerships with other NIH programs, including NIDA’s intramural program, and their resources would facilitate drug discovery efforts. At this stage anything (RFAs, cores, screening libraries, support for custom synthesis, etc.) that would harmonize and integrate more nodes, large and small, into the existing production pipeline would be ideal.Policy IssuesLimits on grant support to single investigatorsNIDA should consider a policy similar to that adopted by NIGMS that puts a ceiling on grant support to an individual investigator. Such a directive would allow NIDA to have a diverse research portfolio with a wide array of investigators and topics and to sustain the research enterprise, and to maximize opportunities for significant scientific advances. The recently issued NIGMS guideline can be found in its entirety at: http://www.nigms.nih.gov/research/pages/unrestricted- support.aspx . An excerpt is below:"Investigators with substantial, long-term, unrestricted research support may generally hold no more than one NIGMS research grant. For the purposes of these guidelines, investigators with substantial, long-term, unrestricted support (“unrestricted investigators”) would have at least $400,000 in unrestricted support (direct costs per year excluding the principal investigator’s salary and direct support of widely shared institutional resources, such as NMR facilities) that extends at least 2 years beyond the onset of funding the NIGMS grant. As in all cases, if NIGMS funding of a grant to an investigator with substantial, long-term, unrestricted support would result in total direct costs from all sources exceeding $750,000, National Advisory General Medical Sciences Council approval would be required through the standard process."
• (1) GWAS – this remains a high risk area to continue investment, with uncertain payoff.  Major depression is probably a better approximation to the complexity of addiction phenotypes than is schizophrenia – and depression researchers are now discussing needing 100,000 cases.  High-risk family studies such as COGA show that while there is substantial overlap across drug classes for risk of becoming a repeat user, once one conditions upon some minimum threshold of use (e.g. 6 or more times lifetime), there is substantial genetic specificity of risk by drug class.  So potentially many times 100,000 cases would be needed! Nonetheless, modest further investment to determine whether there are any ‘low hanging fruit’ for individual drug classes would be worthwhile.  For smoking, a critical step was recognizing the need to exclude individuals who had never become regular smokers, thus had no risk of becoming heavy smokers or nicotine dependent.  This will apply equally to other drug classes.  Indeed for drug classes (e.g. nicotine; opiates) where addiction is normative, it is likely that those unusual individuals who have used many times but failed to become addicted will be critical to give etiologic insights.  These same individuals will be of interest equally from a neuroimaging perspective, so multi-modality research approaches are likely to be most informative.(2) Sequencing studies -  The payoff from whole genome or whole exome plus sequencing of existing data-sets is going to be uncertain – again, drug addiction likely has a much more complex etiology than schizophrenia, autism, or other disorders which have seen a payoff from  sequencing.  Since most clinical studies include an assessment of smoking, there will be value in mining the existing NIH sequencing data-sets using smoking as a model phenotype, which will provide information about whether sequencing might be informative for other drug classes.(3) Tissue repositories; epigenomics; tissue-specific gene expression: - It is very clear now that reliance on peripheral blood samples for epigenomics is not going to get us very far, given the detailed information about tissue-specific effects emerging from the NIH Epigenomics Roadmap Project.  Those data also suggest that traditional ‘brain banks’ are too limited in scope: who knew that there are CHRNA4 genetic enhancers acting in the liver, not just the brain (the data that NIDA R25 fellow Bo-Zhang is developing at WashU on this is very compelling)?   It is has also become apparent from comparative analyses that reliance on rodent data is giving in important respects incomplete picture of what is happening in homo sapiens.  The field needs to make progress in understanding epigenomic effects of chronic illicit drug exposure from post-mortem tissue studies, not limited to post-mortem brain tissue.(4) Metagenomics/microbiome research: - this area is proceeding very fast with publications in Science, Nature and other top journals appearing at a rapid rate.  It is hardly represented in NIDA’s portfolio.  Given the complex interactions between obesity and addiction – smoking being a notable example – some investment to understand substance use effects on oral and gut microbiotas is an urgent need.  A particularly appealing feature is the ability to develop ‘humanized mice’ with the gut microbiota of specific human subjects, via fecal sample transplant, allowing experimental investigation using mouse models.(5) Training:   We need to train a new generation of NIDA researchers who will focus broadly on genomic and metagenomic research.  A colleague at a recent Jackson Lab Workshop on Addiction Genetics (notwithstanding the wonderful opportunity this provides for trainees), challenged us that the methods being used in the field of addiction genetics were already 10 years out of date.
• I think a critical area of focus will be on integrating what we have learned from animal models with experiments and applications in humans. Currently such work is systematically underfunded because it is very difficult and is also because study sections are more likely to find fault with such proposals (they can take issue with the relevance of either the animal or the human component; most reviewers prefer one over the other). While the former difficulty is fundamental, the latter difficulty could be addressed if money was set aside to fund grants that had a significant model organism and human interrogatory theme.Within the mental health community there have been strong statements questioning the value of animal research. I believe that animal research is a critical part of NIDAs behavioral portfolio and should be maintained. Having said that, there is an urgent need to encourage the field to continue to innovate the models that are used to evaluate pathways related to drug abuse. I believe that all levels of model organism work are important: from nonhuman primates down to flies and worms. The mouse and rat have been especially productive and may represent "sweet spot" -- balancing the need to study a mammalian brain with the practical considerations such as cost and throughput (and even ethical considerations about the use of nonhuman primates).I think NIDA has invested too little in genetics. In particular, while initial GWAS approaches have yielded only modest results due to sample size (a notable exception being cigarettes smoked per day) the price of genotyping has dropped and the sophistication of our analytic techniques has improved. It is now clear that a large concerted effort to obtain a very large (tens of thousands) samples will be successful. The evidence for this statement comes from the successes of the PGC for other psychiatric disorders, particularly schizophrenia and bipolar disorder. Unfortunately, NIDAs current portfolio is several years behind in this regard. Work by Joni Rutter and others to form up PGC-addictions group is laudable, however without an infusion of substantial additional funds, such an effort is unlikely to yield spectacular results.In addition to genetic studies focused on drug abuse as a phenotypic endpoint, I believe that NIDA should look to the RDoC approach that has come out of NIMH. I believe that genetic studies of intermediate phenotypes (endophenotypes) are well within the range of possibility and may provide more fundamental insights into the particular stages at which genes influence the transition from recreational drug use to drug abuse. An added benefit of this approach is that the results will likely be informative for NIMH and NIAAA-related traits (but I do not mean to imply that a multiagency approach would necessarily be the most efficient or nimble).Finally, I want to emphasize the importance of training the next generation of scientists in computational techniques. Two major opportunities are not being fully exploited due to a lack of properly trained researchers. First, the advent of next-generation sequencing has enabled enormous quantities of sequence data to be generated. Such data is useful for association studies, studies of rare alleles, studies of somatic mutations, gene expression studies, and studies of epigenetic marks, to name just a few. However, progress in all of these areas is limited by the lack of adequately trained scientists. the analysis of such data requires skills such as computer science, statistical genetics and bioinformatics. The second major opportunity comes from electronic medical records. A variety of important drug abuse related questions may be addressed by taking advantage of the very large "big data" approaches that exploit electronic medical records, however, progress is limited by appropriately trained scientists. In addition to providing training in these areas, NIDA may need to confront the difficult reality that individuals with these skill sets have very lucrative opportunities, making it difficult to retain them without

Basic Science, Public Health, Infrastructure, Unifying Themes

• On behalf of the Prevention Science Institute at the University of Oregon, we have some additional comments for consideration in the FY 2016-2020 Strategic Plan for the National Institute on Drug Abuse. Specifically, although we agree with the strategic plans as currently drafted, we advocate for a separate and specific focus on prevention (in addition to the focus on intervention and treatment). In addition,  to fully support NIH’s proposed strategic plan to invest in evidence-based health care prevention interventions, the directors and researchers at the University of Oregon’s Prevention Science Institute recommend the addition of the following priorities:Improve the understanding of biological processes related to substance use, abuse and addiction risk and resilience and reactivity to preventive interventions.Increase research to understand the cost of effective preventive interventions as well as the economic benefits that follow, to facilitate uptake and support for investing in prevention by policymakers and funders. Develop a strategy to build a strong infrastructure to support the dissemination, diffusion and quality implementation of evidence-based prevention practices that range from screening and assessment of vulnerable populations and communities to the appropriate recommendations for prevention programming and monitoring.Create opportunities for multiple federal agencies to collaborate in funding translational drug abuse prevention and treatment research;Increase opportunities for combining data from previous prevention and treatment trials and use innovative methods to integrate and analyze these data.Address the prevention needs of youth and high-risk populations (in addition to continuing a focus on treatment).Understand the implications of the changing drug policy environment (i.e., marijuana legalization at the state level). Understand the developmental and contextual influences across all areas of research. Thank you for consideration of this input.

Basic Science, Infrastructure, Unifying Themes

• The goal of the Psychiatric Genomics Consortium (PGC) is to conduct mega-analyses of genome-wide genetic data for psychiatric disorders. In existence since 2007, the group, the largest consortium of mental health researchers to date, has contributed substantially to advancing our scientific understanding of the genetic contributions to psychiatric disorders. PGC Addictions was established in 2012. The goal of our group is to study the role of common and rare genetic variants in the etiology of addiction, ranging from diagnostic indices, quantitative indices of use, treatment and relapse and to integrate these findings with emerging results from other efforts targeting substance use, mental health and neuroimaging outcomes. As a group, we propose the following avenues for NIDA’s strategic plan.Continued support for genotyping and sequencing of large repositories of well-characterized samples for the identification of common and rare variants for addictions.Large scale studies of schizophrenia (PMC4112379) have shown that increasing sample sizes can result in a substantial boost in power to detect common variation associated with complex behavioral and psychiatric traits, and most recently brain volumetric assessments. The PGC has already collated a majority of the addiction samples with GWAS data of which we’re aware, however, current numbers of cases  and controls (N=12397/28080 for the most common disorder, alcohol dependence, and many fewer for illicit drugs) are modest. Experience with other disorders indicates that a much larger number of samples will be required.  Continued support for genotyping utilizing modern cost-efficient arrays will substantially improve our ability to identify variants affecting risk for addictions. We stress also the need for samples to be well-characterized for substance use disorders (SUD). With the sustained push for personalized medicine, sequencing of samples with refined assessments of addictions is necessary (e.g. by SSAGA or SSADDA; or from the PhenX toolkit). When combined with GWAS and exome data, sequence information allows for study across the spectrum of allele frequencies and effect sizes for genes affecting risk/protection. In particular, family based data (including dense pedigrees, family trio and affected sibling pair studies) can provide a powerful platform for the study of rarer alleles and their mode of transmission. Support for collection and careful characterization of new samples related to addictions is essential. Also, we encourage additional phenotyping of existing collections when recontact is possible; this includes support for longitudinal studies, particularly during key periods of exposure and risk (e.g. adolescence).Recent studies (e.g. PMC3865158; PMC4233207) show that careful characterization of outcome measures (e.g. symptom counts, quantitative indices during periods of heavy use, such as maxdrinks for alcohol, information on route of administration, exposure opportunity in control population) can impact resolution of genetic signals. While studies of tobacco smoking have seen significant success with the use of ad hoc measures, such as cigarettes per day, there are known challenges associated with such measures when they are applied to illicit substance use behaviors. Future data collection efforts aimed at assembling samples with detailed phenotypic assessments of addiction are needed.Support for genotyping and phenotyping of existing and new longitudinal studies, including studies of high risk families and high risk neighborhoods, can provide unparalleled insights into the evolution of addictive behaviors, from exposure opportunity to remission/relapse. This also necessitates the detailed measurement of both self-report and the built environment (e.g. GIS) and the interplay between environmental vulnerability and genetic liability.Another potential area for substantial growth is developing repositories of genotyped treatment samples (e.g. methadone, buprenorphine) that would allow for the assessment of genetic moderators of treatment outcomes.Extending studies to under-represented groupsA majority of previous genomic efforts have relied on data from participants of European-American (or Native American) descent. Given the vast socio-cultural and linkage disequilibrium/haplotypic differences between Caucasians and other ancestries, developing cohorts of African-American, Mexican-American, Native American and Asian descent will be essential. This should include genotyping and sequencing of well-characterized collections already available, if consent can be obtained, as well as new collections. Consistent with the current literature, it is quite likely that many risk alleles will be population-specific. To obtain findings relevant for further treatment in a population, it may be necessary to study adequately powered samples in that population. Such an effort should be accompanied by international collaborations that leverage data from population isolates, indigenous groups etc.NIH interagency collaboration that would result in targeted studies of the genetic contributions to the comorbidity between addiction and other mental health outcomes.Despite substantial clinical and epidemiological evidence that rates of substance use disorders are considerably elevated in individuals with other psychiatric illness, and support from twin studies that these phenotypes share partially overlapping genetic etiologies, systematic genomic studies of this comorbidity are limited (e.g. PMID24957864).  Large samples ascertained for other psychopathology, such as in the PGC, are likely to include substantial numbers of subjects with detailed clinical assessments of addiction. Support for additional characterizations of substance use/abuse/dependence in other samples, contributions to additional genotyping or sequencing if needed, and for data analysis should be prioritized. Similar efforts at integrating results from recent neuroimaging efforts (e.g. ENIGMA, NCANDA) with emerging GWAS findings and the development of targeted neurogenetic studies can facilitate gene-brain-behavior studies.Support for secondary analysis of existing large repositories of unmined addiction data and for development and implementation of methodological tools for genomic studiesThe past 2 years have witnessed an explosion in polygenic methods, including genetic risk scores, pathway and network analyses, detection of genomewide loci influencing cross-trait covariance, heritability estimation from genomewide data. Such efforts require larger samples that are currently available but require sustained funding support.With emerging GWAS and sequencing findings, there is a strong need for further development of methodological tools that can be used to (a) annotate results, including integration of epigenetic, expression/eQTL data; (b) model complex gene-gene and gene-environment interplay; (c) implement other sophisticated approaches (e.g. graph theory).The development of user/consumer-friendly web utilities that allow for the integration of genomic results for addiction across multiple NIDA-funded consortia and from other analytic platforms (e.g. recent ENIGMA meta; brain functional studies, EEG/ERP) should be a priority. Such utilities should also allow for easy visualization of findings, annotation and download of summary statistics.

Clinical and Translational Science, Basic Science, Infrastructure, Public Health

• The Society for Adolescent Health and Medicine (SAHM) is responding to the Request for Information (RFI) (NOT-DA-15-005) that is seeking public input on research priorities to be included in NIDA’s new Strategic Plan. SAHM is a multidisciplinary organization committed to improving the physical and psychosocial health and well-being of all adolescents through advocacy, clinical care, health promotion, health service delivery, professional development and research. We greatly appreciate the opportunity to provide our perspectives as researchers, practitioners, and advocates for the health of adolescents and young adults.The current draft strategic priorities are overall quite comprehensive and exciting. We hope that the new Strategic Plan will include a special focus on adolescent development and research on adolescents and young adults. We also have several broad suggestions for consideration:Around the need identified to “harness the latest research technologies and apply to the ever- evolving substance abuse landscape,” we would suggest clarifying that there is need for both novel research methods (using ever evolving technologies) as well as development and testing of technology-based interventions to address substance abuse. Finding innovative strategies using technology to connect with hard-to-reach populations, including youth living in vulnerable social contexts, is certainly a key priority area in adolescent health research.Many adolescent health researchers are living in states where medical and recreational marijuana use has been legalized, and we anticipate this legislation to continue to expand in the United States.  We clearly need more science on marijuana pharmacology effects and risks in all of its new forms, and need the scientific community’s support to engage in this research, given the escalating availability, decreased perceived risk in adolescent populations, and new industry promoting the drug. Currently, this is only listed under public health not in the science domains.A third suggestion is to be more explicit about the need to engage more scientists and health providers to be aware of evidence based prevention methods and effects of prolonged drug use in children and adolescents more broadly such that substance use research is more integrated into basic, clinical and public health scientific inquiry. In addition to focusing on producing scientists highly trained in drug abuse research, we also need health providers and community stakeholders who can inform the science and incorporate the translation of science into evidence-based practice. While this stakeholder engagement is evident in the research priorities, it would be beneficial to include developing the capacity of health professionals and community partners as part of the training priorities.We agree that addressing health disparities is best infused in all domains. We would also suggest more specific focus on health disparities research. Currently there are no national efforts to look at why despite having a higher percentage of what are considered risk factors for drug abuse and addiction, African American youth use less drugs and alcohol than other groups. This is not explained by economics.  The concern however is heightened in young adulthood when use spikes in African American young adults and reaches, and sometimes exceeds, national averages. This is at a time when other age-race groups in the US are moving toward lower risk of initiation. Understanding this epidemiology and the trajectories for youth of diverse backgrounds with careful attention to the mechanisms for these disparities should help improve strategies to prevent adolescent drug use and define what new risks emerge for this population in young adulthood that changes their trajectory.Finally, we would recommend a greater emphasis on disseminating what works and strengthening implementation and dissemination science.  A model for this is the Office of Adolescent Health’s Teen Pregnancy Prevention Initiative, where great emphasis has been placed on increasing replication, adaptation, and dissemination of evidence-based interventions along with testing promising practices. While we recognize that this may step into service provision, we believe there is critically important and rigorous science needed to understand implementation and dissemination strategies. Certainly intervention proposals should be attentive to the issues of dissemination and scaling up of these interventions.We greatly appreciate the opportunity to provide our organization’s perspectives on these draft strategic priorities. Please do not hesitate to reach out to us with any further questions or clarifications as the NIDA staff and leadership develop this new Strategic Plan.

