RFI Comments - Basic Science | National Institute on Drug Abuse (NIDA)

Basic Science

Is there room for etiology and epidemiology within the new strategic plan? It seems as though most of the emphasis is on biology, but we still don’t know enough about social-contextual and cultural determinants of substance use and abuse – especially for ethnic minority groups. Please leave room for important etiologic and epidemiological work.
[PII redacted] have just finished updating a short review on the role of endophenotypes in AUD/SUD that might be of interest your team for the strategic plan. It will appear in Current Addictions Reports Salvatore, J.E., Gottesman, I.I., Dick, D.M., 2015. Endophenotypes for Alcohol Use Disorder: An Update on the Field. Current Addiction Reports. doi:10.1007/s40429-015-0046-y
Drug and alcohol addiction is a major health issue in the US, with an estimated 9% of the population over the age of 12 requiring treatment. While the specific receptors for each drug class may differ, they share the downstream pathways involving the dopaminergic neuronal pathways originating in the ventral tegmental area (VTA) associated with the reward pathway that, in turn, influence changes in brain circuitry controlling dependence, withdrawal symptoms and behavioral changes. Opiates are particularly potent at inducing long-lasting changes contributing to addiction that occur in the striatum, pre-frontal cortex, nucleus accumbens, hippocampus and amygdala. Consequently there has been considerable interest in studying changes induced in opiate administration in pre-and post synapse biology in some of these key areas on a proteomic level. To fully explore the complexity and function of the synapse proteome, and be able to analyze changes on a localized level in various cellular and subcellular compartments within the brain, it is essential to establish a comprehensive, highly characterized and standardized collection of specific monoclonal antibodies directed against all individual synapse proteins under native conditions. While hundreds of antibody reagents are commercially available, many are poorly characterized leading to an unnecessary burden of misinformation and wasted research effort. While monoclonal antibodies offer a higher degree of specificity than polyclonal antibodies since each typically binds to one specific epitope within a target antigen, many commercially available antibodies exhibit cross-reactivity to non-related proteins, with one study indicating 75% of commonly used monoclonal antibodies (mAbs) show cross reactivity with other protein. Therefore, continue support is need to develop highly characterized and standardized collection of mAb directed against all individual synapse proteins to enable further study of the synapse proteins and other molecular biomarkers involved in triggering or developing of drug additions.
Some might think that our Senior Citizens are at a stage in their lives where they do not require addiction research and strategies. I am a sixty-six year old senior who resides in a Senior Housing Apartment. I see the consequences everyday of the irresponsible use of alcohol and or prescription medications. Independence for our elders is a very necessary aspect of aging in America due to the rise in the cost of Health Care across the board. We are trying to keep people working for longer years if it is at all possible. And these directions are positive and remarkable. For all those seniors who can not continue to be employed, there is a chance their adaptation to their retirement will include having to take medications for depression. Some will resort on their own to self-medication through the over-use of alcohol. The independence or living alone becomes a liability if not an extreme danger to them. Some become "functional alcoholic retirees". They fall down behind closed doors, if not severely injured, then frightened into a state that helps them to further rationalize the use of alcohol. A vicious cycle evolves with all the attendant health concerns and conditions. Maybe some research into geriatric substance abuse would afford all of us a way to link dementia and elder depression/psychosis to a better way to retire and healthier ways to prevent accidents. Thank you for reading this. I just wish for my fellow elders and citizens a place in this great nation where our lives can still matter and contribute to the solution of the many problems we all face daily.
With regard to issues related to planning for the upcoming Strategic Plan for 2016-2020, I would strongly suggest an increased emphasis be placed on the co-occurrence of PTSD in veterans being discharged after having served in Iraq and/or Afghanistan. Having been a retired therapist of 32 years from the U.S. Department of Veterans Affairs (VA), there has been a long correlation between PTSD and substance abuse in veterans. With these wars having activated numerous Reserve and National Guard units, unlike any other previous wars, the Citizen Soldier is particularly vulnerable. In addition, many individuals have been deployed numerous times, which obviously increases the likelihood of having a difficult time with readjustment. The long term cost of war takes into account more than just dollars and it is my concern that when the wars are finally over the human costs will continue for many years to come and the public, in their myopic view of such matters will be on to other issues seemingly more important. I truly believe the VA is ill prepared to attend to what they will be faced with in the next five to ten years.
Consideration for studies that address opiate addiction and assessment of and handling of pain management simultaneously
Consideration of the effect addiction of a parent particularly addicted single mothers on her children from birth through adolescent should be addressed both in the basic research and translational research areas as well as the clinical impact of addiction of the parent on the child as the child develops. Hence, consideration of more funding for evaluation and treatment of children of addicted parents in order to break the cycle of addiction in these children and their families.
To whom it may concern:This is a response to the following RFI: In the 2010 strategic plan, one of the recurrent themes was decision-making, and its central role in drug addiction. In contrast, decision-making is not mentioned in the current Draft Srtategic Priorities. The closest items mentioned in the draft would be these two: Improve our understanding of brain circuits related to drug abuse and addiction at the cellular, circuit, and connectome levels, including: Normal development and function across the lifespan including mechanisms of reward, self-control, and conditioningIn my view (admittedly biased by my own research interests), understanding the neuronal circuitry of decision-making, in particular value-based decisions and decisions in social contexts, remains a fundamental key to understanding and treating drug addiction. Thus I would strongly recommend including decision-making explicitly as one of the Basic Neuroscience priorities in NIDA's Strategic Plan.
NIDA should invest in somatic neuronal DNA variations as causes and consequences of drug addiction.
The dynamic signalosome of abused drugs (Basic Neuroscience)A major need in the basic neuroscience research field is to understand with greater spatio-temporal resolution, the multiple signaling events elicited by drug exposure at the cellular and molecular level.Drugs of abuse have multiple effects. They initiate signaling cascades leading to changes in channel properties, enzymatic activities and gene expression among others. Furthermore, the effects of abused drug exposure are dynamic and change dramatically from seconds to hours and days.Historically, biochemical, electrophysiological and other studies have focused on a limited subset of downstream effectors such as cAMP levels, calcium currents and others however, it is clear that we need a deeper understanding of the dynamic signalosome of abused drugs, the complete cascades elicited by the presence of drugs and their development over time, to effectively identify novel therapeutic targets.This type of understanding will require the combination of multiple techniques (electrophysiology, imaging, biochemistry, genetics) at high throughput levels applied to carefully selected and controlled backgrounds (homogenous cell types, tissues, etc). Some of these techniques are currently available such as antibodies arrays and whole genome sequencing but more need to be developed.I believe NIDA should further support and encourage two different areas: One is the technical development aspect which goes along the BRAIN initiative. This aim should include novel imaging and electrophysiologycal techniques to achieve multiplexing in data acquisitions and analysis. Second, NIDA should encourage the characterization of the dynamic signalosome. This appeal should call for the obtaining dynamic understanding of multiple variables such as activation of the kinome, genomic and epigenetic regulation in response to abused drugs. These approaches should be applied to carefully validated backgrounds (specific cells and tissues) and conditions to reduce variability and increase reliability of the data.Support of these areas should provide a better understanding of the multiple and dynamic effects elicited by abused drugs, and help identify novel therapeutic targets to reduce or prevent drug abuse.Should you require more feedback or information, please do not hesitate to contact me
More research is needed on the impact of drug abuse on pregnancy, placentation, fetal programming, and the origins of adult disease.
Thanks for the opportunity to comment on NIDA’s strategic planning. It seems that one major factor impacting drug use and abuse in society today, particularly in adolescents which is not specifically addressed is the impact of circadian rhythm and sleep disruptions on the vulnerability for addiction. During adolescence, circadian rhythms shift towards more of an evening chronotype, making it difficult for kids to wake up in the morning for very early school start times. Moreover, kids are becoming more and more sleep deprived for a variety of reasons. The American Academy of Pediatrics recently made a formal recommendation to have high school start times moved so that they are more in line with the biological clocks of teenagers. There is very good evidence to suggest that these changes are incredibly beneficial in terms of test scores, less motor accidents, and even lower levels of obesity, depression and importantly, substance abuse. Therefore, it should be a priority for NIDA to understand how circadian rhythm and sleep disruptions alter reward-related circuits of the brain and lead ultimately to increased vulnerability to addiction. It is also important to educate the public on the importance of sleep and circadian rhythm synchrony for the health of young people.
I would like to make a plug for support research related to cigarette smoke exposure. The addictive properties of nicotine in cigarette smoke is already well established as well as the fact that smoking is associated with a number of chronic and fatal disorders. There is now evidence that smoking is linked to the development of chronic neurodegenerative diseases and can be the source of increased levels of inflammation and oxidative stress in brain. These effects are more likely to occur from exposure to the non-nicotine components in cigarette smoke. Little is known regarding the mechanisms that underlie these effects, and knowledge in this are could certainly benefit from additional resources dedicated to research in this area.