Clinical and Translational Science, Infrastructure

• Big Data My lab has become increasingly involved with the challenges of “big data” through our   escalating use of next generation sequencing (NGS), both RNA-seq and ChIP-seq. As can be gleaned from our initial publications (please let me know if you’d like me to send along PDFs),  we have already generated interesting datasets utilizing both methods and—importantly— overlaying information on RNA expression with that of histone modifications and non-histone chromatin regulatory mechanisms. We have a substantial amount of additional data that is now in preparation or under review, which further establishes this experimental approach. In our drug abuse models alone, we have generated on the order of 100 terabytes of sequencing data with much more in the offing.To analyze this extremely large and complex dataset, we have recruited a faculty-level bioinformatician who, in turn, employs two masters-level bioinformaticians. This group of three full-time computational investigators devotes themselves virtually full-time to the NGS data generated by my lab alone, roughly half of which concerns drug abuse data (the other half is focused on depression). These individuals are very expensive. Faculty-level bioinformaticians command higher salaries than biologically-oriented faculty, and masters-level bioinformaticians command ~50% higher salaries than PhD-level biologically-trained postdoctoral fellows!It is simply impossible to provide this amount of bioinformatics support in R01 grants. It is even difficult to fully fund it from P01 or P50 grants. Thus, I am only able to deploy this amount of bioinformatics resources because much of the support comes from institutional funds, which are limited and non-recurring. And the three individuals I have are not enough. I should employ a fourth person full-time to analyze my lab’s NGS data, but I do not have the funds to do so.A small but increasing number of neuroscience graduate students and postdoctoral fellows have sufficient quantitative aptitude and interest to become partly proficient in bioinformatics. This is a positive evolution, as ultimately we’ll need a workforce of individuals who are equally   comfortable in the biological and bioinformatics domains to drive this research. However, this would not take the place of true bioinformaticians, as the analytical demands of NGS data  require individuals with advanced training in this area, which will not be accessible for the vast majority of biologically-oriented researchers.Proposed solutions:Two innovations are need: 1) building the workforce of appropriately trained individuals, and 2) devising schemes to enable PIs to pay for those individuals from research grants.Provide administrative supplements to R01s, P01s, P50s, etc. to support additional robust bioinformatics support. Rigorous criteria can be applied so that such funding is offered only to those labs with the infrastructure that knows how to use the funding effectively and efficiently.Provide administrative supplements, or designated F or K series grants, to biologically- trained graduate students and postdoctoral fellows to gain more experience in bioinformatics. Review criteria will need to be modified, because such grants do not do well in today’s study sections.Provide administrative supplements to offer partial support for masters- or PhD-level bioinformaticians to enable them to gain more experience in biology.Consider novel T32 or R25 grants to focus on training a mixed biological-bioinformatics workforce. However, such grants must be modified to include masters-level bioinformaticians, since this category of individual represents a large fraction of today’s bioinformatics  workforce.Constitute study sections that provide appropriate review of bioinformatics-oriented grants. Today, a grant focused on sophisticated bioinformatics analysis of brain datasets related to drug abuse, for example, will be killed in biologically-oriented study sections because the members don’t understand or appreciate the value of the proposed work, while they will also be killed in bioinformatics-oriented study sections because brain data are considered too messy for hardcore bioinformaticians.Maintaining  InnovationWhy do some PIs continually introduce new approaches, methodologies, and theoretical frameworks into their research, while others perseverate in using the same experimental approaches addressing the same biological questions? I think this is a basic characteristic of a PI and is not something that can be easily taught. This is not age-related: some of our oldest investigators remain the most innovative (demonstrably), while some of our youngest investigators are the least innovative. The only way that NIH can influence this process is to:Require innovation as a crucial ingredient in all grant reviews. This is already happening but should be accelerated further. This will require further changes to NIH study sections to ensure study section membership of individuals who themselves innovate. Today, too many study sections lack a critical mass of such individuals.Require innovation as a crucial ingredient in all training-related grants. Successful T32s, R25s, F series, and K series grants should demonstrate established capacity for innovation and those that don’t should be defunded. Again, this will require improvements to study sections.In addition, innovation costs money. It is more expensive to use newer methods than to rely on stale methods. As one example, it is simply far less expensive to inject a neurotransmitter agonist or antagonist into a given brain region and study locomotor sensitization than it is to inject viral vectors into a given brain region of a genetically modified mouse or rat and study  drug self-administration behavior. Too many grants still do the former; this approach is flawed because an agonist or antagonist never has perfect specificity and such a locally-injected agent will affect its target in all cellular elements within the injected region (neuronal cell bodies, nerve terminals, and axons of passage as well as a host of non-neural cells). Likewise, self- administration assays, particularly those that examine long-lasting effects of drug exposure on extinction, relapse, and related measures are far better models of drug addiction but are also far more labor-intensive and expensive. As another example, it is far less expensive to analyze levels of one or a few mRNAs or proteins by use of qPCR or Western blotting than to obtain unbiased measures through NGS or proteomic approaches. While there are several reasons  why labs perseverate in using stale, limited methods, the biggest is money. NIH can help by:Increasing the size of modular R01s. The $250K cap has not changed in over a decade. (Perhaps larger budgets should be specifically designated for innovative approaches.)Avoiding administrative cuts. Study sections approve budgets that are required to get the proposed research done. Administrative cuts prevent a PI from achieving this goal and, oftentimes, innovation suffers the most because PIs can make progress more easily (publish more papers) by using older methods.Rewarding innovation. Innovation should be a greater part of the review process (see above). In addition, perhaps there are ways to provide administrative supplements to labs that demonstrate success in innovation.A personal note:I think my lab innovates a lot. As just some examples, in terms of experimental approaches, we have been among the first to use viral-mediated gene transfer in brain, genetic mutant mice with inducible and cell-type specific mutations, RNA-seq and ChIP-seq on discrete brain regions,   and optogenetic tools in drug abuse and depression models. Our most recent innovation is the development of a method to target a single type of histone modification to a single gene within a discrete brain region in vivo (Heller et al., Nat. Neurosci., 2014), thus revolutionizing the quality of proof to establish epigenetic mechanisms of drug abuse. In terms of biological findings, we have been among the first to demonstrate the involvement of post-receptor intracellular  signaling cascades, neurotrophic mechanisms, transcription factors, and epigenetic modifications in drug-induced behavioral abnormalities. The only reason that I have been able  to maintain this level of accomplishment and innovation is because: 1) I work insanely hard; 2) I receive substantial institutional support but most of which is non-recurring; and 3) I do not give up easily, so that I continue to fight for NIH funding even though every NIH grant I get buys less and less, and I have to fight against the “Occupy NIH Movement” which thinks that I have too much grant money.Improving  TranslationThis is an area where the entire biomedical research enterprise has arguably failed and the neurosciences in particular. The latter is no doubt related to the fact that the brain is far more complex than any other organ system and that its diseases are far more complex as well. Still, there are ways in which NIH can help PIs translate key discoveries:Provide administrative supplements for R01s, P01s, P50s, etc. to support targeted drug screening assays and follow up medicinal chemistry to identify and optimize molecules with novel targets. (Separate grants won’t work as effectively because someone like me cannot get another grant.)The NIH’s partnership with the Broad and perhaps other screening facilities is not effective. I had a personal experience where the Molecular Libraries initiative supported a screen at the Broad, but garbage in, garbage out: the Broad went through the screen in a flawed manner that was destined not to work but didn’t care because they did the work and got paid for it.Rather than centralized screening, therefore, NIH should provide the equivalent level of funding but allow PIs to shop around and find the best screening facility that meets their needs (with NIH approval of that facility required).The generation of lead compounds (with new IP for the PI and university), and their validation in animal models, will facilitate collaborations with Pharma and Biotech, who now pretty much require novel chemical matter—already validated—to proceed.Areas to CutI believe there is still a lot of low priority science being supported by NIH. As I walk around SFN, and view the ~25,000 posters, a very large fraction focus on science that is either stale in experimental approach or biological focus or not aligned with the highest priorities of NIH which should be: 1) fundamental discovery science, 2) disease-oriented basic research, and 3) translational research to advance diagnosis and treatment of disease.A big part of the problem remains NIH study sections. I’ve used this analogy before: if I wrote a grant on the role of nose-picking in psychiatry, that grant might go to a study section including several other leaders in the field who study nose-picking in psychiatry. My grant thus might be scored extremely well because of its technical competence and the trade bias of the study section, even though we know that studying nose-picking in psychiatry is not worthy of taxpayers money.Another part of the problem is inertia and perseveration. It is hard to do new things in new ways. It is also far more expensive. But Albert Einstein once said: “If you always do what you always did, you will always get what you always got.” If we applied that rule to NIH funding, there will be a substantial amount of currently funded work that could be cut.I would be happy to be part of a panel that examined NIDA’s portfolio for areas that warrant additional investment and others that should be de-emphasized or de-funded.Tactical Suggestions on Extramural GrantsLonger-term forms of supportThe MERIT award program has been extremely helpful to me. I don’t know how it looks overall. Still, I would suggest a greater number of longer term awards (requiring administrative review only), something in the 7-10 year time frame.Larger budgets for R01sWe’ve discussed this before, but perhaps the greatest challenges I’ve faced in trying to maintain my research program is the repeated pressure on budgets via administrative cuts. I’ve been extremely fortunate to have all of my R01 grants and P01 grant competitively renewed consistently over the past 15 years, but the total dollars have barely increased at all and have,   in fact, significantly decreased in real terms over this period. And this decrease in real funds doesn’t take into account the greater increase in the cost of doing state-of-the-art science. Cell-type specific manipulations of genes or microcircuits in the brain (with viral vectors, mutant mice, optogenetics, DREADDS, etc.), or genetic and epigenetic profiling of brain regions/cells in drug abuse models, have increased the cost of a typical R01’s research significantly.Facilitating the funding of younger investigatorsWe need to continue to find ways to reduce the age of first-time R01 grantees. Funding new investigators at higher (less positive) priority scores has helped a lot. I would urge continuing this policy. Another way to promote this would be to counter the phenomenon of the ever- increasing length of postdocs. NIH might consider a cap on years after training that an NIH grant can be used to support a postdoc’s salary. Expansion of K99s, and loosening some eligibility requirements, might also be considered.Continue prospective grading of grantsSome of my colleagues have proposed that PIs be judged more based on past productivity than on proposed research. However, I’m a fan of the current system where everyone must compete based on proposed research. I don’t think that established PIs need any extra favor.Abolish limits on grant numbers or dollarsLikewise, it’s not fair to establish an arbitrary limit on the number of grants or amount of grant dollars that a given PI can receive. Each grant should be judged on its own merits, with no favors but also no liabilities for PIs based on other support, seniority, etc.Fewer RFAs and Director’s awards: Implications for CSRI’m not a fan of RFAs and Director’s awards. I can see the value of RFAs for a particular public health need, but beyond that I believe those funds are better placed in the regular R01 pool of funding. I feel even more strongly about Director’s awards, whether transformational R01s, innovator awards, etc. Fewer RFAs and no Director’s awards would increase the R01 pool and help alleviate some of the bottlenecks above. Moreover, every grant should be innovative and many potentially transformational. I believe the problem lies with our study sections, some of which remain hostile to innovation although there have been significant improvements. I’d do a thorough review of all study sections and ensure that they have the right membership; too many study sections contain mediocre scientists who are jealous of innovation and success. Recruitment of more senior investigators would help. NIH should require all R01-funded PIs to serve on study sections IF ASKED. (Admittedly not all funded PIs are suitable; that’s for CSR and program officers to determine.)
• Thank you for providing the opportunity to comment on the NIDA Strategic Plan for 2016-2020.  It is essential that scientific agencies have strategic plans that are viable yet visionary and comprehensive enough to deal with the range of challenges facing the field. The 13 priorities and ideas for Basic Neuroscience seem well thought through.  It is not clear to me whether the relatively long list of priorities reflects the planned emphasis on this topic area, and I would encourage the agency to give equal emphasis to other important areas.The 6 priorities and ideas for Clinical and Translational Science touch upon important needs for scientific research.  In my view the priorities would be much better if they gave more attention to important social and behavioral approaches.  A number these interventions have been developed through federal drug abuse research, and many have become mainstays of addiction treatment, including relapse prevention, case management, and behavioral reinforcement.  The recent changes in federal funding of addiction treatment provide encouraging opportunities to develop, hone, and field a new set of social and behavioral interventions centering on identification of substance use, determining how to prevent problems from worsening, and how to apply behavioral principles to treat these problems more effectively.  The 4 priorities and ideas for Public Health touch on important themes that need to be addressed.  For the most part these seem to be general “big think” ideas that would warrant serious programmatic development at the institute.The 12 priorities and ideas for Scientific Infrastructure are vital, far-reaching, and well developed.  These topics seem crucial to the future of addiction science not just in training the upcoming generations of addiction researchers, but also in providing the necessary resources, linkages, and systems to make these efforts maximally productive.  The one area that seems to be missing is consideration of international outreach and collaboration, which has become so important in our developing scientific world. Each of the 5 Unifying Themes provide a kind of framework for mounting the priorities and ideas.I appreciate the opportunity to glimpse the future of NIDA and to give some input into its development
• NIDA Strategic Plan for Supported Research 2016-2020In developing its strategic plan for the future, especially as it relates to addiction, there needs to be a careful reanalysis of the current situation.  First, despite many efforts and strong support of research, treatment of most addictions is still very problematic, and most people are still poorly treated.  Furthermore, in relation to addiction and pain (both long term pain and psychic pain) the current situation appears to have gotten worse, with many people dying from prescription drugs.  Clearly, our current methods and drugs for treating addiction and prolonged pain do not work for most people.A plausible approach to solving many of these problems is to develop drugs that do not lead to the development of dependency, addiction and tolerance in the first place.  We and others have some very promising novel compounds that do not lead to dependency, addiction and tolerance in various animal models of acute and prolonged pain.  These compounds come from new approaches to the design of novel ligands which often are multivalent by design.  To my knowledge, none of these novel ligands have been in clinical trials to see if their activities in animal models translate to man.  Big pharma appears to be uninterested so it will be up to others and to NIDA to further the research and development of these novel ligands.  I realize that there is a reluctance to support approaches in research and drug development that are novel and/or may fail, but unless we are willing to do so, we will continue to fail.  Somehow, we have to re-establish a way to fund innovation and new approaches in drug design.  I have been on many NIH Study Sections in the last 35 plus years, and though innovation has become a criteria for scoring for over a decade, in fact, my observation is that it hardly ever enters into the scoring because most innovative (new) science and new ideas are easy to criticize (it may not work – God forbid).  So, we score our most innovative grants a 40 and go merrily on our way.  I suspect what I have said is of little concern, because an entirely new science and review culture would have to be created, where creativity is encouraged, not punished.  Nonetheless, it is pretty obvious why we are getting more and more data (results) and less and less innovation and new knowledge and understanding.  We have a creativity crisis.  We are not allowed to be creative anymore.  (See attached).So how do we recreate this culture in science?  It has to come from people (us) but apparently neither our scientific nor political leaders appear to be interested.  One possible approach would be to take some small percentage of grants, say 1%, and fund them based on creativity and new ideas and mostly ignore the criticisms.  I doubt if anyone has the desire or guts to do this, but someone has to point out what is happening.  Our most creative students are leaving science.
• We write in response to the above Request for Information, representing the Addiction Research Network (ARN) of the HMO Research Network (HMORN). The ARN of the HMORN includes 18 research centers affiliated with 18 not-for-profit health systems throughout the U.S. The ARN is a network of national reach with researchers representing the HMORN health systems. Researchers from each of the ARN sites and health systems have contributed to this response. Together these include Baylor Scott and White, Essentia Institute of Rural Health, Geisinger, Fallon/Meyers, Group Health, Harvard Pilgrim, Henry Ford, Kaiser Permanente Colorado, Kaiser Permanente Georgia, Kaiser Permanente Hawaii, Kaiser Permanente MidAtlantic, Kaiser Permanente Northern California, Kaiser Permanente Northwest, Kaiser Permanente Southern California, Marshfield Clinic, HealthPartners, and the Palo Alto Medical Foundation. The ARN is a geographically diverse network of health care systems including fully integrated systems (fully capitated, with complete overlap of health insurance and care delivery), hybrid or mixed systems (including substantial care provision by fee-for-service community providers), and multi-specialty group practices (where most care is provided via fee-for-service arrangements).Our investigators focus on addictions research in health systems. We regularly collaborate with patients, clinicians, and administrators both within our systems and more broadly to understand their priorities. The knowledge exchange guides the prevention and management of addictions in our healthcare settings. We bring this background and experience in responding to the RFI. Each of the points mentioned in the Strategic Plan are important in improving understanding of Substance Use (SU) problems and developing effective treatments.  We stress that much of this research would benefit from being conducted within large networks of health systems and suggest a broadening of context to explicitly study new approaches in defined populations. 1)  Basic Neuroscience: Improve our understanding of the basic science of drug use, addiction, vulnerability to addiction, and recovery.Basic research may be more impactful if it can include large, heterogeneous populations, developmental and environmental factors, and genomics as well as broad and diverse outcome measures ranging from patient reported outcomes to clinician measured health outcomes.  For this, the optimal research settings would be health systems with electronic health records (EHRs) that capture comprehensive longitudinal health data on a defined population base of patients, which can be combined with neurobiological, genetic, and environmental data from research studies.  At least as a start, much could be learned by using a “big data” approach to examine large numbers of individuals to identify developmental patterns of addiction and remission and thereby target potential research questions and participants. In addition, because assigning people to a potentially addictive substance within a clinical trial raises ethical concerns, it may be only initially feasible (and ethical) to use large population observational studies to understand relationships before conducting a trial.For basic research to have potential for implementation within health systems (i.e., personalized medicine), when applicable, basic research might take into account measures that allow clinicians to make personalized care decisions based on patient characteristics that are easily available directly from patients or from their health records – thus linking phenotypic data with findings from the proposed research domains. This approach supports promoting use of brief (valid/reliable) measures of SU constructs that can be implemented within routine clinical practice. New clinical approaches in healthcare, based on the comprehensive data that are accumulated in EHRs, need to develop systems whereby physicians and researchers can evaluate and compare outcomes of treatment based on targeted patient characteristics research.  Another important area is the need to integrate developmental factors and environmental interactions in conceptualizing this research. As an example, the ARN of the HMORN has longitudinal health care data on large numbers of individuals with important phenotype data to merge with basic research data, as is now being done with genetics studies. This is accomplished by such systems having the facilities for, and experience with, collection of biological specimens for research, with accompanying patient surveys, patient reported data routinely collected in clinical practice, and EHR/encounter data and claims data. 2)  Clinical and Translational Science: Support the development of new and better interventions and treatments that incorporate the diverse needs of individuals with Substance Use Disorders (SUDs)The research areas listed are important.  We recommend the critical role of research networks be stressed.  Research networks like the HMORN have developed approaches to facilitate harmonized data collection that allow use of “big data” for health services research.  This enables findings to be generalizable to the range of organizations providing SU treatment in the U.S. Research networks are already developed for mental health, cancer, cardiovascular disease, diabetes mellitus, hepatitis C, drug safety, and vaccine safety and effectiveness.  These networks have strengthened capacity to conduct larger and more efficient epidemiological studies, clinical and pragmatic trials, effectiveness evaluations, interventions and analyses that enable rapid responses to important health care questions. In order to capitalize on future studies to be conducted in the SU field, allowing for meta analyses that can inform patient, clinician and health system decisions, we would also reinforce previous suggestions by NIDA and the Institute of Medicine about common data elements in EHRs, reinforcing SU assessment approaches and other measures across studies.  Efficient population-based or comparative effectiveness research will also benefit from innovation and consistency in measurement of SUD outcomes using EHRs. This also includes improving methods and capacity for participant recruitment.  As an example, networks such as the HMORN  have extensive experience with using the EHR to identify, recruit, and consent patients and providers in population-based samples, selected according to diagnosis, patient reported measures collected in clinical practice, treatments received, utilization patterns, or socio-demographic characteristics.  More efficient recruitment using electronic messaging is being developed and is already used in some systems. Some outcomes of SU treatments (SU medications, psychosocial treatments) can currently be collected through existing information systems. Examples of outcomes include birth outcomes among infants exposed to maternal drug use, adverse events (e.g., injuries/poisonings after prescription drug use, mortality), emergency department and inpatient utilization and presenting problems, costs, and mortality.  It is also timely in the addictions field to develop new technologies for collecting data as well as for providing interventions.  For example, health systems are developing clinical decision supports for use in primary care and specialty care which can also be used for research.  They are using innovative technology (video visits, web-based interventions - live or fully automated, interventions delivered via  patient portals into their EHR, or tablet-based interventions) to deliver SU care in primary care as well as in specialty clinics.  This is a critical area to further develop, as the field seeks to expand access and integrate SU treatment into primary care, in response to the Affordable Care Act. Examples include: (a) using the EHR for encrypted electronic messaging accessible by mobile phones, (b) using electronic tablets that interact with a patient’s EHR and record clinician- and patient-reported information at visits, (c) developing online-service delivery through patient portals, or (d) tele-health video visits and (e) use of mobile phone apps.  In addition to including measures in the overall EHR, which can be a detailed process, “smart forms” and other embedded screening and monitoring tools can be efficiently added for specific studies or piloting next steps with EHRs. This is a unique and growing way to assess patient-reported outcomes.3)  Public Health: Increase the public health impact of NIDA research and programsThis is a critical research priority.  Health systems (and other systems, such as criminal justice) are optimal settings for conducting population-based research - important for epidemiology, for treatment development, and for implementation research. We suggest that implementation and dissemination research be emphasized in the Strategic Plan. Conducting research in such systems optimizes the potential of understanding the full population for prevention and treatment and for moving evidence-based research findings into healthcare policy and practice.  Large health networks (such as the ARN) with national coverage are critical  for understanding differences in state policies and other environmental characteristics, organizational complexities, population characteristics, and drug trends as they impact the understanding of SU and interventions.  The national coverage, as well as up-to-date information on new types of substances used by patients who present in emergency rooms, specialty treatment and primary care allows studies that can function as “early warning systems” and identify drug use trends, which can help prepare health systems and specialty treatment programs to address them.  There is a need to measure and intervene with prescription drug problems. These drugs are prescribed within health systems, thus primary prevention intervention, and treatment should also take place in those settings. We also agree that marijuana legalization is an important topic. Studies that focus on adolescents’ and adults’ marijuana use, and potential relation to health, mental health, and development of other SU problems are timely.We would suggest NIDA emphasize a range of types of clinical trials that are population-based. Pragmatic trials (including cluster randomized trials across multiple clinics) can answer broader sets of questions for both effectiveness and implementation studies, including hybrid studies.  Comparative effectiveness research should also be emphasized in the Strategic Plan, taking advantage of the vast amounts of data on populations and interventions available in health systems and other systems as well.  Research should include studies to improve treatment access for the population, strengthen resiliency in the community, and take into account affordability and the outcomes important to consumers and other stakeholders of healthcare.4)  Science Infrastructure: Enhance the national research infrastructure to support advancements in scienceThe Strategic Plan is comprehensive and includes both development of researchers and of database, methods, and technical infrastructure.  Regarding development of researchers, we would suggest that training programs include health systems for training (such as those represented in the ARN).  With the advent of research using “big data”, particularly from health systems, more researchers need to be trained to understand healthcare data systems and the complex methods used, such as statistical methods in causal inference for observational data, economics analysis, clinical informatics, as well as the developing area of Natural Language Processing (NLP) to examine clinicians’ notes. Much of this work can be optimized by using EHRs and other health systems technology.In addition, computerized records can be used to identify, recruit, and consent patients and providers. These systems enhance recruitment time as well as allowing targeting of research subjects with particular characteristics (i.e. recognized addictions, addictions in remission, or specific constellations of addictions with comorbidities). Harmonized data systems are needed such as the HMORN’s Virtual Data Warehouse to make population based clinical, health services, and quality improvement research possible without the cost of maintaining registries, which is expected to lower costs in the long-run. In many studies patients can be consented online for trials, or using interactive voice recording (IVR) technology. We would suggest that the Strategic Plan also emphasize research taking advantage of the health care process.  Many health systems incorporate relevant measures into their EHRs. This has been reinforced both by NIDA and the Institute of Medicine. Research is needed to assess the feasibility and effectiveness of collecting these measures, as well as research on different approaches to collecting clinical SU measures or providing interventions. The ability to conduct this kind of real-world experimentation makes this method appropriate (what the Institute of Medicine and others refer to as critical to Learning Healthcare Systems). Federal agencies, including the National Center for Research Resources and the Health IT Policy Committee, have recommended that the Department of Health and Human Services not require patient consent for the use of EHR data in research on improving the delivery of healthcare services, including when findings are widely shared. We note that numerous NIH studies are using this approach and NIDA would benefit by encouraging these new innovative approaches. In Summary, we emphasize a) broadening the context, settings, and locations of addictions research, as well as strengthening the methods and integration of the domains of research within this larger context; b) a broad range of intervention research, including comparative effectiveness studies using observational data and pragmatic trials, and cluster randomized trials – both of which would involve large population-based samples and allow for studying a wide range of population characteristics and health disparities; and c) encouraging innovative methods being used by other National Institutes of Health in studying the process of care, including Natural Language Processing in electronic health records.