Dear Friends at NIDA,I read with interest your proposal for research direction on addiction. The notion that basic research on the molecular mechanisms of addiction is needed is clearly stated and I certainly agree that this is needed. I wonder, however whether a more specific formulation of goals might be warranted.I think it would be reasonable to single out the study of the enzyme, CaMKII, as a goal supported by NIDA. I have worked on this molecule for over 25 years because it is a candidate for the molecular basis of memory. Given that addiction is a form of memory, I have followed some of the research on CaMKII with regard to addiction. Over much of this period, it was unclear how important CaMKII is as a memory molecule in addiction. That situation has changed with two recent publications. The first was the demonstration by the Vezina lab that a dominant negative form of CaMKII applied to the accumbens could reverse a form of addiction. The second was a recent by the Kasai laboratory showing the second messenger pathways by which dopamine leads to LTP of the synapses involved in addiction. This work shows that dopamine acts by inhibiting phosphatases, thereby allowing CaMKII to become activated, an activation that is critical for synaptic memory.Based on these results, it seems likely that finding a cure for addiction can proceed in a rational and focused way. What is required is a mechanism for reversing the CaMKII-dependent processes that underlie LTP at the accumbens synapses. Towards this end, one needs a better understanding of the CaMKII-dependent memory itself. Perhaps most likely to lead to effective therapy is an understanding of the endogenous processes (LTD and depotentiation) that can reverse LTP. It would seem likely that learning how to activate these endogenous processes could yield an effective therapy for reversing addiction. Still another strategy would be to target to the accumbens the type of peptides that I have shown to reverse LTP in the hippocampus.References:Loweth JA, Li D, Cortright JJ, Wilke G, Jeyifous O, Neve RL, Bayer KU, Vezina P. Persistent reversal of enhanced amphetamine intake by transient CaMKII inhibition. J Neurosci.2013 Jan 23;33(4):1411-6. doi: 10.1523/JNEUROSCI.4386-13.2013.Sanhueza M, Lisman J. The CaMKII/NMDAR complex as a molecular memory. Mol Brain. 2013 Feb 14;6:10. doi: 10.1186/1756-6606-6-10.Yagishita S, Hayashi-Takagi A, Ellis-Davies GC, Urakubo H, Ishii S, Kasai H. A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science. 2014 Sep 26;345(6204):1616-20. doi: 10.1126/science.1255514
I have some ideas that I believe will drive basic science research on drug abuse forward over the next 5 years.Based on our own research and other labs, it is become apparent that a new and exciting mechanisms of gene regulation involves the competition among mRNAs for binding to the same microRNAs (miRNAs). These are known as Competing endogenous RNAs or CeRNAs. As you can see in the attached review, this is an emerging field in biology and there is virtually nothing known about how these mechanisms play a role in neuronal plasticity and drug addiction, except that our own work identified 3 of these CeRNAs, BDNF, CamkinIIa and Arc, as being co-regulated by the same microRNA. Furthermore, we have evidence that two of them BDNF and CAMkIIa mRNA compete for binding to microRNAs and RNA-binding proteins. A second and related new mechanisms of gene expression that has only being examined in a few labs, involves the competition of RNA-binding proteins for the control of the same mRNA, which I termed CeRBPs. FYI, I attached a couple of papers that my colleagues and I published recently demonstrating the role of these mechanisms in neuronal development and plasticity, but to my knowledge these mechanisms have not been examined in the context of drug abuse.Please feel free to contact me if you have any questions about these ideas for future directions
To the committee developing the new NIDA strategic plan:Since 1996 I have been the Director of a NIDA Center of Excellence (PII Redacted). In this role I have gained a broad perspective on the field of prevention science. I am writing to express my view that a strong emphasis on prevention, and on quantitative methods related to prevention, is essential in NIDA’s new strategic plan and critical for NIDA, and the nation, going forward.In my 19 years as a NIDA center director and my 30 years as a NIDA grantee I have seen the field of prevention science form a vibrant professional society (of which I am a past president) and a top-notch journal. I have seen excellent training and mentoring opportunities for junior prevention scientists emerge all around the nation. And, most importantly, I have seen the field of drug abuse and HIV prevention establish a coherent base of scientific knowledge that is being applied in prevention programs all over the nation, as well as internationally. The development of innovative quantitative methods, for both data analysis and experimental design, has played a major role in establishing this base of knowledge. Prevention research of necessity takes place largely outside the laboratory, in field settings such as schools and communities. Although NIDA can be proud that the prevention researchers it funds are outstanding scientists who maintain rigorous standards, the controls that can readily be imposed in a lab often are not feasible in field research. Innovative quantitative methods have helped to strengthen the conclusions that are drawn from prevention data, and enabled scientists to look at their data in fresh and creative ways. New types of experimentation and data collection continue to call for new methods, for example approaches for analysis of complex big data such as that collected via mobile devices. These new approaches will continue to enable prevention scientists to build and refine the knowledge base that informs successful preventive interventions.Drug abuse and HIV prevention may lack the drama of treatment, which can take a life that is in shambles and restore it to productivity. But how much better, and cheaper, it is for society when the life is prevented from becoming a shambles in the first place! Prevention science has kept many lives on a positive trajectory in the last 30 years, and NIDA’s support has been essential to this progress. I believe that prevention science, coupled with innovative quantitative methods, is poised to accomplish even more in the near future. I sincerely hope that both prevention science and methodology are prominently featured in the new strategic plan, as they were in the 2010 strategic plan. NIDA support has made a difference
Key areas in Basic Neuroscience:HIV and pediatric AIDS are critically important areas of basic neuroscience study for the next 5 years:Understand the molecular and cellular interactions interactions between HIV and drugs of abuse.Understand molecular mechanisms of latent HIV reservoirs in animal models of drug abuse.Determine how pediatric AIDS results in drug abuse..
Suggestion for understanding the direction and narrowness of addictive motivationAn important challenge for addiction neuroscience and NIDA to aim to solve in the next decade is to clarify how brain systems control *what gets wanted most* in addiction. Solving that puzzle might open new approaches to effective therapies, which could more selectively target the crucial problem of an addictive focus on pursuing and consuming drugs at the expense of other life rewards, without producing the undesirable side effects of broader approaches.Background: Addiction neuroscience has made great strides in identifying brain markers that become changed in addiction (long-term potentiation/depression; dopamine receptor and AMPA/NMDA receptor levels, etc.). Great strides have also been made in relating which drug-induced brain changes are neural mechanisms that cause elevations in intense motivation to pursue addictive rewards (hyper-reactivity of mesocorticolimbic systems to addictive cues; incentive-sensitization; etc.). As a result, the brain mechanisms underlying the intensity of addictive motivations are now relatively well understood.Current limitations: At the same time, those approaches may be so broad that potential treatments which target either abnormal learning or motivation intensity mechanisms in the brain may have undesirable consequences. For example, reversing drug-induced changes in learning-related synaptic strength could also disrupt normal synaptic mechanisms of learning and memory that recruit many of the same molecular mechanisms. Therapeutic manipulations aiming to reduce the intensity of addictive motivation, such as in cue-triggered relapse situations, could also disrupt normal motivation function too (whether the manipulation aimed to reduce cue-triggered hyper-reactivity of mesocorticolimbic systems, or to boost chronically down-regulated markers such as suppressed D2 dopamine receptor availability). Potential solution. A more effective approach might be to identify and selectively target the neural mechanisms responsible for narrowly focusing intense addictive motivation on the particular incentive target of addiction, rather than to adjust the overall level of motivation or the strength of learning-related synaptic signalling. This is the issue of ‘what gets wanted most’ in addiction, and targets the feature that in addiction the most wanted target (i.e., drugs) becomes intensely pursued at the expense of other life goals. In the brain, this narrow addictive focus combined with high motivation intensity is controlled by interactions between associative learning circuitry (e.g., prefrontal cortex, amygdala and hippocampus) and the mesocorticolimbic circuitry that generates intense reward motivation. It is possible to mimic this interaction in the laboratory, and should be possible to selectively alter a narrow addictive focus. For example, mimicry of a very intense but narrowly-focused motivation similar to addiction has been produced in animal neuroscience laboratories by selective brain stimulations in particular nuclei of amygdala (e.g., optogenetic; opioid microinjections), in ways that modulates such associative-motivation interactions. This may be an entry into solving the brain puzzle of ‘what gets wanted most’ but is only a small step in solving that problem.
Conclusion - Thus a worthy goal for addiction neuroscience in the next few years is to better understand neural circuitry mechanisms that control the *direction* of intense motivation in addiction (i.e., toward a particular reward target, such as drugs) and *narrow focus* (i.e., to the exclusion of other targets). That better understanding could open up the way for more selective interventions to disrupt a narrow and intense addiction, while preserving general learning and motivation functions that are crucial to normal life.
Key areas for basic neuroscience...HIV, neuroAIDS, and Pediatric AIDS are fundamental and urgent areas of basic neuroscience research that deserve highest importance over the next 5 years Included within this area would be studies of the interaction between HIV-1 and drugs of abuse; risk and vulnerability to drug abuse following pediatric AIDS; novel therapeutic approaches for HIV/AIDS including the microbiome-gut-brain axis; and studies addressing latent HIV reservoirs.
1. There is no discussion within the strategic plan for the role of computation or decision-making in these strategies. Addiction is fundamentally a problem with how the person is making their decisions. Decision-making is fundamentally a computational process. A lot of progress has been made in understanding how people make decisions, and that perspective (which can range from neurophysiological to sociological) is not included. Understanding how neural circuitry impacts decision-making is more complex than what is stated in the current plan, and I do not think that the current plan includes these new perspectives on addiction.This has both a basic science side (how do drugs of abuse interact and affect decision-making processes?) and a clinical science side (how are current treatments affecting decision-making processes?).2. There is no discussion within the strategic plan for examining the unitary nature or multiplicity of addiction. This may be extremely important both on the basic science side (what differentiates individuals and drugs and their interactions) or on the clinical side (can treatments be guided to individuals to match the multiplicity of addictive processes?)Actually, we do not know at this point how unitary addiction is. Is it a fundamental process that is the same in all individuals, or is drug use a symptom of many underlying disorders, each of which require their own targeted treatments?3. There is no discussion within the strategic plan for examining the differences between individuals, and addressing whether all users are truly "addicted" to drugs or whether some users are merely using drugs because they don't have other outlets for leisure activities.There is data in animals models now that only subsets of animals show "addictive" processes (such as passing through shock for drug or choosing drug when given a choice).I would be happy to expand on any of these issues if you like.Thank you
Thank you very much for the opportunity to review 2016 Strategic Plan and submit our comments. Because my research mostly deals with Basic Neuroscience, I have reviewed draft of Strategic Priorities for Basic Neuroscience. I found that the draft covered almost all aspect of Basic Neuroscience. However I like to suggest to include the following to obtain mechanistic insights into addition process and to facilitate candidates for therapeutic manipulation of addition.Quantitative proteomics to investigate post-translational modifications induced by exposure to drugs of abuse.Dynamic changes in the expression of noncoding RNAs such as microRNAs and long noncoding RNAs caused by the exposure to drugs of abuse. Characterization of post-transcriptional modifications of transcriptomes to identify novel regulators of addiction. Systems biology approach to identify key regulators to manipulate extinction/ reconsolidation of memory of drugs of abuseThese studies will facilitate detailed molecular dissection of addiction process to develop novel strategies to manage and treat substance use disorders.Hope these comments help. If you want me to elaborate more on these points, I am happy to do so
Recommended addition to list of strategic priorities:Accelerate identification of the underlying genetic factors that contribute to substance dependence disorder risk; including differences by sex. Recruit sufficient well-characterized samples to address these issues in American populations, including minority populations; collect information about environmental factors affecting risk. Genetics studies of substance dependence have been highly successful, with greater yield of risk loci than many other major psychiatric traits (such as schizophrenia and bipolar affective disorder) in proportion to size of sample studied, depending on the substance dependence trait. Compared to other major psychiatric traits, substance dependence traits are also uniquely dependent on NIH as a funding source because unlike, for example, autism, schizophrenia, and bipolar disorder, the philanthropic support for this research is next to nil. The unavailability of philanthropic support has had an unfortunate effect on grant funding: innovation is highly valued, but the first studies in a field, i.e. those that are viewed as most innovative, are those that can be initiated most rapidly. Studies supported by private sources can generally be initiated rapidly. Considering the lag between grant submission, review, generally revision and re-review, and start of funding, studies in fields that are not supported by philanthropy are likely to be viewed as less innovative than those that are. Thus, grant review should be undertaken in a context where the challenges specific to substance dependence research, as well as the importance of the goals, are appreciated. Experience has shown that it is extremely important to have available large, well-assessed samples. Lack of same has been a particular impediment to substance dependence genetics research. In particular, the lack of available samples has greatly impeded efforts to replicate published GWAS results. However, if appropriately-ascertained replication samples are lacking worldwide, lack of replication is not equivalent to failure to replicate; this underlines the need for additional sample collection. Shallow ascertainment, while suitable for some traits such as schizophrenia, is an unacceptable limitation for substance dependence traits, where such traits tend to be highly comorbid. Optimal analysis strategies must rely on taking this comorbidity into account analytically, and this is possible only when all such traits are reliably assessed. We also stress the importance of recruiting controls who have been exposed sufficiently to the substance. This is usually not a problem for alcohol and nicotine dependence which are legal and pervasive in society, but this is a major impediment for research in cocaine, opioids, and other illicit drugs.
1) Are there priorities that are missing and should be addedWhile the drafted strategic priorities look great, we hope the following one can be addedIncrease our knowledge of multigenerational impacts and epigenetic inheritance of drug abuse and addiction. Lines of evidence has suggested multigenerational impacts of abused drugs and addiction behaviors, however the basic mechanisms are poorly understood. The basic science section is in the position to address this knowledge gap. 2) Are there areas that need just a small investment to make big advancements? That Integrating animal models, including invertebrate alternatives, to address behavior, genetics, epigenetics, and other molecular biomarkers and mechanisms for drug abuse and addiction may need relatively small investment to make big advancements. Thank you a lot for the opportunity!.
I have the following comments:The word “genetics“ is mentioned only in one sentence under Basic Neuroscience (“Integrating animal models, behavior, genetics, epigenetics, and other molecular biomarkers for drug abuse and addiction”). While I do agree that such integration would be beneficial, the absence of a strong human genetics component in this draft, does make me a little concerned that there might be plans to reduce emphasis on genetics compared to the previous strategic plan. I do hope this is not the case, as this would be nothing less than a disaster.It is my opinion that a strong emphasis on genetics approaches should be one of the cornerstones of NIDA’s next strategic plan, and that considerable work should be put into identifying the channels most likely to become productive lines of discovery. Pessimism based on limited number of findings in GWAS studies conducted so far is in my opinion premature. For example, the psychiatric genetics consortium has made considerable progress on Schizophrenia in a relatively short time, after a relatively long period of difficulties. The lack of findings in mood disorder GWAS studies and addiction GWAS studies may be related, and perhaps addiction and its co-morbidities need to be studied together. Brain disorders like addiction are complex, and progress is currently hindered by lack of replication samples and lack of data on human brain tissue, RNAseq/gene expression data, for example.It is my opinion that NIDA should make a clear continued commitment to human genetics approaches with the aim of increasing sample sizes, both phenotype and genotype data. First, continued recruitment and phenotyping should be supported to generate novel/new datasets and increasing the sample sizes for existing datasets with the aim of doing thorough genome-wide scans with adequate power, perhaps through meta analyses. Additional samples with rich phenotypic information could be tremendously useful for replication studies, even at relatively small sample sizes. Second, studies on addiction supported by NIDA that have no plans to collect DNA samples because their current study plans do not include DNA analysis, could be empowered to do so nonetheless at relatively little cost (during the review process, for example). Third, the collection of addiction-related data in ongoing studies of known co-morbidities or consequences of addiction primarily funded by other institutes, such as psychiatric conditions, cancers and cardiovascular diseases, might be a way to generate new data sets fast. Fourth, it would be important to support the genotyping/sequencing of existing and future DNA samples to strengthen both discovery and in the shorter term replication studies (lack of data for replication of findings remains a huge problem for human genetics of addiction).
It is my privilege to share my thoughts on the strategic plans of NIDA. I think one of the emerging research need is availability of animal models that allow the study of long-term effects of juvenile cannabinoid usage. Animals, which have a longer duration of the juvenile period and have a longer lifespan than that of the laboratory mouse but have similar maintenance needs, would be ideal. The Peromyscus Genetic Stock Center offers several species with the above mentioned features. Furthermore, recent studies have shown that these animals resemble human physiology more closely. I would suggest to encourage the usage of these animals in the future.
A re-focus on the pharmacological principles of cocaine addiction/abuse. NIDA has been successful at providing innovative psychological interventions for the treatment of drug abuse, e.g. cognitive behavioral therapy and the use of vouchers (based on behavioral economics). However, NIDA has met with no success at developing effective pharmacotherapies for cocaine and other stimulant abuse.In pre-clinical models of addictive behavior, such as the drug self-administration paradigm, psychological approaches are suitable for explaining drug-seeking behavior while the drug is available and in a syringe. But once the drug is injected into the body, pharmacological explanations of drug-seeking behavior work much better. In this way, the psychological and pharmacological approaches to understanding addictive behavior are complimentary. But the pharmacological approach to understanding drug-induced behaviors, focusing on pharmacokinetic/pharmacodynamic (PK/PD) interactions, has been relatively neglected. The study of PK/PD interactions is now facilitated by the ready availability of suitable computational tools. Encouraging the study of PK/PD interactions in pre-clinical models is likely to provide new insights into the basis of drug addiction. Likewise, encouraging the study of PK/PD interactions in clinical studies is likely to inform pre-clinical studies, thereby accelerating NIDA’s medications development efforts.There are examples of the success of this kind of approach in other psychiatric disorders, for example, psychosis. Over the years, a focus on the pharmacological principles underlying these disorders and the pharmacokinetics of different classes of compounds has resulted in a range of widely prescribed medications.
I think the RFI covers very well in a general way, but a lack of detail makes it seems unfocused. This is probably due to the fact of its being a strategic guide. One suggestion could be to prioritize them in several groups (instead of individual directions). I think emphasis should be given to developing new tools. For research in DNA methylation, a lack of interrogation tool is blamed for the slow development in this area currently. one example could be to put efforts in developing molecular tools for LOCUS SPECIFIC manipulation of DNA methylation (something like Nestler's new paper, Heller et al., Nat Neurosci. 2014 Dec;17(12):1720-7 for chromatin, but targeting methylation).I think emphasis should also be given to investigating drug effect in decision-making process in the area of behavioral models, molecular and circuit mechanisms. Deeper understanding of this process will also be beneficial to addiction therapy.
Increase support to understand the extent and content of substance use postings on social media There is emerging evidence that pro-substance use content is rampant on social media platforms (Cavazos-Rehg et al., 2014; Cavazos-Rehg et al., 2014; Cavazos-Rehg et al., 2015). Specifically, several studies have found that commercial and non-commercial (i.e., organic) promotions of alcohol, tobacco, and marijuana are widespread on popular social media outlets such as Facebook and Twitter. Because engagement with social media is becoming more and more commonplace, it is likely that pro-substance use content on social media platforms normalizes substance abuse behaviors. This can detrimentally affect young people who engage with social media at a high rate and are at a stage of development when media messages are highly influential. Research to examine effective ways to reach and engage young people on social media with anti-substance use messages is scant but critically needed.We recommend that NIDA prioritize funding to better understand the scope of substance use messages on social media platforms.Support for longitudinal data collection to understand social media use patterns and exposures to drug and alcohol commercial and non-commercial promotions Individuals are engaging with social media at a very young age, often as early as 10 years of age.There is no known trajectory research that conducts longitudinal assessments from early adolescence to young adulthood and assesses social media use and associations with substance use behaviors and norms. A greater understanding of social media use implications for substance use behaviors may lead to improved preventative interventions, especially for young people who are at a vulnerable period of development when substance use behaviors are transitioning into addiction. Given the high use of social media among young people, it is imperative that NIDA prioritize research on understanding the short and long-term implications of social media use for substance use behaviors and norms.Support the development and implementation of methodological tools for social media data miningSocial media use is incredibly high especially among young people. There is potential for social media data to be used to help identify new and/or dangerous trends in substance use among young people.Researchers have made important but limited progress in understanding the use of social media data to inform substance use surveillance and prevention. Social media data is large and complex, and new methods must be developed and refined to analyze social media data in such a way that meaningful information, patterns, and trends about substance use are revealed. There is a critical need for the development of methodological tools that can be used to analyze social media data. Research on approaches to mining social media data to inform substance use research should be a NIDA priority. References:Cavazos-Rehg P, Krauss MJ, Spitznagel E, Grucza R, Bierut LJ: The hazards of new media: Youth’s exposure to tobacco ads/promotions. Nicotine & Tobacco Research, 2014; 16(4):437-44. PMCID: PMC3954423.Cavazos-Rehg, P, Krauss, M., Grucza, R., & Bierut, LJ. Characterizing the followers and tweets of a marijuana-focused twitter handle. Journal of Medical Internet Research, 2014; 16(6):e157. PMCID: PMC4090385Cavazos-Rehg, P, Krauss, M., Fisher, S. L., Salyer, P., Grucza, R. A., Bierut, L.J. Twitter chatter about marijuana. Journal of Adolescent Health, 2015; 56(2):139-145. PMCID: PMC4306811
Basic Neuroscience: Understand molecular mechanisms of HIV-1 viral proteins in dysfunction of neurotransmission Integrating preclinical HIV-1 transgenic animal models, behavior, molecular approaches for HIV-1 associated neurocognitive dysfunction. Understand individual differences in drug abuse and addictionImprove our understanding of the role of environmental factor during development in addiction. Improve translational strategy of basic neuroscience
I would like to applaud the NIDA staff for developing a very comprehensive draft of strategic priorities. It is particularly heartening to see a strong emphasis on basic neuroscience. It is clear that, without a fundamental cellular and molecular level understanding of the development and function of neural circuitry, which are modifiable by exposure to drugs of abuse, we will not be able to move forward to develop innovative and effective therapeutics to combat addiction and associated disorders. Rodent models have been employed for decades towards drug abuse and addiction researches. Although they have made significant contributions to our understanding of drug abuse and addiction mechanisms, I would like to encourage NIDA to invest more on alternative animal models, which may carry unique strength for addiction research that have been under-explored. In the light of technological revolution in genome editing, it is now possible to manipulate the genome and the cell types in a variety of model organisms that might bring unique attributes to addiction research.
As discussed in the attached article, given the substantial changes in marijuana legalization for both medicinal and recreational purposes, a strategic priority of NIDA should be to increase the knowledge base about the impacts of marijuana and to also support research regarding treatment of marijuana dependence as well as marijuana prevention efforts that specifically address issues of the perceptions of safety or medical benefits of marijuana. In particular, enough scientific knowledge regarding the effects of marijuana must be accumulated so that eventually a “surgeon’s general” report could be issued that addresses many of the claims regarding marijuana. This will of necessity, not only involve additional research regarding the negative impacts of marijuana on development, its effects on medical problems, and its effects on mental illness, but will need to somehow address public concerns/beliefs regarding its medicinal benefits. While NIDA has historically not supported research on the potential benefits of marijuana, the lack of such research is often cited by proponents of marijuana legalization as evidence that NIDA/NIH is biased. NIDAs research portfolio regarding the substantial harmful effects of marijuana needs to be substantially expanded so that the depth and breadth of the portfolio approaches that of tobacco. This will likely involve a substantial increase in studies of prevention, treatment, and epidemiology as well as other disciplines. While much of the past research demonstrates harms associated with marijuana, current consumption patterns may be different as well as potencies greater. Rates of dependence on marijuana have, based upon historical data, been considered fairly low; but those estimates may not be correct in a legal environment where marijuana is heavily marketed and/or legal. The effects of marijuana on adolescent development must be examined in detail using multiple approaches and modalities. While adolescent development should be a major focus, the impact of marijuana use on adults must also be understood in much greater detail, particularly in the current context of increased potencies as well as more permissive environments. Studies must be large and comprehensive enough that the clear weight of scientific evidence cannot be disputed. This is a particularly salient current issue as with marijuana legalization, a substantial marijuana industry effort is underway to dispute claims of harms as well as to promote claims of benefit.