Clinical and Translational Science, Infrastructure, Public Health

• There is an urgent need to reduce the time lag currently observed in scientific inquiry, currently averaging 17 years from intervention development to implementation. More funding for dissemination and implementation methods and trial development would help reduce this lag and bring needed prevention and treatment services to our taxpayers who support NIDA research. As an early career researcher, I am committed to developing quality research, but am aware at the restricted funding. Early career mentored funding that allows researchers to develop their skills and thus more significantly contribute to science should be a priority, especially for under represented groups such as women and people of color. Work that supports the integration of substance abuse and mental health would benefit not only patients, but increasingly burdened service systems and budgets. It is of crucial importance that interventions for substance abuse be delivered in alternative settings that are not necessarily specific to substance abuse and mental health such as primary care, in order to accommodate individuals who have little access to such specialty services, or are hesitant to access alternative services due to stigma. There are many opportunities for such research through the changes to our health system under the implementation of the ACA
• TREATMENT Investigate the effectiveness, feasibility, and patient and provider acceptability of delivering methadone treatment in office-based settingsThere has been a longstanding interest in mainstreaming addiction treatment by integrating it into primary and other health care settings.[1] Because of the relatively effective maintenance therapies available, opioid addiction is among the most promising substance use problems for such integration. In addition, with the passage of the Drug Addiction Treatment Act of 2000, it became possible for healthcare providers, who undergo special training and credentialing, to prescribe buprenorphine for the treatment of opioid addiction. While the uptake of buprenorphine has been significant for some patient populations, evidence suggests that particular patients, namely low income, non-white patients, are less likely to access buprenorphine than more affluent white patients.[2-5] In addition, although methadone maintenance is both cost-effective and effective at reducing use of other opioids, only about 12% of individuals with opioid dependence receive this treatment.[6] Additional research is needed on how to expand access to opioid treatment.Currently, with a few exceptions, methadone for the treatment of opioid dependence is only available through a highly regulated and widely stigmatized system of Opioid Treatment Programs (OTPs). Initial trials have suggested that methadone, like buprenorphine, can be effectively delivered in office-based settings[7-10] and that, with training, physicians would be willing to prescribe methadone to their patients to treat their opioid dependence.[11] Office- based methadone may help reduce the stigma associate with methadone delivered in OTPs [12] and provide a critical window of intervention to address medical and psychiatric conditions.[13] Despite this preliminary evidence, more research is needed to establish whether or not and how methadone can be effectively delivered in office-based settings, whether or not physicians would be willing to prescribe it, what ancillary supports might be needed, and what barriers exist to delivering methadone in such settings. In addition, research is needed to identify patient preferences for treatment and what factors might contribute to disparities in who does and who does not receive such office-based therapies. This research could help inform legislative changes that would be required for the delivery methadone outside of OTPs.Recommendations:NIDA should fund studies that examine the feasibility and effectiveness of office-based methadone. It should also fund studies on physician and patient preferences, barriers, and supports needed for office-based methadone to be successful. Finally, it should fund studies that examine how office-based programs and other factors might contribute to disparities in who does and who does not receive office-based treatment.ReferencesKrantz MJ, Mehler PS. Treating opioid dependence. Growing implications for primary care.Arch Intern Med, 2004,164(3):277-88.Hansen, H.B., Siegel, C.E., Case, B.G., Bertollo, D.N., DiRocco, D., & Galanter, M. Variation in use of buprenorphine and methadone treatment by racial, ethnic, and income characteristics of residential social areas in New York City. Journal of Behavioral Health Services & Research, 2013. 40(3):367-77.Knudsen, H.K., Ducharme, L.J., & Roman, P.M. Early adoption of buprenorphine in substance abuse treatment centers: data from the private and public sectors. Journal of Substance Abuse Treatment, 2006. 30(4): 363-73.Stanton, A., McLeod, C., Luckey, B., Kissin, W.B., & Sonnefeld, L.J. Expanding Treatment of Opioid Dependence: Initial Physician and Patient Experiences with the Adoption of Buprenorphine. American Society of Addiction Medicine, March 2006. Presentation. http://www.buprenorphine.samhsa.gov/ASAM_06_Final_Results.pdf Baxter, J.D., Clark, R.E., Samnaliev, M., Leung, G.Y., & Hashemi, L. Factors associated with Medicaid patients’ access to buprenorphine treatment. Journal of Substance Abuse Treatment, 2011. 41(1):88-96.Raisch DW, Fye CL, Boardman KD, Sather MR Opioid dependence treatment, including buprenorphine/naloxone. Ann Pharmacother, 2002. Feb;36(2):312-21.King VL, Stoller KB, Hayes M, Umbricht A, Currens M, Kidorf MS, Carter JA, Schwartz R,Brooner RK. A multicenter randomized evaluation of methadone medical maintenance. Drug Alcohol Depend, 2002. 65(2):137-48.Fiellin DA, O'Connor PG, Chawarski M, Pakes JP, Pantalon MV, Schottenfeld RS. Methadone maintenance in primary care: a randomized controlled trial. JAMA, 2001. 286(14):1724-31.Krambeer LL, von McKnelly W Jr, Gabrielli WF Jr, Penick EC Methadone therapy for opioid dependence. Am Fam Physician, 2001. 63(12):2404-10.Weinrich M, Stuart M. Provision of methadone treatment in primary care medical practices: review of the Scottish experience and implications for US policy. JAMA, 2000. 283(10):1343-8.McNeely J, Drucker E, Hartel D, Tuchman E. Office-based methadone prescribing: acceptance by inner-city practitioners in New York. J Urban Health, 2000. 77(1):96-102.Salsitz EA, Joseph H, Frank B, Perez J, Richman BL, Salomon N, Kalin MF, Novick DM. Methadone medical maintenance (MMM): treating chronic opioid dependence in private medical practice--a summary report (1983-1998). Mt Sinai J Med, 2000. 67(5-6):388-97.Krambeer LL, von McKnelly W Jr, Gabrielli WF Jr, Penick EC., Methadone therapy for opioid dependence. Am Fam Physician, 2001. 63(12):2404-10.Investigate the mechanisms of “natural” recovery and treatment outcomes beyond abstinenceMost of the literature about drug cessation has focused on the role of treatment, even though the majority of those with substance use problems never seek or receive treatment.[1] Moreover, the vast majority of research on quitting substance use has been done on samples either drawn from treatment settings or among people who have been in treatment. This large body of literature that has focused on the role of treatment in cessation has obscured the prevalence of natural recovery, even though researchers who have examined “natural recovery” contend that this is not an uncommon phenomenon.[2-5]The overwhelming majority of people who use any substance do so non-problematically. [21,  22] Furthermore, what literature is available indicates that many people who are drug- dependent achieve “remission” from their dependence without any form of treatment at all. In fact, evidence suggests it is the common course of most cases of substance dependence. [23- 35]  Most people who use or become dependent on substances seem to “age-out” – that is, they naturally reduce – and ultimately cease – their use as they grow older.[36]“Natural” recovery refers to changes in substance use without the aid of formal interventions.[6- 13] Until recently, the concept of “natural” recovery was considered taboo,[14] but there is potentially a great deal to be learned from those who are able to reduce or stop using drugs on their own. Because research has been biased by the large body of literature on treatment outcomes and sampling that often draws from treatment settings [15-18], little is known about the motivations or circumstances under which people reduce their drug use or quit using drugs on their own. Nor do we understand how an individual’s context or social environment influences reduction or abstinence from drugs.To date, studies of Vietnam veterans provide one of the major sources of information on natural recovery and the role of the social context.[19-20] During the war, an estimated 43% of U.S. Army male enlistees used narcotics, and 20% became dependent. Nevertheless, 8 to 12 months after returning to the US, only 5% of those who had been drug dependent in Vietnam remained so. These data demonstrate the power of environmental and social context as well as drug availability to alter drug use behaviors.A related problem is that much of the exiting research on cessation has been conducted to evaluate different treatment interventions and, thus, is mostly concerned with abstinence as the primary outcome. However, interim milestones are also important in understanding cessation and in their own right, since reductions in use (even if abstinence is not achieved) result in improved health outcomes. Studies of natural recovery could help illuminate what some of those milestones are and how people achieve them.Recommendations: NIDA should fund researchers to study the phenomena of natural recovery in the population across all substances. We recommend longitudinal cohort studies as well as qualitative studies to surface the underlying motivations and mechanisms for spontaneous remission. Samples for these studies should be drawn from non-treatment settings and include individuals who have never sought treatment.  In addition, we suggest that, in all studies about cessation, NIDA also encourage investigators to consider outcomes beyond abstinence, such as reductions in drug use, improved health outcomes, employment, increases in social support, etc.ReferencesGrella CE, Stein JA. Remission from substance dependence: differences between individuals in a general population longitudinal survey who do and do not seek help. Drug Alcohol Depend. 2013 Nov 1;133(1):146-53.Graeven DB, Graeven KA. Treated and untreated addicts: Factors associated with participation in treatment and cessation of heroin use. J Drug Issues 1983; 13(2):207- 218.Klingemann HK. The motivation for change from problem alcohol and heroin use. Br J Addict 1991; 86:727-744.Price RK, Risk NK, Spitznagel EL. Remission from drug abuse over a 25-year period: patterns of remission and treatment use. Am J Public Health 2001; 91(7):1107-1113.Hubbard RL, Craddock SG, Anderson J. Overview of 5-year follow up outcomes in the drug abuse treatment outcome studies (DATOS). J Subst Abuse Treat 2003; 25(3):125- 134.Klingemann HK, Sobell LC. Introduction: natural recovery research across substance use. Subst Use Misuse 2001; 36(11):1409-1416.Preble E, Casey JJ. Taking care of business: The heroin user's life on the streets. Int J Addict 1969; 4:1-24.Chiauzzi EJ, Liljegren S. Taboo topics in addiction treatment. An empirical review of clinical folklore. J Subst Abuse Treat 1993; 10(3):303-316.Granfield R, Cloud W. Social context and "natural recovery": the role of social capital in the resolution of drug-associated problems. Subst Use Misuse 2001; 36(11):1543-1570.Rumpf HJ, Bischof G, Hapke U, Meyer C, John U. Studies on natural recovery from alcohol dependence: sample selection bias by media solicitation? Addiction 2000; 95(5):765-775.Sobell LC, Ellingstad TP, Sobell MB. Natural recovery from alcohol and drug problems: methodological review of the research with suggestions for future directions. Addiction 2000; 95(5):749-764.Edwards G. Natural recovery is the only recovery. Addiction 2000; 95(5):747.Burman S. The challenge of sobriety: natural recovery without treatment and self-help groups. J Subst Abuse 1997; 9:41-61.:41-61.Chiauzzi EJ, Liljegren S. Taboo topics in addiction treatment. An empirical review of clinical folklore. J Subst Abuse Treat 1993; 10(3):303-316.Graeven DB, Graeven KA. Treated and untreated addicts: Factors associated with participation in treatment and cessation of heroin use. J Drug Issues 1983; 13(2):207- 218.Klingemann HK. The motivation for change from problem alcohol and heroin use. Br J Addict 1991; 86:727-744.Price RK, Risk NK, Spitznagel EL. Remission from drug abuse over a 25-year period: patterns of remission and treatment use. Am J Public Health 2001; 91(7):1107-1113.Hubbard RL, Craddock SG, Anderson J. Overview of 5-year followup outcomes in the drug abuse treatment outcome studies (DATOS). J Subst Abuse Treat 2003; 25(3):125- 134.Robins LN. A Follow-up of Vietnam Drug Users. Series A, No. 1. 1973. Washington, D.C., Executive Office of the President. Special Action Office Monograph.Robins LN. The Vietnam Drug User Returns. Series A, No. 2. 1974. Washington, D.C.,U.S. Government Printing Office. Special Action Office Monograph.WHO, U., Principles of drug dependence treatment. Geneva: WHO, 2008.Esser, M.B., et al., Prevalence of Alcohol Dependence Among US Adult Drinkers, 2009- 2011. Preventing Chronic Disease, 2014. 11: p. E206.Grella, C.E. and J.A. Stein, Remission from substance dependence: differences between individuals in a general population longitudinal survey who do and do not seek help. Drug Alcohol Depend, 2013. 133(1): p. 146-53.Slutske, W.S., Why is natural recovery so common for addictive disorders? Addiction, 2010. 105(9): p. 1520-1521.Carballo, J.L., et al., Natural recovery from alcohol and drug problems: A methodological review of the literature from 1999 through 2005, in Promoting self-change from addictive behaviors. 2007, Springer. p. 87-101.Williams, C.R. and B.A. Arrigo, Drug-taking behavior, compulsory treatment, and desistance: Implications of self-organization and natural recovery for policy and practice. Journal of Offender Rehabilitation, 2007. 46(1-2): p. 57-80.Klingemann, H.K.-H., Natural recovery from alcohol problems. The essential handbook of treatment and prevention of alcohol problems, 2004: p. 161.Granfield, R. and W. Cloud, Social context and “natural recovery”: The role of social capital in the resolution of drug-associated problems. Substance use & misuse, 2001. 36(11): p. 1543-1570.Klingemann, H.K.-H. and L.C. Sobell, Introduction: natural recovery research across substance use. Substance Use & Misuse, 2001. 36(11): p. 1409-1416.Cloud, W. and R. Granfield, Natural recovery from substance dependency: Lessons for treatment providers. Journal of Social Work Practice in the Addictions, 2001. 1(1): p. 83- 104.Sobell, L.C., T.P. Ellingstad, and M.B. Sobell, Natural recovery from alcohol and drug problems: Methodological review of the research with suggestions for future directions. Addiction, 2000. 95(5): p. 749-764.Edwards, G., Editorial note: natural recovery is the only recovery. Addiction, 2000. 95(5): p. 747-747.Toneatto, T., et al., Natural recovery from cocaine dependence. Psychology of Addictive Behaviors, 1999. 13(4): p. 259.Burman, S., The challenge of sobriety: natural recovery without treatment and self-help groups. Journal of substance abuse, 1997. 9: p. 41-61.Waldorf, D. and P. Biernacki, The natural recovery from opiate addiction: Some preliminary findings. Journal of Drug Issues, 1981. 11(1): p. 61-76.Lopez-Quintero, C., et al., Probability and predictors of remission from life-time nicotine, alcohol, cannabis or cocaine dependence: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Addiction, 2011. 106(3): p. 657-69.Investigate Heroin-Assisted Treatment and Other Novel Opioid Substitution TherapiesMedication-assisted treatment models for opioid dependence using diacetylmorphine (heroin) have been safely and successfully implemented in several countries, and are now well supported in the academic literature as one tool in an effective, health-based response to problematic drug use, especially among those who have not responded to conventional treatments. Often called heroin-assisted treatment (HAT), such models have proven enormously successful and now operate in Switzerland,[1, 2] Netherlands,[3] United Kingdom,[4] Germany,[5-7] Spain,[8, 9] Denmark,[2] Belgium,[10] Canada,[11] and Luxembourg. HAT allows for the provision of pharmacological grade heroin (diacetylmorphine) to select heroin-dependent people who have not previously responded to other forms of treatment. Typically, patients receive injectable or inhalable heroin 2-3 times per day from a doctor in a clinic setting under strict controls.Peer-reviewed studies around the world have found that HAT is associated with decreased illicit drug use, crime, overdose fatalities, and risky injecting, as well as improvements in physical and mental health, employment and social relations.[1, 3-6, 8, 11-20]  In contrast, few reports have appeared in the scientific literature demonstrating any harmful consequences of HAT.A Cochrane systematic review of all published studies on heroin-assisted treatment (HAT) found significant reductions in illicit drug use and crime, and improvements in health of participants. It concluded, “Each study found a superior reduction in illicit drug use in the heroin arm ratherthan in the methadone arm…the measures of effect obtained are consistently statistically significant.” [13]  An important article in the New England Journal of Medicine on the success ofthe North American Opioid Medication Initiative (NAOMI) in Canada, which provided heroin byprescription to a select group of people who had not responded to other forms of treatment, reported a two-thirds (67%) reduction in illicit drug use or other illegal activity.[11] Similar reductions in illicit heroin use were reported from HAT trials in the UK (72 percent)[4] and Germany (69 percent).[5]The Canadian HAT trial involved an arm of the study that received another opioid agonist, hydromorphone, instead of heroin; these subjects showed similarly impressive results: approximately two-thirds reduction in use of illicit heroin. [21] A second randomized trial in Canada that was recently completed administered both heroin and hydromorphone.[22]Retention rates in HAT programs dwarf those of convention treatments. [5, 11, 13, 23, 24] Patients express a strong preference for HAT over methadone or other standard treatments.[25, 26] While HAT has been restricted to those who do not respond to methadone, evidence now shows it is effective even for people with no previous maintenance experience – suggesting it could be scaled up.[27] Many HAT participants freely choose to move on to another form of treatment (like methadone) or to abstinence,[28, 29] while others continue to receive HAT on a long-term basis, with lasting positive results.[23]HAT is not only more effective at reducing illegal heroin (and other drug) use than methadone, [7] but it has also proven to be more cost-effective.[30] HAT participants are much less likely to commit acquisitive crimes and other non-drug offenses. As a result, HAT programs have been shown to decrease crime in areas where they are situated – leading to additional cost savings of the HAT model.[31-35]Recommendations:Researchers, advocates and health officials have expressed interest in studying and implementing HAT in the U.S. but federal laws and policies have stood in the way of this evidence-based method of treatment. NIDA should fund a heroin-assisted treatment trial in the United States. Such a trial could also compare the safety and efficacy of injectable hydromorphone for opioid dependence. If results are favorable, NIDA should urge the U.S. Congress to amend federal law to allow these innovative opioid replacement treatments to be implemented on a pilot basis in the United States without federal interference.ReferencesUchtenhagen, A., Heroin-assisted treatment in Switzerland: a case study in policy change. Addiction, 2010. 105(1): p. 29-37.Uchtenhagen, A.A., Heroin maintenance treatment: From idea to research to practice.Drug and Alcohol Review, 2011. 30(2): p. 130-137.Blanken, P., et al., Heroin-assisted treatment in the Netherlands: History, findings, and international context. European Neuropsychopharmacology, 2010. 20: p. S105-S158.Strang, J., et al., Supervised injectable heroin or injectable methadone versus optimised oral methadone as treatment for chronic heroin addicts in England after persistent failure in orthodox treatment (RIOTT): a randomised trial. The Lancet, 2010. 375(9729): p. 1885-1895.Haasen, C., et al., Heroin-assisted treatment for opioid dependence: randomised controlled trial. Br J Psychiatry, 2007. 191: p. 55-62.Verthein, U., et al., Long-term effects of heroin-assisted treatment in Germany.Addiction, 2008. 103(6): p. 960-6; discussion 967-8.Verthein, U., C. Haasen, and J. Reimer, Switching from methadone to diamorphine: 2- year results of the german heroin-assisted treatment trial. Subst Use Misuse, 2011. 46(8): p. 980-91.Oviedo-Joekes, E., et al., The Andalusian trial on heroin-assisted treatment: a 2 year follow-up. Drug Alcohol Rev, 2010. 29(1): p. 75-80.Perea-Milla, E., et al., Efficacy of prescribed injectable diacetylmorphine in the Andalusian trial: Bayesian analysis of responders and non-responders according to amulti domain outcome index. Trials, 2009. 10: p. 70.Belgian Monitoring Centre for Drugs and Drug Addiction, 2012 National Report (2011 data) to the EMCDDA by the Reitox National Focal Point: Belgium - New Development, Trends and in-depth information on selected issues. 2013, European Monitoring Centre for Drugs and Drug Addiction (EMCDDA): Lisbon.Oviedo-Joekes, E., et al., Diacetylmorphine versus methadone for the treatment of opioid addiction. N Engl J Med, 2009. 361(8): p. 777-86.Blanken, P., et al., Craving and illicit heroin use among patients in heroin-assisted treatment. Drug Alcohol Depend, 2012. 120(1-3): p. 74-80.Ferri, M., M. Davoli, and C.A. Perucci, Heroin maintenance for chronic heroin-dependent individuals. Cochrane Database Syst Rev, 2011(12): p. CD003410.Fischer, B., et al., Heroin-assisted Treatment (HAT) a Decade Later: A Brief Update on Science and Politics. Journal of Urban Health, 2007. 84(4): p. 552-562.Petrushevska, T., Heroin Maintenance Treatment-Are the Further Investigation Needed?Macedonian Journal of Medical Sciences, 2012. 5(4): p. 453-461.Strang, J., T. Groshkova, and N. Metrebian, New Heroin-Assisted Treatment: Recent Evidence and Current Practices of Supervised Injectable Heroin Treatment in Europe and Beyond. 2012, Lisbon: European Monitoring Centre for Drugs and Drug Addiction. 