Response to Request for Information (RFI): FY 2016–2020 Strategic Plan for the National Institute on Drug Abuse, National Institutes of Health (NOT-DA-15-005)As Principal Investigator or Co-Investigator of three NIDA-funded R01 grants, I am writing to support a continued focus on genetics and epigenetics research for substance abuse (including nicotine, opioids, marijuana, cocaine, and other drugs) when revitalizing the Strategic Plan of The National Institute on Drug Abuse (NIDA). I applaud NIDA for emphasizing these research areas in the first two bullets of the Draft Strategic plan, as follows:Increase our knowledge of biological, behavioral, environmental, and developmental factors involved in risk and resilience for drug use and addiction. Integrating animal models, behavior, genetics, epigenetics, and other molecular biomarkers for drug abuse and addiction. More specifically, I am responding to stress the importance of human genetics as a top priority for NIDA. Substantial investments have been made to collect cohorts and generate the genotyping and sequencing data to conduct genetic epidemiology studies. Continued support by NIDA is needed to fully realize the full potential of these investments. Large-scale collaborative projects have made monumental success in identifying replicable genetic risk factors for various complex diseases by bringing together well over 50,000 human subject participants and hundreds of investigators from the United States and worldwide. Examples include the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (Psaty et al. Circ Cardiovasc Genet 2009) and the Psychiatric Genetics Consortium (Psychiatric GWAS Consortium Steering Committee Mol Psychiatry 2009), among several others. The discoveries made from these large-scale collaborations have been taken into the laboratory and the biological and regulatory functions of specific identified genetic variants are being established. The numbers of subjects being combined for genetic studies of substance abuse phenotypes hasn’t come anywhere close to the numbers available for other complex disease phenotypes: the only exception being a series of genome-wide association study (GWAS) meta-analyses of cigarette smoking behaviors published in Nature Genetics in 2010. However, these studies relied on one-dimensional phenotypes, such as ever/never smoking and age at initiation of smoking. Many more phenotypes that more comprehensively define nicotine and other abuse and addiction are available from NIDA-funded studies. I am thrilled about the concerted effort currently being made by NIDA to provide some funds and bring together investigators to extend the Psychiatric Genetics Consortium into studies of addiction. I envision that our field is at the cusp of making many genetic discoveries for substance abuse, but NIDA must continue and strengthen, where possible, its support for investigators partaking in this and other ambitious endeavors in genetic epidemiology. With the identification of specific genetic variants contributing to substance abuse, researchers will need resources available to study (1) the functional and regulatory effects of identified variants and (2) how those effects relate to disease outcomes. To address this first research question, datasets comprised of post-mortem human brain samples are emerging to study the effects of genetic variants on changes in DNA methylation and mRNA expression, including Brain eQTL Almanac (Ramasamy et al. Nat Neurosci 2014), BrainCloud (Colantuoni et al. Nature 2011; Numata et al. Am J Hum Genet 2012), and Genotype-Tissue Expression (GTEx Consortium Nat Genet 2013). These valuable resources, which are being made publically available, are particularly valuable to early-career researchers, who have not yet established their own cohorts but have innovative approaches to tackling such analyses. As a shortcoming though, these datasets were not designed specifically for substance abuse, so there is limited data available to address how the effects of the identified genetic variants influence addiction outcomes. I encourage NIDA to extend their support to enable datasets, designed specifically for substance abuse, that integrate multi-faceted biological data, including genomic, metabolomic, transcriptomic, proteomic, and metabolomic data, in human brain.Lastly, I was delighted to see “addressing health disparities among underrepresented populations” as a unifying theme in the Draft Strategic plan. Most human genetic studies are comprised only of European ancestry participants. In designing a specific goal to address this theme, I would argue that more support is needed to expand genetics and epigenetics research into a greater number of ethnic minority participants.
Dear Members of the NIDA Strategic Planning Committee,In response to the call for thoughts on the NIDA Strategic Plan and your recent email, we write to suggest that NIDA add an epigenetic-centered program to its list of funding priorities.As you know, drug abuse represents an urgent economic and social problem. Despite ambitious initiatives that have been undertaken to develop therapeutics for this devastating disease, these efforts have been hampered by our limited understanding of the basic molecular mechanisms underlying the function of the brain’s reward system and its maladaptations to drugs of abuse. Therefore, a better understanding of the molecular basis of these processes will be critical in developing effective therapies for drug addiction. Accumulating evidence supports an important role for epigenetic mechanisms in regulating key aspects of the addictive process such as synaptic remodeling and functional plasticity. Although the last five years have witnessed significant advancement in our understanding of the role of epigenetics in the development of addiction, the limited technical arsenal employed in addiction research still presents an impediment to continued progress in this field. Furthermore, in comparison to other systems, the brain is highly complex, featuring both neurochemical and circuit diversity. As such, one cannot overemphasize the necessity in applying cutting-edge epigenetic techniques to address fundamental questions in addiction neuroscience.To this point, significant technical breakthroughs in genomics and epigenomics are making great contributions to recent advances in the fields of stem cell and cancer biology. Genome-wide techniques including ChIP-seq, RRBS, WGBS, DNase-seq, DamID, HiC, and ChIA-PET, when combined with genome editing tools such as CRISPR/Cas9, allow interrogation and manipulation of neoplastic and developmental systems with unprecedented cell-type- and locus-specificity. Indeed, since limited cell availability and cellular heterogeneity also represent challenges to the successful implementation of these genomic techniques in these fields, many of these systems have now been optimized for use with very low cellular input. Owing to the complex circuitry and cellular heterogeneity in the brain, and more specifically the brain reward system, these cutting-edge techniques, when coupled with cell-labeling and purification techniques, can enable molecular studies across various stages of reward processing and development of addiction with unprecedented cell, circuit, and temporal specificity. Moreover, these tools will shed light onto the intrinsic differences amongst neurons of the same neurochemical “identity,” such as midbrain dopamine neurons or pyramidal cells in the hippocampus or prefrontal cortex. In addition to profiling the neuronal networks involved in addiction, which will help identify molecular changes that correlate with addiction behavior, CRISPR/Cas9-based epigenomic perturbation can probe causal roles of these changes, therefore providing novel therapeutic targets. Complex biological problems such as mechanisms underlying drug addiction require interdisciplinary approaches. Addiction epigenetics is a prime example of a field that would greatly benefit from synergistic collaborations between conceptual leaders in epigenetics, genome engineering, and behavioral neuroscience. A multidisciplinary and collaborative approach applying cutting-edge cell labeling, purification, genomic, and epigenomic techniques, as well as the latest genome editing tools, to sophisticated models already established in addiction neuroscience (e.g., drug self-administration and relapse procedures), would greatly facilitate our understanding of basic molecular mechanisms underlying addiction and would expedite the development of novel therapeutics, not only for drug addiction, but also for other pressing psychiatric disorders. Based on the reasons outlined above, we believe that an epigenetic-centered program with an emphasis on applying cutting-edge tools to molecular studies of the brain reward system and addiction will be a necessary and timely initiative for the Division of Basic Neuroscience and Behavioral Research of NIDA.Thank you very much for your consideration!

Basic Science, Clinical and Translational Science

NIDA should include in its strategic plan the following:Investment in somatic brain DNA variation as a cause and consequence of drug addiction. Investment in direct antagonists of cocaine action, ie, triple reuptake inhibitors and other molecules which antagonize rewarding actions of cocaine.
I respectfully submit the role of neuroinflammation in the causes and consequences of substance abuse and the potential of large molecules to provide novel treatments for substance abuse for consideration for inclusion in the NIDA strategic plan.
I think these directions could be important. Neuroinflammation and neuro-immune or neuro-glial interaction: role of TLRs, cytokines, and chemokines Circulating miRNAs as neuromodulators and biomarkersPro-resolution mediators and pathway Stem cells as drug store Testing drug effects in primary human neurons
A review of progress in scientific approaches to understanding the biological basis of substance use and substance use related disorders will reveal several overall themes that indicate expectations that the future yield from certain scientific approaches should be markedly lowered. First, the genetic architecture of substance use is considerably more complex than anticipated. It is unlikely that genetic approaches alone will lead to improvements in diagnosis. However, there is suggestive evidence that genetic information may be beneficial in guiding some forms of treatment. Second, despite their promise, there are clear limitations in existing animal models of substance use. Recent work from the Encode consortium which demonstrates relative lack of conservation of cis regulatory elements suggests that efforts to use or genetically engineer more representative animal models will face stiff challenges. Third, as highlighted in a recent publication by the ENIGMA collaboration which analyzed paired imaging and genetic data from 31,000 subjects (Nature 2015), the likelihood that structural neuroimaging approaches will contribute meaningfully to the mission of NIDA in the foreseeable future is limited.In contrast, there is reason to be optimistic about the field of epigenetics. Using only a fraction of the resources devoted to the above fields of endeavor, considerable scientific progress has been made. Using funding from NIDA, a robust DNA methylation signature of cigarette consumption at AHRR have been published by our group (Monick et al, 2012) and extensively replicated (11 consecutive times at the most recent count, see Table I). NIDA funded efforts to translate this discovery into clinical tools for clinical diagnosis and treatment are in progress. This progress in tobacco consumption is not an outlier in the field of substance use. Already, preliminary profiles exist for both cannabis and alcohol consumption. Both are pending commercial translation into usable clinical tools.Taken as a package, through their allowance more sensitive quantitation of substance use consumption, these DNA methylation tools may lead to more effective prevention and treatment for substance use. Reciprocally, they may also allow us to more effectively interrogate the early developmental processes that underlie substance use initiation and may be the only tool through which to understand the relationship between e-cigarette use and smoking.Best yet, it is quite possible that these discoveries are only the tip of the epigenetic iceberg. There is considerable reason to be optimistic that epigenetic approaches can be used to provide the “personalized medical approach” that has been so often promised, yet not delivered. Though the above methylation detection profiles are relatively robust, it has become quite apparent to those in the field that the vast majority of the epigenetic signatures found in peripheral blood are confounded by GxMeth interaction effects. What is not clear is whether by characterizing these interaction effects that we can improve our ability to predict our ability to substance use or response to medications.This is not a pie-in-the-sky possibility. To give a concrete example, in previous work Volkow and colleagues have shown that monoamine oxidase activity in the CNS is directly in activated by tobacco smoke. Conveniently, at the same time, our first work in our efforts, funded by NIDA, to understand the effects of smoke on peripheral DNA methylation was to show the profound genotype dependent demethylation of the promoter region in response to tobacco smoke. This locus is of considerable interest because the activity of this locus is critical obvious key regulatory role of monoaminergic neurotransmission and the fact that it has been targeted in previous smoking cessation attempts. Unfortunately, those clinical trials did not show significant clinical effect of MAO inhibitors on smoking cessation. Could the reason that these clinical trials did not show an impact be confounding GxMeth effects? By using information from a better understanding of these GxMeth effects, could we more likely improve treatment choice? Is this true for other smoking cessation medications such as varenicline and bupropion? These are open questions.To summarize, it is my belief that further investment in epigenetic technologies could lead to significant advances in our ability to diagnose, treat and prevent substance use. At the same time, it is important to note that advances in the field of epigenetics are closely tied to advances in the field of genetics and that no scientific discipline is an island. Finally, I thank NIDA for giving me the opportunity to conduct my studies for the past 13 years and for listening to my thoughts on improving our national efforts in combating substance use.
NIDA - Draft Strategic Priorities Basic Neuroscience: Improve our understanding of the basic science of drug use, addiction, vulnerability to addiction, and recovery Increase our knowledge of biological, behavioral, environmental, and developmental factors involved in risk and resilience for drug use and addiction Integrating animal models, behavior, genetics, epigenetics, and other molecular biomarkers for drug abuse and addiction Understand the developmental trajectory of addiction and individual heterogeneity Improve our understanding of brain circuits related to drug abuse and addiction at the cellular, circuit, and connectome levels, including:Normal development and function across the lifespan including mechanisms of reward, self-control, and conditioning Drug effects on neuroplasticity, neural structure, and circuit function across the stages of addiction Neurobiological correlates of recovery Neurobiological mechanisms that determine why some people are more susceptible to overdose than othersPulmonary, renal, hepatitic mechanisms that determine why some people are susceptivel to overdose than others.Neural-glial, -immune, and neuroendocrine interactionsBetter define 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 patientsImprove our understanding of the interaction between addiction and co-occurring conditions Elucidate the impact of mental health, HIV, HCV, pain, etc. on addiction; Elucidate the impact of addiction on mental health, HIV, pain etc.Understand molecular mechanisms of latent HIV reservoirs in the brains of substance-abusing populationsClinical 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)Support the development of novel, evidence-based, targeted prevention and treatment interventions including social, behavioral, pharmacological, vaccines, and brain stimulation therapies (e.g., transcranial magnetic stimulation, direct current stimulation, etc.)Accelerate the identification of promising targets and ligands to accelerate new drug discovery and development Accelerate medications development for SUDsFocused development efforts on: Addictions without an FDA approved treatmentDetoxificationIncreasing linkage to evidence-based SUD care after detoxification. Overdose prevention or reversalPharmacological interventionsBehavioral interventionsStructural and environmental interventionsAccelerating neurobiological recoveryAddressing comorbidities (MH, HIV, HCV, pain)Integration of addiction, and other mental health and medical care in adult and pediatric settingsThe effectiveness and comparative effectiveness of treatments in the real worldThe study of health services approaches to the full spectrum of unhealthy substance use (from risky use through severe disorder)Longitudinal care approaches for ongoing substance useWays to improve the quality of care for people with or at risk for addiction. Develop techniques to measure and improve patient adherence in clinical trials (e.g., patient-developed incentives)Identify measures other than abstinence that can reliably assess SUD treatment outcomes Identify biomarkers of addiction, resilience, and recovery to enable personalized treatmentDevelop alternative smoking cessation treatment and regulatory tobacco control mechanismsPublic 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)Improve understanding of the social and structural determinants of substance use, and of receipt of quality services for prevention and treatment of addiction. 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, pharma, biotech, healthcare organizations, policy makers, criminal justice, law enforcement, etc.) to enhance the dissemination of evidence-based research findings into policy and practice Strengthen focus on bi-directional translational research. Development and implementation of evidence based public health approaches to delaying substance use in adolescents. Science Infrastructure: Enhance the national research infrastructure to support advancements in science. 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 Improve training for the next generation of scientistsIncrease effective engagement and training in multidisciplinary research (informatics, engineering, computer science, chemistry, mathematics, physics, etc.)Increase the number of well-trained underrepresented scientists in the drug abuse and addiction field at all career levels. Improve mentoring of young scientistsIncrease effective collaborations in research. Increase the ethics and transparency of research involving people with SUD. Increase effective data and resource sharing (big data, biorepositories, transgenic/optogenetic tools, data standards, etc.)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. Identify and implement strategies to improve the reproducibility of pre-clinical research. 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. Develop and validate computational and systems-level analytics for integrating multi-dimensional data across the addiction trajectory. 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 use disorders and addiction. Addressing health disparities among underrepresented populations. Understanding the role of development across the life span. Addressing the assessment and treatment needs of adolescents based on developmental stage. Addressing the treatment needs of pregnant and post-partum women and their children. Addressing the treatment and prevention needs related to common co-morbidities including HIV/AIDS and hepatitis C.
Because genetic variation is still expected to explain approximately 50% of the variance in addiction risk across drugs of abuse, continued investment in genetics of addiction is needed. Taking multiple approaches will be necessary. Genome-wide association studies (GWAS), begun in 2005, have made many important discoveries in the genetic determinants of human disease. For addiction, discoveries from association studies and follow-up functional studies in humans and animal models have firmly established variants in the nicotinic receptor gene cluster CHRNA5-CHRNA3-CHRNB4 on chromosome 15q25 and CHRNB3-CHRNA6 on chromosomes 8p11 as important contributors to risk of nicotine dependence, as well as lung cancer. The variant rs16969968 in CHRNA5 has been further demonstrated to interact with some pharmacotherapies for smoking cessation in multiples studies. Unfortunately, the success with nicotine dependence as not been mirrored in addiction to other drugs. Standard GWAS with much large samples is one approach to enhancing discovery that has born fruit in other parallel phenotypes (e.g., recent substantial advances in schizophrenia). Psychiatric Genetics Consortium (PGC) Addiction group will be pursuing this, combining existing cohorts. One of the most important, low marginal cost, investments for this effort would be genotyping the many existing samples that lack funding to genotype. Beyond large-scale GWAS, integration of these data with epigenetics, brain imaging, and other biomarkers holds great promise for biologically relevant discoveries and understanding of potential mechanisms. Great strides have been made in understanding epigenetics in human brain tissue among non-addicted “normal” decedents. These data provide very import tools to understanding potential function of genes and variants specifically in tissue most relevant to addiction. Broad sharing of these data (notably BrainCloud, Brain QTL, GTEx) allow researchers to link genes and variants associated with addiction phenotypes to putative functions and set the stage for experimental follow-up of potential molecular mechanism underlying such associations. A critical gap in the epigenetics of addiction is the lack of large-scale genome-wide comparison of epigenetics between those addicted to drugs and non-using controls. To date the literature largely reports targeted expression or methylation experiments for candidate genes/variants, mostly in those of European descent. Adequately powder agnostic genome-wide tests of gene expression and methylation coupled with genome-wide genotyping among cases of addiction and non-using controls would provide data are critical to understanding differential expression and methylation specific to addiction that can not be obtained from existing resources. Additionally there is need for such data across ancestry groups, as there are substantial differences from what we know so far and a substantial under representation of groups that are not of European descent. Publically available resources of such epigenetic information would provide both the ability to “look up” results from GWAS and other genetic studies to assess potential gene function relevant for addiction, but also nominate variants for independent tests of association based on their association with differential expression or methylation. Epigenetic data will provide a view on genetics of differential brain function complementary to brain imaging studies, providing data on one set of mechanisms that could help explain observed differences in brain function between those addicted to drugs and those who are not. Another area worthy of consideration in NIDA’s strategic plan is the development of biomarkers of addiction and of recovery. New technologies such as broad-spectrum metabolomics provide novel opportunities within the field of addiction to identify biological systems perturbed by addiction or cessation of use. Metabolomic profiles that distinguish those addicted and those who are not, or treatment responders and nonresponders could provide novel insights into biological systems important to these outcomes as well as biomarkers for study of causes of individual differences in those systems. HIV acquisition and living the HIV continue to be substantial worldwide problems for which drug users have specific risks and needs. Although environmental interventions have had great success in lowering incidence rates in the U.S., acquisition among drug users continues here and much more so abroad. Based on in vitro work it is estimated that fifty percent of variability in HIV-1 susceptibility is attributable to host genetics. Indeed, mechanisms underlying the only genetic variant conclusively associated with HIV acquisition, a deletion in CCR5, gave rise to maraviroc, an antiretroviral drug. Thus identifying such genetic factors holds great promise in advancing our understanding HIV pathogenesis and providing targets drug development. Similarly, basic research across the spectrum of genomics and other omics can provide unique insights on living with HIV among drug users. Of particularly interest is the interaction between ongoing drug use and progression of HIV in the context of variability in adherence to HAART or its complete absence. Translational science needs high-risk high-reward investment to accelerate discovery and clinical application. Despite the widely held expectation that scientific discoveries will improve patient care, the yield of clinically useful discoveries from basic science remains low (5%) and the time for translation from discovery to implementation long (13-17 years). New paradigms are needed to revolutionize the science of translation: speeding discovery and implementation of evidence-based therapies by innovatively reducing, removing, or bypassing bottlenecks in therapeutic development, while evaluating them in real-world settings. In particular, it may be useful bring discovery science tools (e.g., Omics) to real world treatment settings using large numbers of patients to focus discovery on clinical outcomes specifically (e.g., treatment response), rather than beginning with the disease and then translating those discoveries, hoping the same biological mechanisms for addiction are those that are key to recovery.
Thank you for the opportunity to comment on the strategic plan that has been developed. Vermont staff from the Division of Alcohol and Drug Abuse Programs reviewed the plan and summarized feedback to you in the following paragraphs.Resilience There should be a more expansive exploration of resilience that builds upon and goes beyond existing “neuroscience” or brain circuitry explorations. We suggest including factors such as personality and temperament, parenting and/or education, social supports, cultural and anthropological notions of risk and recovery, contributing cultural and/or racial/ethnic factors, that may result in variations in resilience. These elements would be useful to enhance our knowledge of more effective preventive interventions. Systems ModelsWe support further research to identify some of latest and best advances in chronic disease management and financing, and how the growing emphasis on patient directed care and behavior shape our strategies and systems of care for addressing substance abuse issues. Furthermore, we support research that tests the application of other scientific models and methodologies, and specifically systems models, to look more holistically at this important public health challenge, e.g., operational research, microeconomics, game theory, medical anthropology, social network and market research. We see value both in understanding dynamics having impact upon an individual’s ability to get help, and those dynamics having impact upon effectiveness in delivering services and/or reducing the problem overall.

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

Thank you for your invitation regarding input in the NIDA research priority. I have read the list of 2015-2020 NIDA priorities in NOT-DA-15-005. All listed research priorities are very critical and of great interest. I would add 3 additional topics.1. Correlation of genomic polymorphism or variations with vulnerability to drug abuse in the population.2. Development of vaccine to prevent drug abuse that can be used in the high-risk (genetically or socially) sub-population.3. Integration of social networking behavioral pattern and communication and internet strategy for drug prevention education (like targeted and personalized marketing, high-risk individuals (identified via analyzing social networking behavior and movement data can be targeted with drug abuse prevention educational ads or text messages).