176.Killias, M., M.F. Aebi, and K. Jurist, The impact of heroin prescription on heroin markets in Switzerland. Crime Prevention Studies, 2000. 11: p. 83-100.Nordt, C. and R. Stohler, Incidence of heroin use in Zurich, Switzerland: a treatment case register analysis. The Lancet, 2006. 367(9525): p. 1830-1834.Reuter, P., Can Heroin Maintenance Help Baltimore. Baltimore, MD: Abell Foundation, 2009.Rehm, J., et al., Mortality in heroin-assisted treatment in Switzerland 1994-2000. DrugAlcohol Depend, 2005. 79(2): p. 137-43.Oviedo-Joekes, E., et al., Double-blind injectable hydromorphone versus diacetylmorphine for the treatment of opioid dependence: a pilot study. J Subst Abuse Treat, 2010. 38(4): p. 408-11.Providence Health Care. The Study to Assess Longer-term Opioid Medication Effectiveness (SALOME). Available from: http://www.providencehealthcare.org/salome/index.html.Blanken, P., et al., Outcome of long-term heroin-assisted treatment offered to chronic, treatment-resistant heroin addicts in the Netherlands. Addiction, 2010. 105(2): p. 300-8.Nosyk, B., et al., The effect of motivational status on treatment outcome in the North American Opiate Medication Initiative (NAOMI) study. Drug Alcohol Depend, 2010. 111(1-2): p. 161-5.Bald, L.K., et al., Heroin or Conventional Opioid Maintenance? The Patients' Perspective. J Addict Med, 2013.Marchand, K.I., et al., Client satisfaction among participants in a randomized trialcomparing oral methadone and injectable diacetylmorphine for long-term opioid- dependency. BMC Health Serv Res, 2011. 11: p. 174.Haasen, C., et al., Is heroin-assisted treatment effective for patients with no previous maintenance treatment? Results from a German randomised controlled trial. Eur AddictRes, 2010. 16(3): p. 124-30.Rehm, J., et al., Feasibility, safety, and efficacy of injectable heroin prescription for refractory opioid addicts: a follow-up study. Lancet, 2001. 358(9291): p. 1417-23.Reuter, P., Can Heroin Maintenance Help Baltimore?: What Baltimore Can Learn from the Experience of Other Countries. 2009: Abell Foundation.Nosyk, B., et al., Cost-effectiveness of diacetylmorphine versus methadone for chronicopioid dependence refractory to treatment. CMAJ, 2012. 184(6): p. E317-28.van der Zanden, B.P., et al., Patterns of acquisitive crime during methadone maintenance treatment among patients eligible for heroin assisted treatment. Drug Alcohol Depend, 2007. 86(1): p. 84-90.Killias, M., et al., Effects of Drug Substitution Programs on Offending Among Drug- Addicts: A Systematic Review. 2009.Lobmann, R. and U. Verthein, Explaining the effectiveness of heroin-assisted treatment on crime reductions. Law Hum Behav, 2009. 33(1): p. 83-95.Frick, U., et al., Long-Term Follow-Up of Orally Administered Diacetylmorphine Substitution Treatment. European Addiction Research, 2010. 16(3): p. 131-138.Garcia-Portilla, M.P., et al., Long term outcomes of pharmacological treatments for opioid dependence: does methadone still lead the pack? Br J Clin Pharmacol, 2014. 77(2): p. 272-84.DRUG SCHEDULINGInvestigate the scientific merits of the U.S. drug scheduling systemThe U.S. Controlled Substances Act (CSA) of 1970 created a five-category scheduling system for most legal and illegal drugs (although alcohol and tobacco were notably omitted). Depending on what category a drug is placed in, the drug is either subject to varying degrees of regulation and control – or, in the case of Schedule I drugs, completely prohibited and left to criminals to manufacture and distribute.The CSA divides controlled substances into five schedules originally determined by Congress. The "most dangerous" drugs are listed in Schedule I, defined as including drugs with "a high potential for abuse," "no currently accepted medical use in treatment in the United States," and "a lack of accepted safety for the use of the drug...under medical supervision." Schedule II  drugs also have "a high potential for abuse" and their abuse may lead to "severe psychological or physical dependence," but they have a "currently accepted medical use." Drugs in Schedules III through V have progressively lower potential for abuse, accepted medical uses, and can only cause "limited physical dependence or psychological dependence."Under the CSA, the DEA may initiate proceedings to add, delete or change the schedule of a drug or substance, as may the Department of Health and Human Services (HHS). Additionally, interested parties, including drug manufacturers, medical or pharmacy associations, public interest groups, state or local governments, or individual citizens can petition to add, delete or change the schedule of a drug or substance. When a petition is received by the DEA, they begin their own investigation of the drug. They may begin an investigation of a drug based on information received from state or local law enforcement and regulatory agencies, laboratories  or other sources. Once the DEA initiates an investigation of a drug, it collects relevant data. The DEA then requests that HHS conduct a scientific and medical evaluation and make a recommendation on whether the drug should be controlled or not and where it should be placed in the CSA schedule.HHS in turn seeks information from the Commissioner of the Food and Drug Administration (FDA) – who delegates this task to the FDA’s Controlled Substances Staff (CSS) – as well as evaluations and recommendations from the National Institute on Drug Abuse (NIDA). HHS may also seek input from the scientific and medical community at large. After consulting with FDA, NIDA, and any others, HHS submits to the DEA its medical and scientific evaluation of the drug and a recommendation on whether the drug should be controlled – and if so, in which schedule it should be placed. While HHS's medical and scientific evaluations are binding on the DEA, its scheduling recommendations are not, with one exception: If HHS recommends that a substance not be controlled, then the DEA may not control or schedule it. After receiving the scientific and medical evaluation from HHS, the DEA Administrator will evaluate all the data and make a final decision.While the CSA sets out the means and procedures for scheduling drugs in accordance with science and medicine, the DEA – a law enforcement agency – is ultimately responsible in most cases for making final decisions on how to schedule various drugs. The assignment to the DEA of this decision-making authority has produced some strange results. For instance, while methamphetamine and cocaine are Schedule II drugs making them available for medical use, marijuana is scheduled alongside PCP and heroin as a Schedule I drug, which prohibits any medical use.The DEA has consistently demonstrated that it is incapable of accurately assessing the state of medical and scientific knowledge about drugs and scheduling them appropriately.[1] Final decisions by the DEA on drug scheduling appear to be guided more by politics and the policy priorities of a law enforcement agency than science. The current system for classifying drugs is flawed.The current drug scheduling system fails to comport with scientific evidence about drug pharmacology and psychopharmacology. Schedule I is for drugs that are highly addictive and have no medical value, while the other schedules are for drugs with medical value but varying degrees of safety and dependence risks. There are no categories, however, for drugs that have no medical value but are not highly addictive either. By this measure, some substances listed under Schedule I do not belong there. Nor are there categories for drugs that have not been evaluated for medical value yet. Many emerging drugs, including synthetic cannabinoid compounds, have been placed under Schedule I without due consideration made to potential therapeutic value. [2-4] The current system for classifying drugs is also outdated and structurally cumbersome in ways that impact the ability of the government to nimbly make assessments and adjustments to the schedules that keep pace with evolutions in scientific understanding and emerging issues like synthetic drugs.[5] For instance, marijuana has remained in Schedule I since 1970 despite the emergence of study after peer-reviewed study around the world that have established the medical value of the chemicals in the marijuana plant.Experts and researchers have called for a new scheduling system based on relative harms of drugs.[6-8] For example, a report published in the esteemed Lancet Journal, researchers proposed an alternative method for drug classification in the United Kingdom, which uses a nine-category matrix to assess the harms of a range of licit and illicit drugs. The new classification system recognizes the fact that alcohol and tobacco cause far more individual and social harms than marijuana, LSD, and MDMA, which have less potential for harm relative to other legal and illegal drugs.[9, 10]Recommendations:Four decades ago, Congress created the drug scheduling system that is in place today. The current system relies too heavily on the DEA, a federal law enforcement agency, to make key decisions about how drugs should be classified according to their medical value and potential for abuse. The current system does not adequately conform to new and emerging circumstances or scientific discoveries that have a bearing on how a drug is regulated. NIDA should conduct a comprehensive evaluation of the federal drug scheduling system that examines the process for adding, changing or removing a substance from the schedules, the best way to assess the risks and benefits associated with current and emerging drugs. As part of this evaluation, NIDA should consider alternative scheduling systems based on evidence of harm and whether the current scheduling system should be reformed so that drugs are classified based on their relative risks and associated harms. NIDA should speak to the merit of overhauling the entire federal drug scheduling process to ensure that decisions on whether to criminalize a drug or not, and whether and how to regulate it, are decided by an objective, independent scientific process.ReferencesDrug Policy Alliance and Multidisciplinary Association for Psychedelic Studies, The DEA: Four Decades of Impeding and Rejecting Science. 2014, Drug Policy Alliance.Coulson, C. and J.P. Caulkins, Scheduling of newly emerging drugs: a critical review of decisions over 40 years. Addiction, 2012. 107(4): p. 766-73.Winstock, A.R. and J.D. Ramsey, Legal highs and the challenges for policy makers.Addiction, 2010. 105(10): p. 1685-1687.Kalant, H., Drug classification: science, politics, both or neither? Addiction, 2010.105(7): p. 1146-9.Nutt, D.J., L.A. King, and D.E. Nichols, Effects of Schedule I drug laws on neuroscience research and treatment innovation. Nat Rev Neurosci, 2013.Fischer, B. and P. Kendall, Nutt et al.'s harm scales for drugs--room for improvementbut better policy based on science with limitations than no science at all. Addiction, 2011. 106(11): p. 1891-2; discussion 1896-8.Rolles, S. and F. Measham, Questioning the method and utility of ranking drugharms in drug policy. International Journal of Drug Policy, 2011. 22(4): p. 243-246.Ray, R. and A. Dhawan, DRUG SCHEDULING—SCIENCE AND CULTURAL PERSPECTIVE. Addiction, 2010. 105(7): p. 1151-1153.Nutt, D.J., L.A. King, and L.D. Phillips, Drug harms in the UK: a multicriteria decision analysis. The Lancet, 2010. 376(9752): p. 1558-1565.Nutt, D., et al., Development of a rational scale to assess the harm of drugs of potential misuse. The Lancet, 2007. 369(9566): p. 1047-1053.End the NIDA monopoly on marijuana for research purposesTwenty three states plus the District of Columbia have acknowledged the medical value of marijuana by allowing those with certain medical conditions to use the substance with the recommendation of a licensed physician. While some states, such as California, have recognized the medical value of the marijuana plant for over 15 years, at the Federal level, marijuana remains a schedule I substance. One of the requirements for a substance to be placed in schedule I, is that is has no accepted medical value. The inconsistency of the federal marijuana classification with state level use has prompted numerous petitions to the Department of Health and Human Services over the past four decades asking for an investigation into the evidence for moving marijuana out of the schedule I category. Furthermore, unlike other substances in the schedule I category, the marijuana available for research purposes can be obtained from only one source, the federal government. The federal government, therefore, is put in the position of provider of marijuana for the purposes of researching a medical benefit it denies exists.Peer-reviewed studies [1-14] around the world have established the medical value of the chemicals in the marijuana plant, including THC and CBD, for the treatment of myriad medical conditions and symptoms, including neuropathic pain,[1, 3, 4, 6, 7, 10-13] multiple sclerosis,[1, 14] seizure disorders,[15-17] glaucoma,[18-20] digestive disorders such as Crohn’sDisease,[21-23] nausea and loss of appetite.[24-28] Furthermore, preclinical and limited clinical research suggests that the chemicals in the marijuana plant may also be helpful in treating Alzheimer’s Disease,[29-31] Parkinson’s Disease,[32-36] cancer,[37-47] arthritis,[10, 48, 49] PTSD,[50-54] and severe brain injury [55, 56]. The federal government currently holds a patent on CBD, one of the active chemicals in marijuana, as a neuro-protectant. The medical use of cannabinoids has become an international hotbed of research activity. Yet most labs and research teams are limited to inferior, synthetic versions of cannabinoids, and have their research stifled at the preclinical level due to the federal monopoly on marijuana for research purposes. States that have legalized the adult use of marijuana in the United States are excited to use the revenue from their programs to fund groundbreaking medical research, but they still have to overcome the barriers to obtaining the product for their studies, even in places where marijuana is available at a corner store.In 1999, the Institute of Medicine (IOM) released a report entitled, “Marijuana and Medicine: Assessing the Science Base”.[57] While the IOM suggests that the chemical found in the marijuana plant be developed into standardized formulations apart from the raw plant, they also concluded that, “Advances in cannabinoid science over the past 16 years have given rise to a wealth of new opportunities for the development of medically useful cannabinoid-based drugs. The accumulated data suggest a variety of indications, particularly for pain relief, antiemesis, and appetite stimulation. For patients who suffer simultaneously from severe pain, nausea, and appetite loss, such as those with AIDS or who are undergoing chemotherapy, cannabinoid drugs might offer broad-spectrum relief not found in any other single medication.”[57] In order for these medications that the IOM suggests to be developed, researchers must have access to high-quality raw marijuana material. THC and CBD are only 2 of over 80 cannabinoids found in the marijuana plant.[58] Limiting access to the plant for research purposes delays the discovery and development of medications that utilize these cannabinoids and can unlock the potential treatments for a countless number of conditions for which there is currently no cure, or for which the current treatment is not effective and related to dangerous side effects.The current federal monopoly on marijuana has slowed down the process of developing cannabinoid-based medications considerably. The organization, Multidisciplinary Association for Psychedelic Studies spent 22 years on an effort to obtain marijuana from the federal government for their study of marijuana to treat symptoms of PTSD – 22 years during which thousands of veterans and others might have found relief from their PTSD symptoms had the drug development process not been hindered by the current federal policies on marijuana research.Recommendations:Ideally, the placement of marijuana in the schedule I category would be reviewed as research has shown that marijuana does not fit the definition of a schedule I substance. However, it isimmediately requested that the stipulation that marijuana used for NIH approved research mustcome from the federal supply be removed. After obtaining approval from an IRB and financial support through a research grant, researchers should be able to obtain the marijuana from a third party provider, similar to how research on other schedule I substances, such as MDMA, is conducted. The federal government should do all it can to facilitate the research and development into cannabinoid based medications, and this includes removing the barriers to access for research purposes, and seriously considering moving marijuana out of the schedule I category, as is supported by numerous public health and medical organizations, including most recently the American Academy of Pediatrics.[59]ReferencesGrant, I., et al., Medical marijuana: clearing away the smoke. Open Neurology Journal, 2012. 6: p. 18-25.Ben Amar, M., Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol, 2006. 105(1-2): p. 1-25.Wilsey, B., et al., Low-dose vaporized cannabis significantly improves neuropathic pain.J Pain, 2013. 14(2): p. 136-48.Wilsey, B., et al., A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain, 2008. 9(6): p. 506-21.Abrams, D.I., et al., Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther, 2011. 90(6): p. 844-51.Abrams, D.I., et al., Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology, 2007. 68(7): p. 515-21.Fine, P.G. and M.J. Rosenfeld, Cannabinoids for Neuropathic Pain. Current pain and headache reports, 2014. 18(10): p. 1-9.Riggs, P.K., et al., A pilot study of the effects of cannabis on appetite hormones in HIV- infected adult men. Brain Res, 2012. 1431: p. 46-52.Grotenhermen, F. and K. Muller-Vahl, The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int, 2012. 109(29-30): p. 495-501.Lynch, M.E. and F. Campbell, Cannabinoids for treatment of chronic non‐cancer pain; asystematic review of randomized trials. British journal of clinical pharmacology, 2011.72(5): p. 735-744.Ware, M.A., et al., Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ, 2010. 182(14): p. E694-701.Ellis, R.J., et al., Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology, 2009. 34(3): p. 672-80.Degenhardt, L., et al., Experience of adjunctive cannabis use for chronic non-cancer pain: Findings from the Pain and Opioids IN Treatment (POINT) study. Drug Alcohol Depend, 2014.Corey-Bloom, J., et al., Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. Canadian Medical Association Journal, 2012. 184(10): p. 1143-1150.Maa, E. and P. Figi, The case for medical marijuana in epilepsy. Epilepsia, 2014.Szaflarski, J.P. and E.M. Bebin, Cannabis, cannabidiol, and epilepsy—From receptors to clinical response. Epilepsy & Behavior, 2014.Porter, B.E. and C. Jacobson, Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy & Behavior, 2013. 29(3):p. 574-577.Pertwee, R.G., Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci, 2012. 367(1607): p. 3353-63.Yazulla, S., Endocannabinoids in the retina: from marijuana to neuroprotection. Prog Retin Eye Res, 2008. 27(5): p. 501-26.Kogan, N.M. and R. Mechoulam, Cannabinoids in health and disease. Dialogues Clin Neurosci, 2007. 9(4): p. 413-30.Schicho, R. and M. Storr, Cannabis finds its way into treatment of Crohn's disease.Pharmacology, 2014. 93(1-2): p. 1-3.Naftali, T., et al., Cannabis Induces a Clinical Response in Patients with Crohn’s Disease: a Prospective Placebo-Controlled Study. Clinical Gastroenterology and Hepatology, 2013. 11(10): p. 1276-1280 e1.Alhouayek, M. and G.G. Muccioli, The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity. Trends Mol Med, 2012. 18(10): p. 615-25.Sharkey, K.A., N.A. Darmani, and L.A. Parker, Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. European journal of pharmacology, 2014. 722: p. 134-146.Borgelt, L.M., et al., The pharmacologic and clinical effects of medical cannabis.Pharmacotherapy, 2013. 33(2): p. 195-209.Todaro, B., Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting. Journal of the National Comprehensive Cancer Network, 2012. 10(4): p. 487- 492.Parker, L.A., E.M. Rock, and C.L. Limebeer, Regulation of nausea and vomiting by cannabinoids. British Journal of Pharmacology, 2011. 163(7): p. 1411-1422.Izzo, A.A. and K.A. Sharkey, Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther, 2010. 126(1): p. 21-38.Cao, C., et al., The Potential Therapeutic Effects of THC on Alzheimer's Disease. J Alzheimers Dis, 2014.Martin-Moreno, A.M., et al., Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease. Mol Pharmacol, 2011.79(6): p. 964-73.Mulder, J., et al., Molecular reorganization of endocannabinoid signalling in Alzheimer's disease. Brain, 2011. 134(Pt 4): p. 1041-60.Chagas, M.H., et al., Effects of cannabidiol in the treatment of patients with Parkinson's disease: An exploratory double-blind trial. J Psychopharmacol, 2014.Lotan, I., et al., Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clin Neuropharmacol, 2014. 37(2): p. 41-4.Chagas, M.H., et al., Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's diseasepatients: a case series. J Clin Pharm Ther, 2014. 39(5): p. 564-6.García, C., et al., Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ9-THCV in animal models of Parkinson's disease. British Journal of Pharmacology, 2011. 163(7): p. 1495-1506.Zuardi, A.W., et al., Cannabidiol for the treatment of psychosis in Parkinson's disease. J Psychopharmacol, 2009. 23(8): p. 979-83.Chakravarti, B., J. Ravi, and R.K. Ganju, Cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget, 2014. 5(15): p. 5852.Pacher, P., Towards the use of non-psychoactive cannabinoids for prostate cancer. Br J Pharmacol, 2013. 168(1): p. 76-8.Pisanti, S., et al., The endocannabinoid signaling system in cancer. Trends Pharmacol Sci, 2013. 34(5): p. 273-82.Bar-Sela, G., et al., The medical necessity for medicinal cannabis: prospective, observational study evaluating the treatment in cancer patients on supportive or palliative care. Evidence-Based Complementary and Alternative Medicine, 2013. 2013.Brown, I., et al., Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators. Prog Lipid Res, 2013. 52(1): p. 80-109.Velasco, G., C. Sánchez, and M. Guzmán, Towards the use of cannabinoids as antitumour agents. Nature Reviews Cancer, 2012. 12(6): p. 436-444.Salazar, M., et al., Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. The Journal of Clinical Investigation, 2009. 119(5): p. 1359-1372.Fernández-Ruiz, J., et al., Prospects for cannabinoid therapies in basal ganglia disorders. British Journal of Pharmacology, 2011. 163(7): p. 1365-1378.Guzman, M., Cannabinoids: potential anticancer agents. Nat Rev Cancer, 2003. 3(10): p. 745-55.Singer, E., et al., Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death Dis, 2015. 