General Terrific (and ambitious) plan Consider including feeding behavior/overeating and the interactions with addictive behaviors, given the overlap in circuitry and compulsive features. The continued emphasis on basic science, including genetics, epigenetics and biomarkers, is very important. The emphasis on the integration of evidence-based research findings into healthcare policy and practice is also excellent. Additional areas that received less emphasis but which continue to be important include: -Improve understanding of the common mechanisms and trajectories underlying addictive disorders and complex health behaviors associated with addiction, including sleep problems and obesity. For example, such research could inform whether a sequential approach to treatment is more or less efficacious than changing multiple behaviors simultaneously.-Under clinical and translational science, it appears that “focused development efforts” do not include addictions for which FDA approved treatments ARE available (e.g., nicotine dependence, opioid dependence). While approved treatments may be available, there is substantial room for improvement in outcomes and development of new treatments. Perhaps this is not meant to imply that development efforts in these areas are not a priority; however, as written it implies that only addictions without FDA approved treatments will be a priority. - Integration and application of evidence to promote changes in local and federal regulation relevant to addiction. We are reaching a threshold of having sufficient data, for example, on particular tobacco products and messaging, that can and should applied to inform regulatory efforts. -Determine not only the risks, but also the potential therapeutic benefits, of changes in medical marijuana access and use. The current portfolio focuses exclusively on the risks. However to facilitate evidence-based regulation, a risk and benefit analysis would be important.-Identify efficacious methods for increasing the broad utilization of evidence based treatment in underserved populations, such as those of lower SES and those with comorbid medical or psychiatric conditions. While the current plan highlights implementation science to influence integration of findings into healthcare practice, this does not ensure that the most vulnerable individuals will avail themselves to utilize these services.
Thank you for the opportunity to provide comments on your draft 2016-2020 Strategic Plan. As someone who has spent the past 15 years working on hepatitis C and/or overdose prevention among injection drug users and in the criminal-justice involved population in public health settings, I applaud your efforts to achieve the following objectives:Basic NeuroscienceBetter define 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 patientsImprove our understanding of the interaction between addiction and co-occurring conditions Elucidate the impact of mental health, HIV, HCV, pain, etc. on addiction; Accelerate medications development for SUDsClinical and translational scienceFocused development efforts on: Overdose prevention or reversalAccelerating neurobiological recoveryAddressing comorbidities (MH, HIV, HCV, pain)Identify measures other than abstinence that can reliably assess SUD treatment outcomes Identify biomarkers of addiction, resilience, and recovery to enable personalized treatmentThis last point is critical because a fixation on abstinence as the sole goal of drug treatment is serving as a major barrier to people with addiction and/or hepatitis C accessing housing, shelter, and life-saving hepatitis C treatment due to policy requiring abstinence even when this is not a desired or even necessarily realistic goal for many individuals. Part of the problem has been that “harm reduction” as a term is anathema to policymakers, yet no alternative framework seems to have been accepted into common usage. Public HealthImprove 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.)Unifying ThemesUnifying 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 addictionAddressing health disparities among underrepresented populationsUnderstanding the role of development across the life spanAddressing the treatment needs of adolescents and pregnant and post-partum womenAddressing the treatment and prevention needs related to common co-morbidities including HIV/AIDSIn collaboration with CDC and HRSA, it is critical that NIDA help establish / bolster the evidence base demonstrating the ability of persons who use drugs to adhere to medications for infectious diseases such as HIV, tuberculosis, and hepatitis C. While it would seem that some of this research does exist, many states have nonetheless implemented policies limiting access to life-saving hepatitis C treatment to those who cannot prove they have been abstinent from all illicit drugs for at least six months, despite the lack of evidence for such policies. In collaboration with CDC, it is also critical that NIDA help establish models for using multidisciplinary programs to prevent hepatitis C among young injectors, through a combination of medication assisted treatment, syringe access, antiviral treatment, and education. In collaboration with CDC (and perhaps the Bureau of Prisons), it would be great if NIDA could support a proof of concept to treat a finite group of persons with HCV, such as in a prison setting, to interrupt secondary transmission at the population level
RESPONSE TO NIDA REQUEST FOR INFORMATION-NIDA Strategic Directions SOCIETY FOR PREVENTION RESEARCH General ObservationsEach year, over six million young people receive treatment for mental, emotional, or behavioral problems. The financial costs for treatment services and lost productivity attributed to the related behavioral health problems of depression, conduct disorder, and substance abuse are estimated at $247 billion per year (O'Connell ME, Boat T, Warner, 2009; Woolf). These costs are for a system that only reaches a small portion of those in need of treatment. While treatment of existing problems remains a critical service and focus of behavioral health care, over 40 years of research shows that we can prevent substance abuse and behavioral health problems from developing in the first place (Catalano, Fagan, Gavin, Greenberg, Irwin, Ross, Shek, 2012). We must increase that focus to have substantial impact on rates of disorder and related harm. The Institute of Medicine report on prevention (O’Connell et al., 2009) documents numerous controlled trials of interventions across development that have shown prevention of substance abuse and related problems is possible. Many of these interventions exhibit effects long after intervention exposure. Most provide a significant return on investment in terms of reduced personal and societal costs (Biglan, 2015). Further, young people exposed to the highest levels of risk factors, including disproportionately low-income and/or youth of color, frequently benefit most from preventive interventions.(Hill, Bailey, Hawkins et al., 2014; Campbell, Ramey, Pungello, Sparling, Miller-Johnson, 2002; Clark, Cornelius, Kirisci, Tarter, 2005; Conduct Problems Prevention Research Group, 2014) Prevention of drug abuse, alcohol misuse and other addictions differs from most other diseases and disorders in that initiation of substance use is a socially-determined behavior. Drug use, abuse and addiction develop in a complex context of diverse psychological and behavioral precursors. Research shows that modifying one or more risk or protective factors for these problems often has additional benefits in preventing other problems such as mental health problems, aggression, and academic failure. Thus, preventive interventions can be highly efficient in addressing multiple social problems and their associated costs.NIDA funding has been essential in building the prevention science that has led these accomplishments, creating a diverse portfolio that includes basic research, methodology, efficacy trials, effectiveness research, systems research, and services research. The report on prevention from the Institute of Medicine (O’Connel, et al., 2009) highlights the contribution that NIDA has made to the progress of prevention research. Their conclusion is clear: the most effective way to halt the manifestation of substance use and allied behavioral health disorders is through prevention. Despite this, prevention intervention research remains a small portion of the NIDA portfolio, only 8% in 2012. A continued focus on and increased funding for prevention studies are imperative to improve population health. Prevention needs to play a more prominent role in the proposed 2015 NIDA strategic plan. Despite this accumulation of core prevention research, there remains much to be learned to further improve the prevention knowledge base. I suggest three broad prevention priorities be incorporated into the NIDA 2015 strategic plan: 1) prevention- related basic research to discover and specify the mechanisms of action of biopsychosocial risk and protective factors and their interaction across development; 2) prevention intervention research to develop and test new interventions that extend existing efficacy research, test emerging findings about biopsychosocial risk, specify how intervention effects are realized and for whom effects apply, and understand the salutary effects of substance abuse prevention on related problems ; and 3) research to understand how best to “scale up” (adoption, implementation, and sustainability) effective prevention intervention with reach and fidelity to achieve population-wide reductions in substance use, abuse and addiction, with related economic and health gains to individuals, families, communities, and state and federal governments. Specific suggestions are made below and denoted by a vertical line in the left margin.Basic Research: The current Strategic Priorities recognize the importance of biological science to understanding substance use, abuse and addiction. However, the priorities underemphasize the critical role of social and behavioral science in understanding and addressing these problems. I suggest that a revision is made to include both Neuroscience and Social and Behavioral research in their own subsections of Basic Research.Neuroscience: Improve our understanding of the basic science of drug use, addiction, vulnerability to addiction, and recovery Increase our knowledge of biological , behavioral, environmental, and developmental factors involved in risk and resilience for drug use and addictionIntegrating animal models, behavior, genetics, epigenetics, and other molecular biomarkers for drug abuse and addictionUnderstand the developmental trajectory of substance use, abuse, and addiction and individual heterogeneityImprove our understanding of brain circuits related to drug use, abuse and addiction at the cellular, circuit, and connectome levels, including:Normal development and function across the lifespan including mechanisms of reward, self-control, and conditioningDrug effects on neuroplasticity, neural structure, and circuit function across the stages of addictionNeurobiological correlates of recoveryNeural-glial, -immune, and neuroendocrine interactionsBetter define the interactions between substance use, abuse, and addiction and pain, including molecular, genetic, behavioral , and neural-circuit-related factors, to guide the development of alternate treatment strategies for pain patientsImprove our understanding of the interaction between substance use, abuse, and addiction and co-occurring conditions Elucidate the impact of mental health, HIV, HCV, pain, etc. on addiction; Understand molecular mechanisms of latent HIV reservoirs in the brains of substance-abusing populationsBiological processes related to substance use, abuse and addiction risk and resilience and reactivity to preventive interventionsSocial and Behavioral Research: Research suggests that despite biological predispositions, the decision to use drugs is environmentally triggered, and that socio-cultural environments (e.g., policy, peers, family, communities) play pivotal roles in the initiation, maintenance, and desistence from drug use, abuse, and dependence. Understanding the developmental and environmental influences on biological mechanisms will increase the likelihood that biological research will strengthen efforts at prevention and treatment to improve the public health.Increase our knowledge of social, environmental and developmental predictors of substance use, abuse and addiction.Increase our knowledge of interactions between biological mechanisms and social, environment and developmentally salient predictors of later substance use, abuse, and addiction.Increase understanding of neurobiological changes in response to prevention interventions and messages.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.Increase understanding of interaction effects of stress and contextual factors on drug abuse risk.Expand research on the relationships between drug use, abuse, and addiction on communicable and non-communicable diseases.Clinical and Translational Science: Support the development of new and better preventive interventions and treatments. that incorporate the diverse needs of individuals at risk for the development of and those with Substance Use Disorders (SUDs) Treatment research is important but reducing the number of those who contract the disorder is also critical. In addition, treatment and prevention have some distinct operational, population assumptions, and likely mechanisms of effects that merit separate but substantial attention (Weisz, Sandler, Durlak, & Anton, 2005). I suggest separate sections on Treatment and Prevention Research.Treatment Research: Support the development of novel, evidence-based, treatment interventions including social, behavioral, cognitive, pharmacological, vaccines, and brain stimulation therapies (e.g., transcranial magnetic stimulation, direct current stimulation, etc.)Accelerate the identification of promising targets and ligands to accelerate new drug discovery and development Accelerate medications development for SUDsFocused development efforts on: Addictions without an FDA approved treatmentDetoxificationOverdose prevention or reversalAccelerating neurobiological recoveryAddressing comorbidities (MH, HIV, HCV, pain)Develop techniques to measure and improve patient compliance in clinical trialsIdentify measures other than abstinence that can reliably assess SUD treatment outcomes Identify biomarkers of addiction, resilience, and recovery to enable personalized treatmentUsing pooled data from previous evidence-based treatment trials, identify mechanisms and moderators of intervention efficacyPrevention Research Integrate discoveries from the basic biological (e.g. neurobiological), psychological (e.g. emotional, behavioral, cognitive, and developmental) and social (e.g. social learning, peer network, and communications, laws and norms) sciences to develop and test innovative preventive interventions that specifically target underlying mechanisms in drug abuse risk.Research what are critical windows during childhood to adulthood that may produce the greatest effects for specific types of preventive interventions. Increase the translation of knowledge about basic biological, genetic, and neurobiological mechanisms underlying drug use and abuse to serve as indicators of change in preventive intervention research, and/or to help determine the intervention course (psychosocial, psychopharmacological) that is most likely to be effective for an individual given underlying biological mechanisms of action.Increase research to fill critical gaps in understanding the impact of preventive intervention on vulnerable populations including low income, people of color, youth in the child welfare system.Increase research to determine the impact of preventive interventions utilizing new and emerging electronic communication technologies. In addition to efficacy of utilizing these technologies for delivery of preventive interventions, the reach (who accesses), and the usefulness of these modes of delivery for generalization and maintenance of intervention impact is needed.Increase research to identify malleable mediators and moderators of preventive intervention effects to better understand which interventions work best for whom and why, and what preventive components predict intervention effects to understand how to improve prevention effects for all.Increase research to understand what malleable underlying person or environmental conditions interfere with or promote intervention effects.Increase research to examine the impact of preventive interventions on the neural substrate level. An understanding of how an effective intervention can alter brain development and function is critical for the field.Increase research to replicate effective prevention interventions in new populations and under different conditions to understand what contributes to whether the intervention continues to be effective or is less effective. Further, research is needed on the impact of fidelity, quality, and adaptation on the effectiveness of replications.Increase research on the combination of behavioral and biomedical preventive intervention.Increase research to incorporate understanding of individual differences in response to different types of persuasion and different types of drugs in preventive intervention development. This includes further culturally-sensitive and responsive research for understanding the needs of vulnerable and high risk populations. Increase research on embedding efficacious or new prevention interventions in health care organizations to examine the impact on health costs and a range of substance related outcomes at population level. Public Health: Increase the public health impact of NIDA research and programs: 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.Improve the understanding of factors that influence the integration of evidence-based basic science, prevention and treatment research findings into healthcare policy and practice (implementation science)Increase the understanding of how organizational, leadership, and fiscal factors influence the adoption and sustainment of evidence-based practices to prevent and treat substance use and abuse in key public service sectors (mental health, health, justice, child welfare)Improve the understanding of factors that influence the integration and sustainability of evidence-based basic research, prevention and treatment research findings into state and local public health, behavioral health, education, and child welfare, and maternal health.Increase dissemination research efforts of evidence based prevention programs and policies to determine what works best, for whom and why so that programs and policies can be further refined to achieve optimal results to improve the public healthIncrease research to understand the needed elements of infrastructure development to ensure the capacity and necessary supports for large scale adoption, implementation and sustainability of evidence based preventive and treatment interventions.Increase research on training health care and other providers in prevention knowledge and practices. 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.Increase readiness to respond to emerging public health priorities (opioid overdose epidemic, potential consequences of marijuana legalization, new populations (elderly), changing healthcare landscape, emerging drug trends, etc.)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 Strengthen focus on bi-directional translational researchScience Infrastructure: Enhance the national research infrastructure to support advancements in scienceAccelerate the development and utilization of advanced technologies (e.g. the President’s BRAIN Initiative), data repositories (e.g. Big Data to Knowledge (BD2K) initiative, new technology for intervention delivery, and statistical models to spur innovative research 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.Improve training for the next generation of scientistsIncrease effective engagement and training in multidisciplinary research (informatics, engineering, computer science, chemistry, mathematics, physics, etc.)Increase the number of well-trained underrepresented scientists in the drug abuse and addiction field at all career levelsImprove mentoring of young scientistsIncrease effective collaborations in researchIncrease the transparency of researchIncrease effective data and resource sharing (big data, biorepositories, transgenic/optogenetic tools, data standards, etc.)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. Create opportunities for multiple federal agencies to collaborate in funding translational drug abuse prevention and treatment research; e.g., SAMSHA, ONDCP, OJJDP, CYF, MCH, etc.Increase opportunities for combining data from previous prevention and treatment trials and use innovative methods to integrate and analyze these data.Identify and implement strategies to improve the reproducibility of pre-clinical researchEnable efficiency and lower the cost of clinical trials via innovative statistical models, data standards, leveraging technology (e.g. electronic health records) and partnerships, etc.Develop and validate computational and systems-level analytics for integrating multi-dimensional data across the addiction trajectoryUnifying 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 addictionUnderstanding the interrelation between preventive and treatment interventions affecting substance abuse and impact on other aspects of physical and mental health, social functioning, and productivityAddressing health disparities among underrepresented populationsUnderstanding the role of development across the life spanAddressing the treatment needs of adolescents and pregnant and post-partum womenAddressing the treatment and prevention needs related to common co-morbidities including HIV/AIDSAddressing the prevention needs of youth and high-risk populations.Understanding the implications of the changing drug policy environment (i.e., marijuana legalization at the state level)Understanding the developmental and contextual influences across all areas of research ReferencesBiglan, A (2015) The Nurture Effect: The Evolution of Behavioral Science, Psychology Today, 1/5/15. Campbell FA, Ramey CT, Pungello E, Sparling J, Miller-Johnson S. (2002) Early childhood education: Young adult outcomes from the Abecedarian Project. Appl Dev Sci, 6(1):42-57.Catalano, R. F., Fagan, A. A., Gavin, L. E., Greenberg, M. T., Irwin, C. E., Ross, D. A., & Shek, D. T. L. (2012). Worldwide application of the prevention science research base in adolescent health. Lancet, 379, 1653-1664.Clark DB, Cornelius JR, Kirisci L, Tarter RE. (2005) Childhood risk categories for adolescent substance involvement: A general liability typology. Drug Alcohol Depend. 77(1):13-21.Conduct Problems Prevention Research Group. (2014). Impact of early intervention on psychopathology, crime, and well-being at age 25. Am J Psychiatry..Hale DR, Fitzgerald-Yau N, Mark Viner R. (2014) A systematic review of effective interventions for reducing multiple health risk behaviors in adolescence. Am J Public Health.104(5).Hawkins JD. (2006) Science, social work, prevention: Finding the intersections. Soc Work Res. 30(3):137-152.Hill KG, Bailey JA, Hawkins JD, et al. (2014) The onset of STI diagnosis through Age 30: Results from the Seattle Social Development Project intervention. Prev Sci.;15 (Suppl 1):S19-S32.O'Connell ME, Boat T, Warner KE, editors. (2009) Preventing mental, emotional, and behavioral disorders among young people: Progress and possibilities. Washington, DC: National Academies Press.Sloboda, Z. (2012) Substance Use & Misuse, 47:1557–1568, 2012.Western B, Pettit B. (2010) Incarceration & social inequality. Daedalus. 139(3):8-19,146-147.Woolf SH. (2008) The power of prevention and what it requires. JAMA. 299(20):2437-2439.
If concerns over the rising costs of health care persist and remain important for most Americans, then support and investment for evidence-based prevention interventions is both warranted and indispensable. Unfortunately, and too often, American society’s response to major problems has been mostly reactive. Such responses have evolved out of understandable efforts to deal with problems once they have emerged. We have devised a treatment system for most of the common and costly substance use and allied psychological and behavioral disorders once these problems have developed. Some of these policies have actually increased social inequity (Western & Petit, 2010). Each year, over six million young people receive treatment for mental, emotional, or behavioral problems. The financial costs for treatment services and lost productivity attributed to the related behavioral health problems of depression, conduct disorder, and substance abuse are estimated at $247 billion per year (O'Connell ME, Boat T, Warner, 2009; Woolf). These costs are for a system that only reaches a small portion of those in need of treatment. While treatment of existing problems remains a critical service and focus of behavioral health care, there is widespread recognition and empirical evidence from over 40 years of research that we can prevent substance abuse and behavioral health problems from developing in the first place (Catalano, Fagan, Gavin, Greenberg, Irwin, Ross, Shek, 2012. We must increase that focus to have substantial impact on rates of disorder and related harm. Major advances in reducing the incidence and prevalence of addiction and behavioral health problems become possible with the continued development of prevention science and the opportunities for more integration of prevention into health care through the Affordable Care Act. The Institute of Medicine report on prevention (O’Connell et al., 2009) documents numerous controlled trials of interventions across development that have shown prevention of substance abuse and related problems is possible. Many of these interventions exhibit effects long after intervention exposure. And, most provide a significant return on investment in terms of reduced personal and societal costs. (Biglan, 2015).NIDA funding has been essential in building the prevention science that has led these accomplishments, creating a diverse portfolio that encompasses basic research, methodology, efficacy trials, effectiveness research, systems research, and services research. The report on prevention from the Institute of Medicine (O’Connell, et al., 2009) highlights the contribution that NIDA has made to the progress of prevention research. Their conclusion is clear: the most effective way to halt the manifestation of substance use and allied behavioral health disorders is through prevention. We think that the emphasis on prevention in the NIDA 2010 strategic plan reflects acknowledgement of this viewpoint, that prevention be a major emphasis. Despite this, prevention intervention research remains a small portion of the NIDA portfolio, 8% in 2012, which is less than half the proportion allotted to treatment intervention research (17%). This is a decrease of 20% of the NIDA prevention portfolio from 2011 to 2012 (Sloboda, 2012; 1564). We think that increasing, not decreasing, the percentage devoted to prevention studies is imperative to continue the quality and quantity of research to fulfill this goal in the strategic plan and for continued progress in population health. Prevention needs to play a more prominent role in the proposed 2016-2020 NIDA strategic plan.We also think increased funding is justified to support the multi-focused portfolio that has spurred the important advances in the past two decades by providing ongoing and efficient feedback from epidemiology to basic descriptive studies to intervention designs and test of efficacy, effectiveness, and readiness for to-scale implementation. This funding has contributed more robust and rapidly innovating evidence base for basic research, substance abuse prevention, as well as treatment research. Research results examining bio-behavioral- developmental interactions have underscored the importance of the inter-relation between these mechanisms and the environment. Prevention of drug abuse, alcohol misuse and other addictions differs from most other diseases and disorders in that, at the initiation stage, substance use is well-characterized as a socially-determined behavior; there is a choice to use a particular substance. The notion of choice is complex and influences and information vary by life stage. The combined portfolio approach has produced research that demonstrates that drug use, abuse and addiction develops in a complex context of diverse psychological and behavioral precursors; thus, guiding prevention that modifies one or more risk or protective factors for these problems and also showing that such prevention often has additional benefits in preventing other problems such as mental health problems, aggression, and school achievement.Prevention research has also revealed that such efforts may have biggest effects where risk is greatest and opportunity or protection scarcer. Young people exposed to the highest levels of risk factors, including disproportionately low-income and/or youth of color, frequently benefit most from preventive interventions (Hill, Bailey, Hawkins et al., 2014; Campbell, Ramey, Pungello, Sparling, Miller-Johnson, 2002; Clark, Cornelius, Kirisci, Tarter, 2005; Conduct Problems Prevention Research Group, 2014).Despite this accumulation of core prevention research, there remains much to be learned to further improve the prevention knowledge base. Below, within in the basic bullet points of the Request For Information on NIDA’s strategic plan, we have added