6: p. e1601.Orellana-Serradell, O., et al., Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep, 2015.La Porta, C., et al., Involvement of the endocannabinoid system in osteoarthritis pain.European Journal of Neuroscience, 2014. 39(3): p. 485-500.McDougall, J.J., Cannabinoids and Pain Control in the Periphery. 2009. p. 325-345.Roitman, P., et al., Preliminary, Open-Label, Pilot Study of Add-On Oral Δ9- Tetrahydrocannabinol in Chronic Post-Traumatic Stress Disorder. Clinical drug investigation, 2014. 34(8): p. 587-591.Neumeister, A., et al., Elevated brain cannabinoid CB receptor availability in post- traumatic stress disorder: a positron emission tomography study. Mol Psychiatry, 2013.Neumeister, A., The endocannabinoid system provides an avenue for evidence-based treatment development for PTSD. Depress Anxiety, 2013. 30(2): p. 93-6.Passie, T., et al., Mitigation of post-traumatic stress symptoms by Cannabis resin: A review of the clinical and neurobiological evidence. Drug Testing and Analysis, 2012.4(7-8): p. 649-659.Fraser, G.A., The Use of a Synthetic Cannabinoid in the Management of Treatment- Resistant Nightmares in Posttraumatic Stress Disorder (PTSD). CNS Neuroscience & Therapeutics, 2009. 15(1): p. 84-88.Johnson, B.N., et al., Augmented Inhibition from Cannabinoid-Sensitive Interneurons Diminishes CA1 Output after Traumatic Brain Injury. Front Cell Neurosci, 2014. 8: p. 435.Zhang, J., et al., Inhibition of monoacylglycerol lipase prevents chronic traumatic encephalopathy-like neuropathology in a mouse model of repetitive mild closed headinjury. J Cereb Blood Flow Metab, 2014.Joy, J.E., S.J. Watson, and J.A. Benson, Marijuana and medicine: assessing the science base. 1999, Washington, DC: Institute of Medicine, National Academies Press.El-Alfy, A.T., et al., Antidepressant-like effect of delta9-tetrahydrocannabinol and othercannabinoids isolated from Cannabis sativa L. Pharmacol Biochem Behav, 2010. 95(4): p. 434-42.Ammerman, S., et al., The Impact of Marijuana Policies on Youth: Clinical, Research,and Legal Update. Pediatrics, 2015. HARM REDUCTIONAddress the treatment and prevention needs related to common co-morbidities including HIV/AIDS and hepatitis C by researching supervised injection facilities –Supervised injection facilities (SIFs) are controlled health care settings where people can more safely inject drugs under clinical supervision and receive health care, counseling and referrals to health and social services, including drug treatment. They have shown promise in preventing  the transmission of blood-borne diseases such as HIV and hepatitis C and are also effective at reaching people who are currently out of care and linking them to treatment, both for drug dependence and for HIV and hepatitis C. SIFs can play a unique and vital role as part of a  larger public health and treatment approach to drug policy. SIFs are intended to complement – not replace – existing prevention, harm reduction and treatment interventions. This intervention deserves serious consideration and research.SIFs – also called safer injection sites, drug consumption rooms and supervised injecting centers – are legally sanctioned facilities designed to reduce the health and public order issues often associated with public injection by providing a space for people to inject pre-obtained drugs in a hygienic environment with access to sterile injecting equipment and under the supervision of trained medical staff. [1, 2]There are at least 98 SIFs operating in 66 cities around the world in ten countries (Switzerland, Germany, the Netherlands, Norway, Luxembourg, Spain, Denmark, Greece, Australia and Canada) – but none in the United States. [1-5]Numerous evidence-based, peer-reviewed studies from those countries have demonstrated the positive impacts of SIFs.[1-4, 6-32]These benefits include:Increased uptake into treatment for drug dependence, especially among people who are unlikely to seek treatment on their own.[22, 23, 27]Reduced public disorder, reduced public injecting, and increased public safety.[[6, 20, 21, 31, 33]Attracting and retaining a high risk population of people who inject drugs, who are at heightened risk for infectious disease and overdose. [8, 9, 28, 29, 34-36]Reducing HIV and Hepatitis C risk behavior (i.e. syringe sharing, unsafe sex)[3, 6, 8, 9, 11, 19-21, 26, 37, 38]Reducing the prevalence and harms of bacterial infections.[2, 3, 6]Successfully managing hundreds of overdoses and reducing drug-related overdose death rates. [2, 10, 25, 39-41]Cost savings resulting from reduced disease, overdose deaths, and need for emergency medical services. [12, 13, 16, 42]Providing safer injection education, and a subsequent increase in safer injectingpractices.[21, 43]Not increasing community drug use.[2, 3, 24]Not increasing initiation into injection drug use.[18]Not increasing drug-related crime.[6]Increased delivery of medical and social services.[6, 7] [22, 44, 45]There is an extensive body of research studying Insite in Vancouver, British Columbia, with more than two dozen peer-reviewed articles now published examining its effects on a range of variables, from retention to treatment referrals to cost-effectiveness.[3, 9] These reports are in line with reviews of the Australian [4, 33, 46] and European SIFs [5], which show that these facilities have been successful in attracting at-risk populations, are associated with less risky injection behavior, fewer overdose deaths, increased client enrollment in drug dependence treatment services, and reduced nuisances associated with public injection. For example, one recent study found a 30 percent increase in the use of detoxification services among InSite clients. NIDA-funded research could review those potential outcomes in the context of US health care provision and funding.InSite has proved to be cost-effective in terms of overdose and blood borne disease prevented as well. One cost-benefit analysis of InSite estimates that the facility prevents 35 new cases of HIV each year, providing a societal benefit of more than $6 million per year after accounting for the costs of the program.  A recent study published in the prestigious journal The Lancet found that the fatal overdose rate in the immediate vicinity of InSite decreased by 35 percent since it began operating in 2003, while the rest of the city experienced a much smaller reduction of 9 percent.[2, 3, 6]SIFs are worth researching and evaluating as a component of a comprehensive public health approach to reducing the harms of drug dependence, especially the co-morbidities of HIV and hepatitis C. The pilot implementation of a legal supervised injection facility staffed with medical professionals to reduce overdose deaths, increase access to health services, and further expand access to safer injection equipment to prevent the transmission of HIV and hepatitis C is worth investigating in the United States.ReferencesSchatz, E. and M. Nougier, Drug Consumption Rooms: Evidence and Practice. 2012, International Drug Policy Consortium.Semaan, S., et al., Potential role of safer injection facilities in reducing HIV and hepatitis C infections and overdose mortality in the United States. Drug Alcohol Depend, 2011.118(2-3): p. 100-10.Kerr, T., et al., Findings from the Evaluation of Vancouver’s Pilot Medically Supervised Safer Injection Facility—Insite (UHRI Report). Vancouver, BC: BC Centre for Excellence in HIV/AIDS. Addiction and Urban Health Research Initiative, 2009.Maher, L. and A. Salmon, Supervised injecting facilities: how much evidence is enough?Drug Alcohol Rev, 2007. 26(4): p. 351-3.Hedrich, D., T. Kerr, and F. Dubois-Arber, Drug consumption facilities in Europe and beyond. MONOGRAPHS, 2010: p. 305.Potier, C., et al., Supervised injection services: What has been demonstrated? A systematic literature review. Drug Alcohol Depend, 2014. 145C: p. 48-68.McNeil, R., et al., Impact of supervised drug consumption services on access to and engagement with care at a palliative and supportive care facility for people living with HIV/AIDS: a qualitative study. J Int AIDS Soc, 2014. 17: p. 18855.MacArthur, G.J., et al., Interventions to prevent HIV and Hepatitis C in people who inject drugs: A review of reviews to assess evidence of effectiveness. International Journal of Drug Policy, 2013.Boyd, N., Lessons from INSITE, Vancouver's supervised injection facility: 2003-2012.Drugs: education, prevention and policy, 2013. 20(3): p. 234-240.Christian, G., et al., Overdose deaths and Vancouver's supervised injection facility. The Lancet, 2012. 379(9811): p. 117.Pinkerton, S., How many HIV infections are prevented by Vancouver Canada's supervised injection facility? Int J Drug Policy, 2011. 22: p. 179 - 183.Pinkerton, S., Is Vancouver Canada's supervised injection facility cost-saving? Addiction, 2010. 105: p. 1429 - 1436.Andresen, M. and N. Boyd, A cost-benefit and cost-effectiveness analysis of Vancouver's supervised injection facility. Int J Drug Policy, 2010. 21: p. 70 - 76.DeBeck, K., et al., Police and public health partnerships: Evidence from the evaluation of Vancouver's supervised injection facility. Substance Abuse Treatent, Prevention and Policy, 2008. 3(1): p. 1 - 5.Wood, R., et al., Nurse-delivered safer injection education among a cohort of injection drug users: evidence from the evaluation of Vancouver's supervised injection facility. IntJ Drug Policy, 2008. 19(3): p. 183 - 188.Bayoumi, A. and G. Zaric, The cost-effectiveness of Vancouver's supervised injection facility. Can Med Ass J, 2008. 179(11): p. 1143 - 1151.Des Jarlais, D., K. Arasteh, and H. Hagan, Evaluating Vancouver's supervised injection facility: Data and dollars, symbols and ethics. Can Med Assoc J, 2008. 179(11): p. 1105- 1106.Kerr, T., et al., Circumstances of first injection among illicit drug users accessing a medically supervised safer injection facility. Am J Public Health, 2007. 97(7): p. 1228-30.McKnight, I., et al., Factors associated with public injecting among users of Vancouver's supervised injection facility. Am J Drug Alcohol Abuse, 2007. 33(2): p. 319 - 325.Petrar, S., et al., Injection drug users' perceptions regarding use of a medically supervised safer injecting facility. Addict Behav, 2007. 32: p. 1088 - 1093.Stoltz, J., et al., Changes in injecting practices associated with the use of a medically supervised injection facility. J Pub Health (Oxford), 2007. 29(1): p. 35 - 39.Wood, E., et al., Rate of detoxification service use and its impact among a cohort of supervised injection facility users. Addiction, 2007. 102: p. 916 - 919.Wood, E., et al., Service Uptake and Characteristics of Injection Drug Users Utilizing North America’s First Medically Supervised Safer Injecting Facility. American Journal of Public Health, 2006. 96(5): p. 770-773.Kerr, T., et al., Impact of a Medically Supervised Safer Injection Facility on Community Drug Use Patterns: A Before and After Study. Br Med J, 2006. 332: p. 220 - 222.Kerr, T., et al., Drug-related overdoses within a medically supervised safer injection facility. Int J Drug Policy, 2006. 17: p. 436 - 441.Tyndall, M., et al., HIV Sero-prevalence among participants at a supervised injection facility in Vancouver, Canada: implications for prevention, care and treatment. Harm Reduction Journal, 2006. 3(36): p. 1 - 5.Tyndall, M., et al., Attendance, drug use patterns, and referrals made from North America's first supervised injection facility. Drug Alcohol Depend, 2005. 83(3): p. 193 - 198.Wood, E., et al., Prevalence and correlates of hepatitis C among users of North America's first medically supervised safer injection facility. Public Health, 2005. 119(12):p. 1111 - 1115.Wood, E., et al., Do supervised injecting facilities attract higher-risk injection drug users?Am J Prev Med, 2005. 29(2): p. 126 - 130.Small, D., Mental illness, addiction and the supervised injection facility. Visions: BC's Mental Health and Addictions Journal, 2004. 2(1): p. 37 - 39.Wood, E., et al., Changes in public order after the opening of a medically supervised safer injection facility for injection drug users. Can Med Assoc J, 2004. 171(7): p. 731 -734.Fairbairn, N., et al., Women's experiences in North America's First Medically Supervised Safer Injection Facility. Soc Sci Med. 67(8): p. 817 - 823.Salmon, A.M., et al., Five years on: What are the community perceptions of drug-related public amenity following the establishment of the Sydney Medically Supervised InjectingCentre? International Journal of Drug Policy, 2007. 18(1): p. 46-53.Reddon, H., et al., Use of North America’s first medically supervised safer injecting facility among HIV-positive injection drug users. AIDS education and prevention: official publication of the International Society for AIDS Education, 2011. 23(5): p. 412.Hadland, S.E., et al., Use of a Medically Supervised Injection Facility Among Drug- Injecting Street Youth. Journal of Adolescent Health, 2014. 54(2): p. S88-S89.Wood, E., et al., Factors associated with syringe sharing among users of a medically supervised injecting facility. Am J Infect Dis, 2005. 1(1): p. 50 - 54.Kerr, T., et al., Safer injecting facility use and syringe sharing among injection drug users. Lancet, 2005. 366: p. 316 - 318.Kerr, T., et al., The role of safer injection facilities in the response to HIV/AIDS among injection drug users. Current HIV/AIDS Reports, 2007. 4(4): p. 158-164.Kerr, T., et al., A Micro-Environmental Intervention to Reduce Harms Associated with Drug-Related Overdose: Evidence from the Evaluation of Vancouver's Safer Injection Facility. Int J Drug Policy, 2007. 18: p. 37 - 45.Marshall, B.D., et al., Reduction in overdose mortality after the opening of North America's first medically supervised safer injecting facility: a retrospective population- based study. The Lancet, 2011. 377(9775): p. 1429-1437.Milloy, M.-J., et al., Non-fatal overdose among a cohort of active injection drug users recruited from a supervised injection facility. The American journal of drug and alcoholabuse, 2008. 34(4): p. 499-509.Jozaghi, E., A. Reid, and M. Andresen, A cost-benefit/cost-effectiveness analysis of proposed supervised injection facilities in Montreal, Canada. Substance Abuse Treatment, Prevention, and Policy, 2013. 8(1): p. 25.Wood, E., et al., Safer injecting education for HIV prevention within a medically supervised safer injecting facility. Int J Drug Policy, 2005. 16: p. 281 - 284.Wood, E., et al., Attendance at supervised injecting facilities and use of detoxification services. 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Addiction, 2010. 105(4): p. 676-683.Expand NIDA’s research priorities to include risk factors and harm reduction within nightlife and festival settingsA significant portion of drug use, especially among young people, takes place in nightlife and festival settings and yet the quantity of available research does not reflect that.[1-6]The majority of this drug use is non-problematic; that is, does not meet the traditional definitions of dependence or addiction.[5-17]  However it can involve risky use behaviors that can lead to hospitalization and deaths.[18] Given the current popularity of large-scale festivals and events with attendance in the tens of thousands or even hundreds of thousands, we need a better understanding of the demographic makeup of these populations, as well as epidemiological data on the rate and nature of drug-related hospitalizations and deaths.Another trend that is not well understood in the US context is patterns of use and misuse of novel psychoactive substances (NPS), for which only limited prevalence data are collected. [19, 20]  In contrast to many European countries, [21] which have monitored the situation for several years – having seen higher rates of intentional use of NPS (such as with the example of mephedrone) – this issue has more recently emerged in the US. [21-23] It deserves attention since as popular drugs such as cannabis, MDMA and other psychedelics remain illegal and hard to acquire, the iterative copycat versions of these drugs will keep appearing on the scene.[23-25] [26]The escalating speed with which NPS appear as well as the current popularity of large scale music events and festivals make further study of harm reduction responses crucial.  This includes not only deepening evaluations of peer-based drug education efforts, for which support in the research already exists, [2-4, 27, 28] but also looking seriously at the practice of drug testing for adulterants. This practice, also known as “pill testing” or “drug checking” in the European context where it has been in place for many years, can provide a critical tool for people to identify dangerous or unexpected substances in the drugs they intend to consume. [29-33]  Further research is needed to identify how this changes drug-using behavior, as well as to determine which among the technologies available are most practical and effective. Other factors that may contribute to changes in drug using behavior, like the location of drug checking services and their coordination with counseling and connection to treatment services if needed, should be explored.Recommendations:NIDA should fund research aiming to collect epidemiological data on hospitalizations and  deaths related to attendance at US music festivals and other large-scale nightlife venues and events. NIDA should conduct further research on novel psychoactive substance use patterns in the US – including investigation into which substances are being by whom and in what contexts. Finally, NIDA should invest in studies on the efficacy of harm reduction interventions in nightlife environments – particularly regarding the efficacy of recreational “drug-checking” and impact of such practices on drug use behavior.ReferencesVan Havere, T., et al., Drug use and nightlife: more than just dance music. Substance abuse treatment, prevention, and policy, 2011. 6(1): p. 18.Hunt, G., M. Moloney, and K. Evans, Youth, Drugs, and Nightlife: Pleasures, Risks, and Identity. 2010: Routledge.Calafat, A., et al., Recreational nightlife: Risk and protective factors for drug misuseamong young Europeans in recreational environments. Drugs: Education, Prevention, and Policy, 2008. 15(2): p. 189-200.Bolier, L., et al., Alcohol and drug prevention in nightlife settings: a review of experimental studies. Subst Use Misuse, 2011. 46(13): p. 1569-91.Winstock, A., P. Griffiths, and D. Stewart, Drugs and the dance music scene: a survey of current drug use patterns among a sample of dance music enthusiasts in the UK. Drug and alcohol dependence, 2001. 64(1): p. 9-17.Winstock, A., The Global Drug Survey 2014 findings. 2014.Siliquini, R., et al., Recreational drug consumers: Who seeks treatment? European Journal of Public Health, 2005. 15(6): p. 580-586.Sanders, B., Drugs, clubs and young people: Sociological and public health perspectives. 2012: Ashgate Publishing, Ltd.Ramo, D.E., et al., Cocaine use trajectories of club drug-using young adults recruited using time-space sampling. Addict Behav, 2011. 36(12): p. 1292-300.Parks, K.A. and C.L. Kennedy, Club drugs: reasons for and consequences of use.Journal of psychoactive drugs, 2004. 36(3): p. 295-302.Miller, B.A., et al., Assessment of club patrons’ alcohol and drug use: the use of biological markers. American journal of preventive medicine, 2013. 45(5): p. 637-643.Miller, B.A., et al., Group influences on individuals' drinking and other drug use at clubs.J Stud Alcohol Drugs, 2013. 74(2): p. 280-7.Kelly, B.C., J.T. Parsons, and B.E. Wells, Prevalence and predictors of club drug use among club-going young adults in New York City. Journal of Urban Health, 2006. 83(5): p. 884-895.Järvinen, M. and S. Ravn, From recreational to regular drug use: qualitative interviews with young clubbers. Sociology of health & illness, 2011. 33(4): p. 554-569.Grov, C., B.C. Kelly, and J.T. Parsons, Polydrug use among club-going young adults recruited through time-space sampling. Substance use & misuse, 2009. 44(6): p. 848-864.Duff, C., The pleasure in context. Int J Drug Policy, 2008. 19(5): p. 384-92.Anderson, T.L., et al., Variations in clubbers' substance use by individual and scene- level factors. Adicciones, 2009. 21(4): p. 289-308.Ridpath, A., et al., Illnesses and deaths among persons attending an electronic dance- music festival-New York City, 2013. MMWR: Morbidity and mortality weekly report, 2014.63: p. 1195-1198.Substance Abuse and Mental Health Services Administration, Results from the 2013 National Survey on Drug Use and Health. 2014, Substance Abuse and Mental Health Services Administration: Rockville, MD.Johnston, L.D., et al., Monitoring the Future national survey results on drug use: 2014 Overview, Key Findings on Adolescent Drug Use. 2015, Ann Arbor: Institute for Social Research, The University of Michigan.Hughes, B. and P. Griffiths, Regulatory approaches to new psychoactive substances (NPS) in the European Union. Addiction, 2014. 109(10): p. 1591-1593.Spiller, H.A., et al., Clinical experience with and analytical confirmation of "bath salts" and "legal highs" (synthetic cathinones) in the United States. Clin Toxicol (Phila), 2011. 49(6): p. 499-505.Measham, F., et al., Tweaking, bombing, dabbing and stockpiling: the emergence of mephedrone and the perversity of prohibition. Drugs and Alcohol Today, 2010. 10(1): p.14-21.Payer, D., Novel synthetic drugs: A neuroscience perspective, in Club Health. 2013, Drug Policy Alliance: San Francisco.Winstock, A. and C. Wilkins, ‘Legal highs’ The challenge of new psychoactivesubstances. Series on Legislative Reform of Drug Policies, Number Amsterdam: Transnational Institute, 2011.Perrone, D., R.D. Helgesen, and R.G. Fischer, United States drug prohibition and legalhighs: How drug testing may lead cannabis users to Spice. Drugs: Education, Prevention, and Policy, 2012: p. 1-9.Sumnall, H., et al., A choice between fun or health? Relationships between nightlifesubstance use, happiness, and mental well-being. Journal of Substance Use, 2010.15(2): p. 89-104.Whittingham, J.R., et al., Avoiding counterproductive results: an experimental pretest of  a harm reduction intervention on attitude toward party drugs among users and nonusers. Subst Use Misuse, 2009. 44(4): p. 532-47.Winstock, A.R., K. Wolff, and J. Ramsey, Ecstasy pill testing: harm minimization gone too far? Addiction, 2001. 96(8): p. 1139-1148.Hungerbuehler, I., A. Buecheli, and M. Schaub, Drug Checking: A prevention measure for a heterogeneous group with high consumption frequency and polydrug use- evaluation of zurich's drug checking services. Harm reduction journal, 2011. 8(1): p. 16.Camilleri, A.M. and D. Caldicott, Underground pill testing, down under. Forensic Science International, 2005. 151(1): p. 53-58.Murray, R.A., et al., Putting an Ecstasy test kit to the test: harm reduction or harm induction? Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 2003. 23(10): p. 1238-1244.MacCoun, R.J., Testing Drugs Versus Testing for Drug Use: Private Risk Management in the Shadow of Criminal Law. DePaul L. Rev., 2006. 56: p. 507.

Clinical and Translational Science, Public Health, Basic Science, Unifying Themes, Infrastructure

• The following is a list of priority areas that we feel represent understudied topics and/or knowledge gaps in the field:Evaluate agonist treatments for stimulant and cannabis use disorders - find ways to balance risks and benefitsRe-engineer the pipelines for med development with human laboratory studies and alternative early Phase II clinical trial designsCharacterize the use of electronic cigarettes for treating nicotine use disordersDetermine more effective ways of studying emerging drug problems ("dabbing," Spice, etc.)Examine co-abuse of substances (e.g., nicotine-marijuana, opiates-alcohol, marijuana-alcohol, opiates-benzodiazepines, cocaine-marijuana, etc.) and develop effective ways of treating co-abuseUse imaging techniques to identify treatment responseImprove the understanding of neurobiological and neuroimaging studies by incorporating drug-taking behavior and other abuse liability measures into the research where possibleStrongly support more efforts to promote research that directly examines the impact of sex and gender on drug abuse and addictionIn addition to the above, another important component for consideration is to improve how the Strategic Plan is implemented. The following are suggestions for accomplishing this:Develop procedures for communicating NIDA's interest and disinterest in certain research areas to the scientific communityDevelop a central forum at NIDA for IND's that can be accessed by granteesDevelop a more active interaction between NIDA and the DEA and FDA with regard to drug scheduling.

Clinical and Translational Science, Public Health, Infrastructure

• The American Society of Addiction Medicine (ASAM) is grateful for this opportunity to comment on the National Institute on Drug Abuse’s (NIDA) 2016 Strategic Plan.  ASAM is hopeful that the following comments regarding the draft 2016 research strategy strengthen what is already a thoughtful and robust agenda for future NIDA research.Clinical and Translational Science PrioritiesWhile the identification of new, evidence-based treatment interventions  is necessary to address the diverse treatment needs of patients suffering with addiction, equally important is the development of practice guidelines and performance measures to encourage widespread adoption of these novel therapies.  Furthermore, standardized methods for assessing quality of care, adherence to treatment and patient outcomes (e.g., urine drug testing) are needed to validate the relationship between evidence-based treatment and patient improvements in health and function.Public Health PrioritiesAddiction remains a highly stigmatized disease, despite the heightened awareness of prescription drug misuse and overdose death.  NIDA, in collaboration with the Surgeon General, the Centers for Disease Control and Prevention and other federal stakeholders, could facilitate the development and dissemination of a broad public education campaign that addresses the common misperceptions, myths and fears related to addiction, treatment and recovery.Science Infrastructure PrioritiesThe vast majority of physicians do not receive any training on addiction in medical school. This results in a physician workforce with little to no knowledge about how to identify and treat patients suffering with addiction.  Research that supports the integration of addiction curriculum into medical school would support efforts to both integrate addiction treatment into primary care and address shortages in the addiction provider workforce.  Moreover, improved education may address the disinclination of many physicians to treat patients with addiction and, thereby, improve patient access to high-quality care.For physicians who do specialize in the treatment of addiction, the paucity of performance measures and practice-based research networks available to test the measures that do exist limits the specialists’ ability to gauge their effectiveness and the value of their medical expertise. ASAM respectfully requests that NIDA support the development of a practice-based research network of addiction physician specialists, in order to improve outcomes measurement and ongoing advancement in the field of addiction medicine.Again, ASAM is grateful for this opportunity to inform NIDA’s next strategic plan.  Our members look forward to continued collaboration with NIDA, to advance the science and practice of addiction treatment.

Format, Basic Science, Clinical and Translational Science, Infrastructure

• Background The mission of NIDA is to lead the nation in bringing the power of science to bear on drug abuse and addiction. NIDA fulfills this mission by supporting research to prevent and treat drug abuse and addiction and mitigate the impact of their consequences, including the spread of HIV/AIDS and other infectious diseases. NIDA-supported programs span basic, clinical, and translational sciences and incorporate genetics, epigenetics, neuroimaging (functional, biochemical, structural), social neuroscience, medication and behavioral therapy development, as well as prevention and health services research.The current NIDA Strategic Plan was published in 2010. Since that time, there have been major advances in the science of drug abuse and addiction. Therefore the Institute has begun a planning process to develop a revitalized Strategic Plan for 2016–2020. NIDA seeks to harness the latest research technologies and apply them to the ever-evolving substance abuse landscape. Toward this goal, NIDA staff developed a draft set of strategic priorities and are seeking feedback to guide the development of NIDA’s Strategic Plan.Information RequestedThis RFI is intended to gather broad public input on the draft strategic priorities outlined below as well as general recommendations that will sustain recent advances and accelerate discovery in addiction research over the next five years. NIDA invites input from researchers in academia and industry, health care professionals, patient advocates and advocacy organizations, scientific or professional organizations, federal agencies, and other interested members of the public. Organizations are encouraged to submit a single response that reflects the views of their organization and membership as a whole.Please provide your perspective on the following items as they relate to the draft strategic priorities outlined below. Your comments can include, but are not limited to:  Suggested changes or additions to the list of strategic priorities, including   emerging research needs and future opportunities that should be considered in   the plan   The scientific rationale for the changes or ideas proposed and the anticipated   impact on advancing the science of drug abuse and addiction   Anticipated challenges that will need to be addressed to achieve these   priorities   Appropriate benchmarks for gauging progress toward each recommended priority   Recommended measurable objectives associated with an individual priority NIDA also welcomes your general comments, including those regarding the extent to which this plan will guide and encourage participation in drug abuse research.Draft Strategic Priorities (A general comment is these objectives are almost too broad and too general to be meaningful – in an industrial setting they would be rejected as likely to unachievable no matter how many teams of researchers you “throw” at them.   So I have made some track changes I hope are helpful to the NIDA team.) ed note: changes are incorporated, comments are parenthetical.Basic Neuroscience: Continue to increase the preclinical database concerning drug use, vulnerability to addiction, withdrawal, relapse and recovery.  with focus on biological, behavioral, environmental, and   developmental factors involved in risk for drug use and   addiction and the factors influencing resilience and recovery   This requires: 1)Integrating the preclinical data base across behavioral genetic, epigenetic and potential molecular biomarkers of drug use, abuse and addiction.    2) Continuing to determine the developmental trajectory of addiction  (Since these studies in the preclinical setting are done in the absence of a social environment, not likely to yield directly translatable information.  I might omit this particular sentence and stick to vulnerability of developing brain to addiction and determining which drug class is preferred at various  developmental stages)  3) Continuing to delineate the brain circuits related to drug abuse and   addiction at the cellular, circuit, and connectome levels, which includes:: Normal development and function across the lifespan including mechanisms of   reward, self-control, and conditioning The effects of drugs of dependence on neuroplasticity, neural structure, and circuit function from acquisition/use to addiction/dependence, through to withdrawal and recovery.     Neural-glial, -immune, and neuroendocrine interactions as applicable to the studies above.   Defining the interactions between addiction and pain, including   molecular, genetic, behavioral , and neural-circuit-related factors, to guide   the development of alternate treatment strategies for pain patients (Is this not better served by a cross institute approach as only focusing on the interaction between addiction and pain may miss important intervention opportunities for pain in general)  3) Continuing to elucidate the significant determinants of addiction in those with comorbid conditions (eg.psychiatric, HIV, HCV, pain).     And the converse to determine the impact of addiction on the underlying diseases such as whether the molecular mechanisms of latent HIV reservoirs in the brains of SUDindividuals differ from those without SUD Clinical and Translational Science: Support (Support is a weak term – how about Direct resources toward the development?) the development of new and better interventions including preventative and treatments  for SUDs. To fulfil this objective resources will be allocated as follows:  Support the development of novel, evidence-based (If they are novel it is hard to have a clinical evidence base yet – just using buzz words?), targeted prevention and   treatment interventions including social, behavioral, pharmacological,   vaccines, and brain stimulation therapies (e.g., transcranial magnetic   stimulation, direct current stimulation, etc.) Target the introduction of novel prevention and treatment interventions that may be social, behavioral, pharmacologic (including vaccines)or devices (transcranial magnetic stimulation as an example)Identify the most promising targets and or ligands to assiste in new drug discovery and developmentCollaborate in the effort to accelerate medications development for SUDFocus this development on SUD with no known pharmacologic treatment for either dependence, toxicity, withdrawal or agents to hasten neurobiologic recoveryTarget treatments for SUD plus comorbidities (HIV,pain as examples)  Develop techniques to measure and improve patient compliance in clinical   trials (This should be a cross agency endeavor if limited to addiction may result in tailored but not generalizable data/techniques – I would develop the techniques broadly then apply to SUD)2)  Describe and quantify measurable outcomes beyond abstinence that can be used in clinical trials/clinical assessment of SUD.  These outcomes could include biomarkers of addiction, withdrawal, relapse risk or sustained relapse.   Public Health: Increase the public health impact of NIDA research and programsImprove the understanding of factors that influence the integration of   evidence-based research findings into healthcare policy and practice   (implementation science) Increase readiness to respond to emerging public health priorities (opioid   overdose epidemic, potential consequences of marijuana legalization, changing   healthcare landscape, emerging drug trends, etc.) Increase strategic partnerships with the community (academia, PhRMA or pharmaceutical companies, biotechnology companies,   healthcare organizations, policy makers, etc.) to enhance the dissemination of   evidence-based research findings into policy and practice Strengthen the focus on bi-directional translational research Science Infrastructure: Enhance the national research infrastructure to support advancements in science 1) Accelerate the development and utilization of advanced technologies (e.g. the   President’s BRAIN Initiative), data repositories (e.g. Big Data to Knowledge   (BD2K) initiative, and statistical models to spur innovative research  2) Improve training for the next generation of scientists  3) Increase effective engagement and training in multidisciplinary research   (informatics, engineering, computer science, chemistry, mathematics, physics,   etc.)  4) Increase the number of well-trained underrepresented scientists in the drug   abuse and addiction field at all career levels because this ensures diversity in scientific discovery and the inclusion of the needs of diverse populations  5)Improve mentoring of young scientists and junior faculty 6) Increase effective collaborations in research (All research or specific to SUD?/mission)  7)Increase the transparency of research performed by grantees and within NIDA 8) Increase effective data and resource sharing (big data (More buzzwords of the moment – but big data means: mining data from insurers, large care providing institutions and available data from pharmaceutical companies??), biorepositories,   transgenic/optogenetic tools (Sharing resources developed by grantees, such as optogenetic tools), data standards, etc.)  9) Increase collaborations with other NIH Institutes and Centers (e.g.   Collaborative Research on Addiction at NIH (CRAN)), Federal and State   agencies, academic and industry partners, etc.( We try to avoid etc in industry – people interested in how their money is spent don’t like it much)  10) Identify and implement strategies to improve the reproducibility of   pre-clinical research(This is probably the most important statement in the document but belongs with transparency and should be the highlighted rationale for transparency – you can even comment on it under drug development)  11)Enable efficiency and lower the cost of clinical trials via innovative   statisticalmethods such as adapative design, helping to establish SUD data collection and reporting standards, leveraging technology (e.g. electronic   health records) and developing partnerships  12)Develop and validate computational and systems-level analytics for integrating   multi-dimensional data across the addiction trajectory(And in reality this means?) Unifying themes: A number of unifying themes that will be addressed across each of the domains listed above include:  Promoting research that considers the impact of sex and gender on drug abuse   and addiction   Addressing health disparities among underrepresented populations   Understanding the role of development across the life span   Addressing the treatment needs of adolescents and pregnant and post-partum   women (For what it is worth first time mentioned in whole document)   Addressing the treatment and prevention needs related to common co-morbidities   including HIV/AIDS

Format, Basic Science, Public Health, Clinical and Translational Science, Unifying Themes, Infrastructure

• On behalf of the American Psychiatric Association (APA), the medical specialty association representing 36,000 psychiatrists and their patients and families, I am pleased to share APA’s comments on the National Institute on Drug Abuse’s draft strategic plan. We would like to commend NIDA on developing a well-organized draft that is thoughtful, comprehensive, impactful and wide-reaching in its scope. Our feedback on the draft strategic priorities reflects our great concern about the impact of substance use disorders on people in the U.S. and great hope for improvement in the realm of research going forward.APA strongly supports NIDA's mission. Abuse of and addiction to alcohol, nicotine, and illicit and prescription drugs cost Americans more than $700 billion a year in increased health care costs, crime, and lost productivity.1-3 Each  year, illicit and prescription drugs and alcohol contribute to the death of more than 90,000 Americans, while tobacco is linked to an estimated 480,000 deaths per year.4-5 These disorders are diagnosable and treatable, and when not treated are associated with suffering, premature death and diminished quality of life. The presence ofsubstance use disorders can also exacerbate the severity of other medical illnesses, inhibit appropriate medical management, and is associated with increased general medical costs.We particularly appreciate several aspects of NIDA’s current work and its draft strategic plan including in the basic neuroscience domain.  Efforts to gain greater knowledge about the multiplicity of factors for risk and resilience in drug use and addiction and understanding the developmental pathways of addiction and individual heterogeneity are extremely important. NIDA’s awareness of the need to focus on drug use and co- occurring conditions including HIV/AIDs is to be applauded. This priority is consonant with NIDA’s excellent work on comorbidities in relation to mental health, HIV, and the Hepatitis C virus.NIDA’s draft strategic priority centered on the development of novel, evidence-based, targeted prevention and treatment interventions in a variety of domains is essential. In particular, focused development efforts on overdose prevention and reversal hold great promise in the face of the recent epidemic levels of opiate use disorders and mortality due to overdose. The APA agrees with and praises NIDA on its attention to the public health domain and its prioritization of the identification of factors that facilitate the integration  of evidence-based research findings into healthcare policy and practice. In addition, the APA concurs with NIDA about the importance of increasing partnership with a wide variety of stakeholders to advance the dissemination of evidence-based research findings into policy and practice.APA appreciates NIDA drawing attention to the need for acceleration of development and utilization of advanced technologies. In addition, we commend NIDA’s focus on generating higher levels of transparency and reproducibility of research.We wish to acknowledge that NIDA has proposed appropriately that the domains of its draft priorities on drug use be regarded through the multiple lenses of gender, age spectrum and life course, underrepresented and underserved populations, and common comorbidities.NIDA’s draft has stimulated several additional suggestions and recommendations which we respectfully offer for NIDA’s consideration. The highlights of these suggestions span the full range of areas covered in the draft and are summarized as follows:Basic Neuroscience: Encourage research on neurobiological correlates of vulnerability to addictions and the study of treatment targets as a consideration of neurobiological correlates of recovery.Clinical and Translational Science:  Support bidirectional research involving translation  of bench findings to clinical research in humans as well as research on strengthening bedside to bench.  Ensure that functional measures are included along with biomarkers of addiction, resilience and recovery to enable personalized treatment. Support  dissemination of research so that evidence-based practices are applied in the community. Develop evidence-based approaches to substance use disorder interventions in integrated care settings. Increase efforts to develop more efficacious medications for treating addictions. Foster collaborative research involving psychiatry and general medicine given the high morbidity and mortality associated with comorbidity of substance use disorders and medical illnesses. Expand focused development efforts to study population-based strategies for treatment adherence in patients living with substance-related disorders,  HIV, and the hepatitis C virus.Public Health:  Conduct research on cost analysis and economic feasibility of treatments. Engage in greater dissemination of NIDA progress, initiatives, research and education to outlets with strong public health impact including the health media. Undertake initiatives to improve training of clinicians at the front lines of public health, equipping them with tools for clinical implementation to decrease the research-practice gap. Consider pursuing efforts to improve the understanding of how interventions should be tailored to meet the needs of diverse populations: gender, race/ethnicity, sexual orientation, gender identity and limited English proficiency. There is also a need for greater attention to the interrelationship between substance use disorders and trauma, given that sexual assault and abuse frequently trigger substantial rates of substance use disorders.Science Infrastructure: Encourage collaborative efforts with:  federal agencies including the Department of Veterans Affairs and SAMHSA; cross Institute and academic centers with brain banks and genetic material depositories; and professional organizations such as APA, American Association of Addiction Psychiatry, American Society of Addiction Medicine, and others. Develop and mentor well-trained female and underrepresented scientists in the drug abuse and addiction field at all levels. Establish a partnership between the APA and NIDA modeled after the highly successful Program for Minority Research Training in Psychiatry (PMRTP), which was funded by NIMH, to lead young researchers into the field.Unifying Themes:  Consider bringing this section to the front of the draft to assist readers in placing specific strategic priorities in context. In order to ensure that NIDA’s work addresses the full breadth of the U.S. population, include factors such as age, race, ethnicity, gender, sexual orientation, gender identity and social determinants of health.The following paragraphs delineate our detailed response to each area of NIDA’s draft strategic priorities:Basic NeuroscienceAPA proposes additions to the draft priorities in this area.Neurobiological CorrelatesWith regard to the improvement of understanding of brain circuits related to drug abuseand addiction at the cellular, circuit, and connectome levels, neurobiological correlates of vulnerability to addiction should also be included. Another area in the category of basic neuroscience that deserves attention is treatment targets, which should be a consideration of the neurobiological correlates of recovery.Comorbidity of Substance Use Disorders and Chronic DiseasesAPA requests NIDA bolsters its attention to the comorbidity of substance use disorders and medical illnesses. Thanks to previous NIDA research, it is well recognized thatsubstance use disorders are a significant contributor to the severity, morbidity, and mortality from many illnesses, including cardiovascular disease, gastrointestinaldisorders, HIV/AIDS, and pain disorders. APA recommends that NIDA expand its support for collaborative research between psychiatry and general medicine to furtheraddress these comorbidities and develop an array of effective interventions.4DiversityDrawing on one of the aforementioned unifying themes of diversity, it also is importantto consider the role of race as a determinant in the prevalence of co-occurring disorders. This issue is particularly relevant among racially diverse, vulnerable populations experiencing what has been referred to as “the triple whammy” of mental illness, addiction, and chronic disease, particularly HIV.Clinical and Translational ScienceAPA would like to suggest augmentation to NIDA’s vision in this area.Bidirectional Research, Functional Measures, Animal Models and Complex AddictionsWe recommend that NIDA consider supporting the translation of bench findings to clinical research in humans, as well as research on strengthening bedside to benchapplications (bidirectional research). With regard to clinical and translational scientific approaches, we recommend the inclusion of functional measures along with biomarkersof addiction, resilience, and recovery to enable personalized treatment. Clinical and translational research could also be used to assess the applicability of animal models or addiction mechanisms identified from animal models for human addiction vulnerability and treatment. APA encourages NIDA to support efforts on the treatment of complex addiction involving multiple substances.Age and Developmental ConsiderationsWhile addressing clinical and translational research domains, it is essential to concentrateon populations of study for focused developmental efforts including adolescents, young adults, and geriatric populations. One example of this is the need for research on addiction to prescription and pain/benzodiazepine medications and interventions for withdrawal in older adult populations.Dissemination of ResearchAPA strongly supports NIDA's dissemination of research and implementation of science so that evidence-based practices are dispersed to the community. NIDA's Clinical TrialNetwork (CTN) is an outstanding example of this important public health concept.Substance Use Disorder Treatment in Integrated SettingsChoosing where and how to invest finite resources is critically important. APA supportsNIDA's strong emphasis on the identification and evaluation of high-quality, cost- effective models for substance use disorder treatment services in integrated care settings. However, APA recommends this work build on the current excellent NIDA efforts (e.g., the development of screening tools for primary care and other healthcare professionals to assess patients or clients for tobacco, alcohol, and other drug use) to begin to focus on development of evidence-based approaches to substance use disorder interventions in these settings, such as the primary care opiate dependence intervention program.6 Theseactivities highlight the importance of integrating primary care with behavioral health components.There is a robust and growing research base documenting the ability of integrated care models to improve health outcomes. More research is needed on the dissemination and implementation of these models in a wide range of real-world practice settings, as well ason increasing our understanding of the economic impact of integrated care. APA enthusiastically supports research on the responsible integration of technology into all levels of the health care system, in the service of enhancing clinical interventions, and improving patient outcomes.Similarly, mental health services are benefiting from a growing interest in the development of collaborative care programs. Indeed, there is clear evidence of the role for integrated care in managing mental illness and reducing the disease burden of comorbid chronic conditions, such as hypertension and diabetes. Furthermore, the work of Jürgen Unützer, M.D., has identified that racial/ethnic minority women may have a more robust response to collaborative care programs than White (non-Latino) counterparts from similar socio-economic backgrounds. However, there is still a need for more research identifying effective models for the integration of substance use disorder treatment into primary care clinics. This is an additional area where NIDA can make a significant contribution.Medications for Addiction TreatmentAPA is appreciative of the development efforts on treating addictions that are currentlywithout FDA-approved medications. APA suggests these efforts include the treatment of addictions both with and without FDA-approved medications. Currently, FDA-approved medications for addictions do not lead to completely satisfactory outcomes. For example, both bupropion and varenicline (FDA-approved medications to assist with tobacco smoking) have a 1-year abstinence rate of approximately 10%, which is only double the success rate of people trying to quit without medication. Clearly, there is a great need for medications with better efficacy. A recent study showed that varenicline combined with nicotine replacement therapy was more effective than varenicline alone in achieving abstinence from tobacco but further study is needed to assess long term efficacy andsafety. 7Comorbidities of Substance Use Disorder, HIV/AIDS and Hepatitis CAPA asks that NIDA consider expanding its focused development efforts in its strategic plan to researching population-based strategies for treatment adherence in patients livingwith substance-related disorders, HIV, and the hepatitis C virus. Translational science such as this will be critical to ensuring that clinicians, substance abuse counselors, andothers have effective tools to curb the HIV epidemic. As research continues to show promising HIV-prevention interventions in drug abuse treatment settings, a cascadecontinues to exist in which the rates of treatment adherence declines for persons living with HIV and substance-related disorders who were previously linked to care.8 APA believes that continued research in treatment adherence strategies is a key to preventing the spread of HIV/AIDS and improving the vitality of patients living with HIV and asubstance-related disorder.Furthermore, the medical field has concluded that those currently most at risk for HIV are black men who have sex with men (MSM), yet there are still unmet HIV-related service delivery needs among black MSM.9 Additionally, recent evidence has shown that social determinants such as incarceration, stigma, discrimination, social isolation, mental health disparities, or social networks play a significant role in the elevated incidence rates of HIV.10 APA asks that NIDA further consider including investments in research of preventative biopsychosocial interventions that aim to meet the needs of dual-minority populations, such as the black MSM community, into their strategic plan.Public HealthEffective progress in the prevention, reduction, and recovery from substance usedisorders is a complex undertaking. Of note, prevention of substance use disorders is not thoroughly delineated in the current draft strategic priorities. In the realm of public health and the need to increase the public health impact of NIDA research and programs, APA has a number of suggestions to expand upon prevention priorities in the draft strategic plan.Cost AnalysisConducting research on costs associated with drug abuse and the economic feasibility oftreatments would be helpful to the field.Publicizing NIDA ProgressGreater dissemination of NIDA progress, initiatives, research, and education to outletswith strong public health impacts would be useful, including the health media. In particular, support for studying the efficacy of NIDA’s and other organizations’ public health messages, especially to vulnerable groups, such as adolescents, is crucial.Training of Clinicians in Public Health SettingsImplementing public health strategies for substance use disorders necessitatesimprovement in the training of clinicians at the front lines of public health, including developing and arming them with tools for clinical implementation to decrease the research-practice gap. A critical component of developing well-trained clinicians at the forefront of public health is mentorship of trainees interested in public health leadership to help address workforce shortages, an area for which NIDA is urged to consider continuing its robust support.Diverse PopulationsAPA requests that NIDA further improve the public health sector's understanding of how interventions should be tailored to meet the needs of diverse populations (e.g., gender,race/ethnicity, sexual orientation, gender identity and limited English proficiency). A specific example related to this is the recent decriminalization of non-medical cannabisuse in Washington State and Colorado. There has been an emergence of sales outlets located in communities of color. The APA suggests that NIDA consider assessingpatterns of legal sales, drug use, and disparities in impact, for example, co-location of drug oases in food deserts.Connection between Substance Use Disorders and TraumaAPA strongly encourages NIDA to focus attention on the interrelationship between substance use disorders and trauma. The field of psychosomatic medicine offers a uniquevantage point to see a powerful interplay between trauma, mental illness, stigma, addiction, and the costly medical consequences of unrecognized/untreated conditions.Data reveal that sexual assault/abuse frequently results in substantial rates of substance use disorders, and substance use disorder treatment may precipitate re-emergence ofPTSD symptoms. NIDA is uniquely positioned to advance this research through its Clinical Trial Network.Science InfrastructureEnhancing the national Science Infrastructure is required to support advancements in science. APA appreciates the suggested areas of focus in NIDA’s draft strategic plan andoffers additional input.Fostering CollaborationAPA recommends that NIDA further strengthen its collaboration with the Department ofVeterans Affairs (VA) and the Substance Abuse and Mental Health Services Administration (SAMHSA). NIDA's cooperation with the Department of Defense and the VA is critically important to advance the development of non-opioid pain management medication. Cross-institute/academic center collaborations with brain banks and other biological material depositories (such as genetics) will lead to important partnerships and advances in the field; this will require concerted efforts across the NIH Institutions. APA offers its assistance to increase collaborative efforts between NIDA and professional organizations including the APA, American Academy of Addiction Psychiatry (AAAP), American Osteopathic Academy of Addiction Medicine (AOAAM), and the American Society of Addiction Medicine (ASAM).Increase Diversity in the Scientific WorkforceWith regard to the development of human resources to augment the science infrastructure, APA requests NIDA's further efforts to cultivate well-trained female andunderrepresented scientists in the drug abuse and addiction field at all career levels. Training should include health disparities and cultural competence. Relatedly, more emphasis on the mentoring of young scientists, particularly women and under- represented minorities would be helpful to the field and would have a positive impact on patient care. APA has had great success in the past partnering with NIMH in the development of such a program, the Program for Minority Research Training in Psychiatry. This program was extremely successful, leading to the development of over 500 psychiatrist researchers from underserved and underrepresented populations whohave achieved at the highest levels of science.11 Such a program focused on women and minorities could easily be duplicated involving a partnership between the APA andNIDA.Increasing the Pipeline of Scientific ResearchersAPA recognizes the federal funding environment has impacted all of NIH. Difficultdecisions have been made at every Institute to adapt to flat research financing. Nevertheless, APA is concerned that the mechanisms to fund training and mentorship are declining and request NIDA re-examine these tools which are a critical area to develop researchers. Of particular concern to the APA is the declining number of physician- scientists and the significant delay in funding RO1 grants for young researchers. The struggle for young researchers to be funded has had an adverse effect on building the scientific workforce. Current fiscal pressures have negatively impacted research program grants (P30, P50, P60) which are utilized to develop local hubs with strategic scientific focus that can support training.  NIDA recently limited Centers to two periods of funding. APA requests NIDA revisit this funding policy to more efficiently develop sustained research programs and further develop scientific researchers on critical topics.Unifying ThemesAPA suggests that the section on unifying themes is better suited for placement at thebeginning of the plan so that each point can be considered as readers review the specific strategic priorities. Further, APA recommends this section be expanded to include a number of the following important issues.Integration of Behavioral ProcessesThe integration of behavioral processes that underlie drug abuse and addiction is a criticaland overarching issue that APA suggests NIDA give prime consideration in drug abuse research.Chronic Pain SyndromesTaking into account the treatment and prevention needs related to comorbid chronic pain syndromes and other psychiatric disorders is another example of challenges facing ournation that can guide NIDA's unifying themes going forward.DiversityIn order to ensure that NIDA’s work addresses the full breadth of the U.S. population, the impact of factors such as age, culture and ethnicity, and social determinants are areas thatAPA suggests that NIDA explore. APA applauds NIDA's dedication to studying the developing brain. The differential effects of substance use and substance use disorders onthe brains of individuals vary at different stages of development, including late childhood, early adolescence, middle and late adolescence, young adulthood, and latelife. NIDA may wish to consider expanding its research on cannabis use (medical or recreational) in the older adult population. APA supports NIDA's research on the impact of race/ethnicity, sexual phenotype, gender identity, sexual orientation, and social determinants on drug abuse. This includes research focusing on culturally- and linguistically-appropriate services among groups experiencing health disparities, such as women and underrepresented and underserved minority populations.APA appreciates the opportunity to comment on the NIDA draft strategic plan. I look forward to further discussions and continued collaborative initiatives.

Format, Infrastructure, Basic Science

• I am very surprised by the high number of priorities. There is ~35 strategic priorities covering pretty much every single aspect of the neuroscience of drug addiction. I don’t know a single PI whose research would not fall into one of these categories. If everything is a priority then there is no priority, and it will be a guaranteed failure. I would recommend to drastically decrease the number of priorities from 35 to ~10.To me there are 2 most critical priorities which deserve immediate actions. Successuly implementing these 2 priorities has the potential to DRAMATICALLY improve NIH-funded research, drug development and ultimately healthcare. On top of that they are most likely among the least expensive to implement.The vast majority of researchers do not need more money for their research they need better tools and better orgamizations to do their research. My car mechanic and my local grocery store has better tool than the vast majorities of labs to organize, standardize and report their business. Improve technology transfer from NIH intra-mural to extra-mural sites by fostering collaborative grants, develop short-term (3 months) intra-mural training program for extra-mural PI/postdocs/technicians and open intra-mural cores to extra-mural investigators.Improve intra-extra mural research by implementing solutions to oversee research projects, experiments and publications (development of standardized GLP-based electronic notebook, project management, and reporting, sample storage, SOPs, etc…)For the rest of the priorities below is my top 10.Basic Neuroscience: Improve our understanding of brain circuits related to drug abuse and addiction at the cellular, circuit, and connectome levels, including:Neurobiological correlates of recovery, and resistance to addiction Improve our understanding of the interaction between addiction and co-occurring conditions Clinical and Translational Science: Accelerate medications development for SUDsIdentify biomarkers of addiction, resilience, and recovery to enable personalized treatmentPublic Health: Increase the public health impact of NIDA research and programsIncrease strategic partnerships with the community (academia, pharma, biotech, healthcare organizations, policy makers, etc.) to enhance the dissemination of evidence-based research findings into policy and practice Science Infrastructure: Enhance the national research infrastructure to support advancements in scienceIncrease effective data and resource sharing (big data, biorepositories, transgenic/optogenetic tools, data standards, etc.)Enable efficiency and lower the cost of clinical trials via innovative statistical models, data standards, leveraging technology (e.g. electronic health records) and partnerships, etc.Implement GLP Experimentation of extra-mural laboratories (mandatory standardized electronic notebook, sample storage, SOPs, etc…)Improve technology transfer from NIH intra-mural to extra-mural sites

Format, Infrastructure, Unifying Themes

• Dear Colleagues -Thank you for the opportunity to comment on the drafted Strategic Plan elements for NIDA for 2016-2022.I am writing about three items needing attention.  One item is a general language issue.  Second are two gaps I noticed in a priority. And the final one is a priority item that I think needs expansion.  I submit these considerations as an individual and not on behalf of any group or entity.  My titles and professional information are provided only to verify that these come from me in my professional capacity as an researcher, educator, licensed clinician, mentor, and advocate.FEEDBACK ON NIDA 2016-2022 STRATEGIC GOALS1. First I will address the general language issue needing attention.  The document needs to strike the word abuse from it in its entirety, excepting where there may be some historical reference to this antiquated and stigmatizing term.  Use of the word abuse is out of step with current diagnostic nosology, pejorative, and reinforces stigma.  SUGGESTED CHANGE:  I urge the removal of the term "abuse" and substitution of the word "use" and/or the phrase "use disorders" as appropriate.  RATIONALE:  This will not only remove inappropriate, outdated language, but will keep the focus across the entire range of problems we see related to substance use -- from exposure, to experimentation, to use, to problematic use, and use involving addiction.   2.  Second, I aim to address the gaps of concern to me, both of which were on science infrastructure.  On the element: Science Infrastructure: Enhance the national research infrastructure to support advancements in science, you note "improve training for the next generation of scientists."  Problem A:  What strikes me about this is that it does not explicitly address a need for work on educational technologies (we do use science in making good education, and this increasingly uses technology) and a broader focus on education of professionals.Problem B:  Additionally, it does not address the need for improving training for the next generation of clinicians, clinician-scientists, and academics - who are not necessarily scientists.  With all this talk about translation - beyond implementation in the field with those already trained - we need a focus on training that is broader and connected to basic educational matters for all professionals involved at this level of the game.So the gaps that you are talking about re: scientific infrastructure should really highlight education more generally and include educational methods and technology, not just "training."  Additionally, it needs to go beyond "scientists" to all those engaged in learning science at that level more advanced (e.g., higher level clinicians and clinician scientists and other scholars (e.g., scholars, practitioners, and scholar-practitioners).NOTE:  Conceptualization of training for these other groups really is not limited to public health matters (another element of your plan), or simply implementation science.  Instead, we are talking about, just as with researchers, part of their scientific education and training that clinicians, clinician-scientists, and scholars in this area receive, just like that received by researchers while in school, apprenticeship, fellowship, etc.  Supporting educational innovations and training of these groups is imperative as all groups receive training in science related to addictions and substance use behavior, beyond what is covered in your current expression of "improving training for the next generation of scientists." This also is not covered elsewhere adequately in your goals.   SUGGESTED CHANGE:   I suggest this noted element be amended as:  "improve education and training for the next generation of scientists, clinician-scientists, scholars, and clinicians" or "improve education and training for the next generation of professionals working in substance use and addiction science, practice, scholarship, and their interfaces." ADDITIONAL RATIONALE:  It is harder to train people after they have left their programs than while they are in them.  Let us equip the educators and trainers with the technology and funding they need do get things right while new trainees are going out the door. And let us be inclusive of the entire "symphony" of players involved - not just focusing on the scientists.  If we are truly moving into integrative, and collaborative efforts, then let us start this early, in the classrooms of all involved with the best technologies we can use.3.  Third, I aim to address the minor change and expansion of Unifying Theme priorities:  Promoting research that considers the impact of sex and gender on drug abuse and addictionAddressing health disparities among underrepresented populations PROBLEM A:  I was most pleased to see both of these items included.  However, I was somewhat taken aback to see the issue be framed with an absence of the general contribution of culture, race, and ethnicity and their contribution to use and addiction.  Our literature is deficient in these areas.  it is not just with underrepresented groups that these issues need attention.  These issues need attention on their own for their unique contributions.PROBLEM B:  These issues (sex, gender, race, ethnicity, culture) may interact with each other and/or the status of being in an underrepresented group.  Our literature remains fairly ignorant on these matters, particularly with regard to developmental issues.  Therefore age is also relevant as a universal theme, as is how these items may interact.PROBLEM C:  Socioeconomic status is a relevant demographic that needs to be teased out sensitively around all of these previously mentioned descriptors. This is because it may interact with any one or number of them to affect risk, or be its own unique risk factor.  It also may be confused with one or another of these for its impact and so should be included.SUGGESTED CHANGE:  I suggest amendment of the first bullet to fix language, address these much needed concepts (e.g., race, ethnicity, culture, age, socioeconomic status) on their own merits and not simply as a function of lumping them in to "underrepresented populations."  I also suggest amendment that accounts for how these issues may interact.  A continued focus on health disparities among underrepresented populations is not disputed, so can stand on its own.  However, the phrase "underrepresented" is inadequate to address these other very important demographic concepts and should not be used as some sort of a proxy in a strategic plan. Promoting research that considers the impact of age, sex, gender, race, ethnicity, culture, and socioeconomic status, including their interactions, on substance use and addictionAddressing health disparities among underrepresented populations RATIONALE:  Our population in the US is constantly changing.  Underrepresented status may, in and of itself, transition and be a risk factor but function in different ways for different populations.  Additionally, with our changing demographics, varied descriptors may combine to create unique risk factor patterns (for example, gendered racism) that demands study of the interaction of demographic factors such as age, race, ethnicity, and culture with sex and gender.  We also need to be careful not to confuse variables such as socioeconomic status and its impact with these other demographic issues. As such, these all need continued study for their unique and potentially interactive impact to substance use and addiction.Thank you for your consideration of these thoughts.  Again, they are submitted on my behalf as an individual, not as representing any group or entity with which I may be affiliated..

Infrastructure, Basic Science

• In looking over the strategic planning points that were delineated the feedback I would offer is that the aims are generic and risk-averse (as might be expected from something deriving from a committee-based effort) and cover the scientific landscape as it may currently be conceptualized.Recommendation:A bullet for ‘transformational’ ‘out-of-the-box’-esque approaches. I don’t know how this would be administered but something akin to the EUREKA Awards (but with more funds) and having a truly spectacular group of reviewers and applicants would be a start. Also it would be helpful if they were widely advertised and highlighted once awarded (e.g. akin to the NIH Pioneer Awards).I’m also struck by the fact that the despite the vast funds expended for basic neuroscience research by both NIH and pharma over the past 10-20 years, little in the way of useful and transformational treatment options have emerged. This is the case for all the major brain institutes (NIMH, NIDA, NINDS, NIAAA).Recommendation:I can confidently predict (and have) that if we continue with the same overall approaches (as outlined in the planning document on the web) it is unlikely that we will achieve any greater success than we have in the past. Again having at least some funds set aside for truly innovative approaches might be helpful.I see nothing specifically related to genomics!
• This email is in response to the request for information from NOT-DA-15-005. I include several thoughts on priorities for NIDA in the coming years.While the most often stated goal of the NIH BRAIN initiative involves mapping the brain’s connections, the extracellular environment has much to do with the control of neuronal networks, and hence organism behavior. In addition, drugs of abuse (and endogenous metabolites, lipids, transmitters, peptides, proteins) control the activities of neuronal circuits. Technologies to probe the dynamic chemical environment in small domains in and around these neuronal circuits are lacking and are as important as physical maps. While technologies to enable chemical measurements of cells and their surrounding environments are becoming available, further developments are needed to allow higher throughput global measurements. Without these developments, the application to NIDA related neuroscience priorities will be slowed or not occur.Let me provide a little more detail. A surprisingly large number of physicochemically and structurally distinct molecules are involved in communication among the cells of the brain. These range in size from the small nitric oxide molecule to large >100 kDa heavily post-translationally modified proteins. Significantly, these are the endogenous molecules many of the drugs of abuse mimic in terms of receptor binding and other functions. Therefore, these molecules are particularly relevant in drug abuse research and present high-value targets for pharmacological intervention. An issue is that even in 2015, the parts list of the brain is not complete, nor are their localizations and metabolic pathways of formation and degradation of many of these molecules known. Without an understanding of the molecular basis of normal and addicted processes, it becomes difficult to design molecular and genetic probes to track these processes, nor understand how drugs of abuse modulate neuronal network function.  Hence, an important fundamental area for NIDA includes functional single cell metabolomics of defined networks and brain regions. A goal would be to enable intercellular in-vivo and in-situ sampling and metabolomics analyses across scales: cell/network/region/animal. In addition, this technology would enable the interactions between glia, neurons and immune cells to be followed, including the flow of molecules and chemical information between them, allowing one to address longstanding questions about subpopulations within so-called homogeneous cellular populations of neurons and astrocytes.As a last area of priority, NIH (including NIDA) has created effective repositories of genetic data, but has not kept up with resources to store, annotate and disseminate anatomical, metabolomics and proteomics data. I encourage NIDA to support and participate in any such NIH efforts. While individual groups and regional centers have created some resources, these are temporary as their associated databases can disappear as center funding is eliminated.
• I am writing to state my interest in and support of the draft strategic priorities for NIDA. As a postdoctoral fellow, I am especially interested in the improvement of mentoring and training of young scientists, to include the development of education on potential (and alternative) career paths and how to prepare for each. I also think that some of the important areas to focus on in the new strategic plan are the improvement of the reproducibility of pre-clinical research, and a stronger focus on bi-directional translational research.

Infrastructure, Basic Science, Clinical and Translational Science

• Increase international collaboration on basic neuroscience, clinical and translational science and public health; Establish measurement of the effectiveness on training young scientists for the above areas;Understand protein foldings during the signal transduction process;Conformational changes and sub-units' interactions/communications of G-proteins and coupled receptors;Better understanding memory processing of brain function;More insights on tumor growth-related signaling processes;Design of newer generations of more efficient neuro drugs with fewer and minimized side effects;Development of greener and environmentally friendly strategies and tactics for synthesizing neuro drugs and their building blocks.Globally establish comprehensive statistic correlations of harmful/toxic contents of cigarettes/smoking and drugs/their abusing with related diseases in different countries/regions.

Infrastructure, Clinical and Translational Science

• The key goal of NIDA is to improve our understanding of the etiology, course, and treatment of drug use behaviors and addiction.  As a taxpayer, I want to see progress in improved prevention and treatment based on knowledge gained through the extensive research portfolio funded through NIDA.  My suggestions are based on this overall goal of improved productivity with NIDA.“Measure our success” Improved evaluation of NIDA’s scientific portfolioTo date, we have used crude metrics of scientific progress.  Publications have been a standard metric used by both study sections and promotion committees.  Unfortunately, a publication metric results in a large quantity of papers, often with low quality that lack of replication.  Even in high impact journals, a large proportion of reported findings are not replicated.  Ioannidis and Khoury (2014) have suggested potential metrics to evaluation biomedical research: P-productivityQ-qualityR-reproducibilityS-sharingT-translationNIDA should take the lead in developing and applying quality metrics to its research portfolio.http://www.ncbi.nlm.nih.gov/pubmed/24911291 “Share and Protect” Improved sharing of data within the scientific communityThere needs to be an ongoing push to share data within the scientific community.  It is clear that large-scale studies are needed and these studies are much larger than what one laboratory can generate.  We have many resources that are currently available but underused.  Some of these resources include data from the NHSDUH, Monitoring the Future, NESARC, as well as data from SAMSHA.  Limited sharing and difficulty in accessing resources holds back the field and limits our gains in scientific knowledge.  We now have the tools to both share and protect big data.  We need to push the culture of sharing in all studies (Sorlie & Sholinsky, 2015).http://circ.ahajournals.org/content/131/1/17.long“Does it work in the real world?” Large, efficient clinical trialsClassically we have undertaken efficacy trials and then treatments are scaled up to test effectiveness. Historically this approach has been used to weed out trials that are not efficacious as a method to improve efficiency.  However, given the change in infrastructure (common databases and networking possibilities), we can now undertake large-scale, efficient trials. I  suggest we move more clinical trials straight to effectiveness trials. This approach will also speed the translation of research findings into clinical care (Eapen et al., 2014; Gordon et al., 2013).http://jama.jamanetwork.com/article.aspx?articleid=1857342http://www.ncbi.nlm.nih.gov/pubmed/24224625A focus on geneticsGenetics has undergone a successful paradigm shift in the science of health.  Genetic science has identified 10,000s of variants associated with many diseases. Importantly, the large-scale genetic studies have started to provide crucial knowledge in complex genetic disorders, including complex gene-environment interactions. An example of how this area is underfunded can be demonstrated by the low number of studies of addiction on dbGAP (search NIDA) compared to the large number of studies for other severe mental illnesses such as schizophrenia, bipolar disorder, major depressive disorder and so on (search NIMH). Areas for prioritization in genetics:Increase the number of population-based genetic studies of addiction with inexpensive genome-wide data.Require sharing of a common list of key phenotypic variables by all NIDA-funded studies.  Study under-represented groups.ReferencesEapen ZJ, Lauer MS, Temple RJ. The imperative of overcoming barriers to the conduct of large, simple trials. JAMA, 2014; 311:1397-1398.Gordon D, Taddei-Peters W, Mascette A, Antman M, Kaufmann PG, Lauer MS. Publication of trials funded by the National Heart, Lung, and Blood Institute. N Engl J Med., 2013; 369:1926-1934.Ioannids JP, Khoury MJ. Assessing value in biomedical research: the PQRST of appraisal and reward. JAMA, 2014; 312:483-484.Sorlie PD, Sholinsky PD, Lauer MS. Reinvestment in government-funded research: A great way to share. Circulation, 2015; 131:17-18.

Infrastructure, Clinical and Translational Science, Basic Science, Unifying Themes

• I am writing on behalf of the College on Problems of Drug Dependence, Inc. (CPDD), in response to the Request for Information regarding the FY 2016–2020 Strategic Plan for the National Institute on Drug Abuse, National Institutes of Health (NOT-DA-15-005). CPDD is the longest standing scholarly society in the United States that devotes its focus to the issues of drug addiction and other drug use disorders. The College has over 1000 members, and serves as an interface among governmental, industrial and academic communities maintaining  liaisons with regulatory and research agencies as well as educational, treatment, and prevention facilities in the drug abuse field. We appreciate the opportunity to provide comments regarding the NIDA draft strategic priorities, which clearly represents considerable thought and discussion regarding the topics of critical relevance to our field. We had the following comments after our review of the proposed plan. Several of these are referenced in the plan, but are so important that they should be more clearly stated to ensure that they be given full consideration in the Plan.NIDA should work with other government and private agencies such as The Liaison Committee for Medical Education (LCME) to increase the education of medical students, residents (especially pediatricians) and other health care providers to enhance their ability to recognize the behavioral signs in  children that have been shown to be predictors of drug abuse in adolescence. This will be helpful in addressing treatment NIDA should develop mechanisms to work with industry, both big pharma and the biotechnology industry, as well as with academia, to enhance the development of medications to treat diseases of drug addiction.  Special financial incentives and new approaches may be necessary.Research with pediatric populations that looks at the role of other mental diseases on drug abuse and dependency is necessary. While we realize and appreciate the “ABCD” study is related to this topic, other work in this area is needed.In addition to work in children and adolescents, there is a need for increasing focus on drug use in older populations – especially in the context of the growing number of older baby boomers. There is opportunity to characterize this phenomenon (e.g., prevalence), and to also examine biologic underpinnings that may be helpful in understanding broader issues of drug use (such as factors that contribute to continued use for some persons).Work that examines the similarities and differences among drug dependencies to various abused substances (e.g., opioids, cocaine, cannabis, alcohol) is needed. This has the potential to better elucidate common vulnerabilities to drug use (both biologic and environmental), and will help in the development of better treatment and prevention methodologies.There is a need for a concentration on studies investigating the relationship of co-morbidity of mental disease and drug dependency. One population where this work is essential is veterans with PTSD and their families, but it also has applicability to other populations with substance use disorders.There is a need to continue support of basic science research that has downstream potential to help understand the etiology, proclivities, and sustaining factors associated with drug use. This should include an increase in knowledge of the genetic factors that predict drug abuse and dependency.There should continue to be an emphasis on support of young investigators in the field. The loss of a future generation of scientists would be a catastrophe!We would encourage that work conducted by the intramural research community be effectively leveraged for work by the extramural community. This can be accomplished by supporting travel and presentations by intramural scholars at national scholarly meetingsThe College continues to be a strong advocate for the work of NIDA, and we greatly appreciate the opportunity to address this Plan.

Infrastructure, Public Health, Clinical and Translational Science

• In thinking about NIDA’s strategic plan, we cannot help but think of Galileo, a scientist ahead of his time hobbled by the establishment of his time, especially the Church. NIDA is certainly familiar with the translational science problem of getting clinical practitioners to embrace and adopt new findings into their professional practice. A greater obstacle currently, it seems to us, is how NIDA deals with the uninformed, the backward, the willfully ignorant, and the outright hostile in the public at large.  How does NIDA move public opinion forward from thinking and belief systems that range from magical and mystical, to Puritan, moralistic and authoritarian, to marketplace selfishness and greed – all of which impede, oppose or defy progress NIDA makes? This “disease,” if you will, spreads backward as well, infecting those purporting to treat substance use disorder, making translation science all the more difficult to enact.  Hotbeds of the “disease” are those pseudo-scientific and/or spiritual organizations which resist forfeiting their stake in addiction treatment.  None of this is news to NIDA, to be sure.  What we are suggesting is an urgency to overcome these obstacles.  All the progress in the world is for little or naught until these roadblocks are addressed or circumvented.Herewith, in no particular order thoughts, ideas, suggestions from two concerned laypeople: NIDA, among others, recognizes the correlation between addiction and mental illness.  How do we make it imperative that doctors in hospital ER’s understand this? How do we make this part of their certification before they begin practice?   We need to untie the hands of doctors who are aware so that patients, especially those presenting as overdosed, can be given proper psych evaluations that result in appropriate treatment rather being released the moment they are “stabilized?” A year ago we learned of a  potential arrangement between the chemical dependency unit of a hospital and a treatment facility, both in NYC.  If the hospital could not find a bed for full and proper treatment, the treatment facility would pick the patient up immediately and begin treatment – regardless of insurance status.  In the end, this plan did not work out.  The problem remains…how do addicts get treatment the moment they request it?  How can they be embraced, not turned down when they seek treatment?  The moments when addicts seek treatment willingly are too few to be wasted.Is it possible to mandate enforced treatment?  Similar to or the same as existing laws in Massachusetts? Section 35 is a Massachusetts General Law that allows a judge to "involuntarily commit someone whose alcohol or drug use puts themselves, or others, at risk."The law allows for the individual to be put into an inpatient substance abuse program for up to 90 days, but the level of commitment and the location of treatment varies. The section allows families and/or the judge to choose a licensed treatment facility. If no beds are available, the individual might be sent to a separate unit at the correctional facility at Bridgewater for men or Framingham for women.  Is it possible to mandate prolonged treatment for anyone who arrives at an ER having overdosed and/or having received Narcan?How can the quality of medical training be improved so that residents and interns in ER’s are properly educated and properly sympathetic to the patients they treat?  Currently many are ignorant or even outright hostile about SUD as a mental health issues. How can we ensure the advice they give is current and evidence based? ER’s are a flashpoint where SUD manifests itself.  How can NIDA help ensure best practice initial treatment in ER’s? It needs to be more than a couple of Xanax and sending people on their way.  How do we avoid kicking people out of SUD treatment, because they are uncooperative?  Addiction treatment should be about saving lives, not cooperation?The rules about who treats addicts and how much training they have need to be much more stringent.  Merely being in recovery oneself is not sufficient to treat someone with SUD,  especially with co-morbidity a prevailing issue. 60 hours of training, for example, is grossly insufficient.  How do we get real physicians to be available more prominently and more often, or at all, at treatment centers?  The deficit of certified doctors treating addiction must be addressed. There has to be an easier way for families to save a child’s life than to deal with HIPAA obstacles.  Being incapacitated is part of the disease.  How can family members be appropriately engaged and informed during the treatment process?  Age 18 should not be a magic cutoff point, especially with a disease that affects the capacity for good judgment in those suffering from the disease.  Is NIDA doing any research with those in long term recovery?  What can we learn about those who are leading sober, productive lives over a significant period of time?How can NIDA contribute to the network of family members of both those lost to SUD and those in various stages of recovery?  How does NIDA recognize the family aspect of this disease?How can NIDA help frame information about SUD to young people so that what they hear doesn’t seem to be “cranky old people talking at them and scolding them?”How can NIDA turn the “Don’t do drugs.” message into positive action?  How can young people become part of the solution?  How might NIDA generate a list of questions kids might ask their parents about drugs?  How do we reach parents and teachers? How do we reach those content in their ignorance?  Can NIDA help prioritize insurance regulations that need to be changed at any and every level of government?How can any institution’s SUD treatment be made more transparent, so that families and institutions know what they are getting?  Can NIDA help set universal standards, for utilization review (assuming we have to live with this beast)?How can NIDA stop the bickering and infighting over MATs and between MATs.Can NIDA help establish guidelines for hospitals and ER’s for admission and treatment.  We can no longer afford to hear, “Patient doesn’t meet the criteria,”  whatever that means. What criteria?  Whose criteria?Is it possible to establish or organize a model ER, a model treatment center, model sober living houses, etc.  All under the same roof, or separately.  Models of best practices that can be followed elsewhere?  To have at least one institution where the gap between “bench and clinic” is minimal?  We realize finding solutions to these questions may be overwhelming or beyond the strict purview of NIDA’s charge.  Our big question is to what extent can NIDA engage in “translational psychology” so that the ideas and attitudes that perpetuate the stigma surrounding addiction can make way for proper science and best practices to prevail.

Public Health, Infrastructure

• Hello,I am writing to comment on the NIDA strategic plan for the next 5 years, focusing on the last 3 sections of the strategic plan. Public Health - Bullet one: Improve the understanding of factors that influence the integration of evidence-based research findings into healthcare policy and practice (implementation science) - I would propose modifying to read "Improve the understanding of factors that influence the integration of and promote the uptake of evidence-based research findings into healthcare policy and practice" The main point of the above change is to emphasize that the goal of implementation science is to promote the uptake of evidence-based research findings and not simply to understand what influences the process. - Bullet three:  Increase strategic partnerships with the community (academia, pharma, biotech, healthcare organizations, policy makers, etc.) to enhance the dissemination of evidence-based research findings into policy and practice - I would propose modifying to read "Increase strategic partnerships with the community... to enhance the relevance of evidence-based research findings and the dissemination of research findings into policy and practice.  The rationale for the above is that a primary critique of evidence-based practices is that they are not relevant for community providers. It is therefore imperative that we partner with community providers to ensure the relevance of our work before simply trying to disseminate it to the community. Science Infrastructure: - In this section, I think that the bullets about training the next generation of scientists or the bullet or improving the mentoring of young scientists could potentially be combined. It also might be worth specifying stating something about the goal of improving the mentoring of early career investigators to improve the conversion of training awards to independent career programs (as the conversion rate from Ks to Rs is consistently disappointing) Unifying themes- In this section, it might be worth explicitly addressing other populations that are often affected by addictions such as prisoners, the homeless, and sexual minorities. As another unifying theme, it might also be worth explicitly addressing the need to prepare healthcare systems and treatment delivery strategies for addicition in light of impending health care reform (via integration into traditional health care settings, for instance). Thank you!

Public Health, Unifying Themes, Infrastructure

• Below are suggestions to assist the Substance Use Disorder field to follow the NIDA 2016-2020 strategic plan priorities. The suggestions apply equally to all four priorities of Prevention, Interventions, Treatment and Recovery Support Services. Suggested research topics for Prevention, Interventions, Treatment and Recovery Support Services are as follows: a) emerging issues, such as opiates and the changing marijuana environment; b) workforce development; c) research for specific populations including, youth through older adults, ethnic and sexual minority populations, high risk populations, such as pregnant and parenting women, geographic differences in providing services between urban and frontier communities.  Understanding which interventions are most likely to be successful with which population is important and NIDA can lead the way. Continuing to learn and grow in the four areas listed above may help to achieve the NIDA 2016-2020 strategic plan. Our division credits NIDA’s previous work and continued supportive commitment to increase Medication Assisted Treatments, therapies for those with co-occurring conditions, and continue to prioritize identifying innovation strategies to address our nation’s most significant drug issues (not including alcohol); marijuana and opiates. In closing it is critical that NIDA work in collaboration with NIAAA on Alcohol Issues, and CDC on nicotine therapies.

Unifying Themes, Infrastructure

• Thanks for this opportunity to contribute thoughts on your strategic plan.  I think that NIDA could contribute more to the genetic, epigenetic, hormonal, and other biological mechanisms around eating disorders, weight gain, and obesity, in that many of these are shared pathways with those involved with substance addiction.  Knowing what is similar and different between eating behaviors and substance addiction behaviors and the underlying biological mechanisms would help a large proportion of the public.  NIDA and its investigators have deep expertise in this arena and could contribute substantially if NIDA could add this topic area to its portfolio, rather than leaving it to NHLBI or NIDDK.Also, NIDA’s R25 programs in statistical genetics have been useful for recruiting quantitative researchers into statistical genetics of addiction but because those who are on visas are not eligible for K awards, some of our trainees may struggle in launching b/c they have to compete directly for R awards.  The bridging support of K awards are very helpful for the transition into independence with a safety net for those who are eligible.