important and poorly understood aspects of prevention that require additional rigorous research. Structurally, we strongly suggest the augmentation of the Basic Research area to include both biological and social environmental research and the augmentation of the clinical and translational research to include a prevention section in addition to the treatment section. We detail what we think are the strategic areas for research in these new sections and provide comments (in red) on the existing document.In general, we suggest three broad prevention priorities incorporated into the NIDA 2016-2020 strategic plan: 1) prevention-informed and related basic research to discover and specify the mechanisms of biopsychosocial risks and protective factors and their interaction across development; 2) prevention intervention research to develop and test new interventions that extend the comprehensiveness of existing efficacy research, test emerging findings about biopsychosocial risk, specify how intervention effects are realized and for whom effects apply, and understand the salutary effects of substance abuse prevention on related problems; and 3) research to understand how best to “scale up” (adoption, implementation, and sustainability) effective prevention intervention with reach and fidelity to achieve population-wide reductions in substance use, abuse and addiction, with related economic and health gains to individuals, families, communities, and state and federal government. This includes development and testing of efficient and effective modes of intervention delivery, as well as understanding how to integrate these effective preventive interventions into routine service delivery systems from health care and education to child welfare and mental health services. In addition, research tounderstand the role of substance use, abuse and addiction prevention as part of the Affordable Care Act and in regulatory efforts to affect substance use and other related problems is needed. Basic Research: The current Strategic Priorities recognize the importance of biological science to understanding substance use, abuse and addiction. However, the priorities underemphasize the critical role of social and behavioral science in understanding and addressing these problems. We suggest that a revision is made to include both Neuroscience and Social and Behavioral research in their own subsections of Basic Research.Neuroscience: Improve our understanding of the basic science of drug use, addiction, vulnerability to addiction, and recovery (SPR’s edits to NIDA’s draft strategic plan are highlighted in red.)Increase our knowledge of biological , behavioral, environmental, and developmental factors involved in risk and resilience for drug use and addiction. Integrating animal models, behavior, genetics, epigenetics, and other molecular biomarkers for drug abuse and addiction. Understand the developmental trajectory of substance use, abuse, and addiction and individual heterogeneity. Improve our understanding of brain circuits related to drug use, abuse and addiction at the cellular, circuit, and connectome levels, including: Normal development and function across the lifespan including mechanisms of reward, self-control, and conditioning. Drug effects on neuroplasticity, neural structure, and circuit function across the stages of addiction. Neurobiological correlates of recovery - Neural-glial, -immune, and neuroendocrine interactionsBetter define the interactions between substance use, abuse, and addiction and pain, including molecular, genetic, behavioral , and neural-circuit-related factors, to guide the development of alternate treatment strategies for pain patientsImprove our understanding of the interaction between substance use, abuse, and addiction and co-occurring conditions. Elucidate the impact of mental health, HIV, HCV, pain, etc. on addiction; Understand molecular mechanisms of latent HIV reservoirs in the brains of substance- abusing populations. Biological processes related to substance use, abuse and addiction risk and resilience and reactivity to preventive interventions. Social and Behavioral Research: Research suggests that despite biological predispositions, the decision to use drugs is environmentally triggered, and that socio-cultural environments (e.g., policy, peers, family, communities) play pivotal roles in the initiation, maintenance, and desistence from drug use, abuse, and dependence. Further, evidence has demonstrated that the impact of preventive interventions on biological processes or predispositions is also important to study. We expect that there is an interplay of environmental and biological influences in the development of addiction. Understanding the relative contribution and mechanisms of change are critical to understanding the development of substance use, abuse, and addiction. Understanding the developmental and environmental influences on biological mechanisms will increase the likelihood that biological research will strengthen efforts at prevention and treatment to improve the public health.Increase our knowledge of social, environmental and developmental predictors of substance use, abuse and addiction. Increase our knowledge of interactions between biological mechanisms and social, environment and developmentally salient predictors of later substance use, abuse, and addiction. Increase understanding of neurobiological changes in response to prevention interventions and messages.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.Increase understanding of interaction effects of stress and contextual factors on drug abuse risk.Expand research on the relationships between drug use, abuse, and addiction on communicable and non-communicable diseases. Clinical and Translational Science: Support the development of new and better preventive interventions and treatments. that incorporate the diverse needs of individuals at risk for the development of and those with Substance Use Disorders (SUDs) Treatment research is important but reducing the number of those who contract the disorder is also critical. In addition, treatment and prevention have some distinct operational, population assumptions, and likely mechanisms of effects that merit separate but substantial attention (Weisz, Sandler, Durlak, & Anton, 2005). We suggest separate sections on Treatment and Prevention Research.Treatment Research: Support the development of novel, evidence-based, treatment interventions including social, behavioral, cognitive, pharmacological, vaccines, and brain stimulation therapies (e.g., transcranial magnetic stimulation, direct current stimulation, etc.). Accelerate the identification of promising targets and ligands to accelerate new drug discovery and development. Accelerate medications development for SUDs. Focused development efforts on: Addictions without an FDA approved treatment. Detoxification Overdose prevention or reversal. Accelerating neurobiological recovery. Addressing comorbidities (MH, HIV, HCV, pain). Develop techniques to measure and improve patient compliance in clinical trials. Identify measures other than abstinence that can reliably assess SUD treatment outcomes Identify biomarkers of addiction, resilience, and recovery to enable personalized treatment. Using pooled data from previous evidence-based treatment trials, identify mechanisms and moderators of intervention efficacy. Prevention ResearchIntegrate discoveries from the basic biological (e.g. neurobiological), psychological (e.g. emotional, behavioral, cognitive, and developmental) and social (e.g. social learning, peer network, and communications, laws and norms) sciences to develop and test innovative preventive interventions that specifically target underlying mechanisms in drug abuse risk. Research what are critical windows during childhood to adulthood that may produce the greatest effects for specific types of preventive interventions.Increase the translation of knowledge about basic biological, genetic, and neurobiological mechanisms underlying drug use and abuse to serve as indicators of change in preventive intervention research, and/or to help determine the intervention course (psychosocial, psychopharmacological) that is most likely to be effective for an individual given underlying biological mechanisms of action. Increase research to fill critical gaps in understanding the impact of preventive intervention on vulnerable populations including low income, people of color, youth in the child welfare system.Increase research to determine the impact of preventive interventions utilizing new and emerging electronic communication technologies. In addition to efficacy of utilizing these technologies for delivery of preventive interventions, the reach (who accesses), and the usefulness of these modes of delivery for generalization and maintenance of intervention impact is needed. Increase research to identify malleable mediators and moderators of preventive intervention effects to better understand which interventions work best for whom and why, and what preventive components predict intervention effects to understand how to improve prevention effects for all.Increase research to understand what malleable underlying person or environmental conditions interfere with or promote intervention effects.Increase research to examine the impact of preventive interventions on the neural substrate level. An understanding of how an effective intervention can alter brain development and function is critical for the field.Increase research to replicate effective prevention interventions in new populations and under different conditions to understand what contributes to whether the intervention continues to be effective or is less effective. Further, research is needed on the impact of fidelity, quality, and adaptation on the effectiveness of replications.Increase research on the combination of behavioral and biomedical preventive intervention.Increase research to incorporate understanding of individual differences in response to different types of persuasion and different types of drugs in preventive intervention development. This includes further culturally-sensitive and responsive research for understanding the needs of vulnerable and high risk populations. Increase research on embedding efficacious or new prevention interventions in health care organizations to examine the impact on health costs and a range of substance related outcomes at population level.Public Health: Increase the public health impact of NIDA research and programs: 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.Improve the understanding of factors that influence the integration of evidence-based basic science, prevention and treatment research findings into healthcare policy and practice (implementation science)Increase the understanding of how organizational, leadership, and fiscal factors influence the adoption and sustainment of evidence-based practices to prevent and treat substance use and abuse in key public service sectors (mental health, health, justice, child welfare)Improve the understanding of factors that influence the integration and sustainability of evidence-based basic research, prevention and treatment research findings into state and local public health, behavioral health, education, and child welfare, and maternal health. Increase dissemination research efforts of evidence based prevention programs and policies to determine what works best, for whom and why so that programs and policies can be further refined to achieve optimal results to improve the public healthIncrease research to understand the needed elements of infrastructure development to ensure the capacity and necessary supports for large scale adoption, implementation and sustainability of evidence based preventive and treatment interventions.Increase research on training health care and other providers in prevention knowledge and practices.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.Increase readiness to respond to emerging public health priorities (opioid overdose epidemic, potential consequences of marijuana legalization, new populations (elderly), changing healthcare landscape, emerging drug trends, etc.) 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 practiceStrengthen focus on bi-directional translational researchScience Infrastructure: Enhance the national research infrastructure to support advancements in scienceAccelerate the development and utilization of advanced technologies (e.g. the President’s BRAIN Initiative), data repositories (e.g. Big Data to Knowledge (BD2K) initiative, new technology for intervention delivery, and statistical models to spur innovative researchDevelop 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.Improve training for the next generation of scientists. Increase effective engagement and training in multidisciplinary research (informatics, engineering, computer science, chemistry, mathematics, physics, etc.)Increase the number of well-trained underrepresented scientists in the drug abuse and addiction field at all career levels. Improve mentoring of young scientistsIncrease effective collaborations in researchIncrease the transparency of research Increase effective data and resource sharing (big data, biorepositories, transgenic/optogenetic tools, data standards, etc.)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.Create opportunities for multiple federal agencies to collaborate in funding translational drug abuse prevention and treatment research; e.g., SAMSHA, ONDCP, OJJDP, CYF, MCH, etc.Increase opportunities for combining data from previous prevention and treatment trials and use innovative methods to integrate and analyze these data.Identify and implement strategies to improve the reproducibility of pre-clinical researchEnable efficiency and lower the cost of clinical trials via innovative statistical models, data standards, leveraging technology (e.g. electronic health records) and partnerships, etc.Develop and validate computational and systems-level analytics for integrating multi- dimensional data across the addiction trajectory. 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. Understanding the interrelation between preventive and treatment interventions affecting substance abuse and impact on other aspects of physical and mental health, social functioning, and productivity. 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 womenAddressing the treatment and prevention needs related to common co-morbidities including HIV/AIDSAddressing the prevention needs of youth and high-risk populations.Understanding the implications of the changing drug policy environment (i.e., marijuana legalization at the state level)Understanding the developmental and contextual influences across all areas of research ReferencesBiglan, A (2015) The Nurture Effect: The Evolution of Behavioral Science, Psychology Today, 1/5/15.Campbell FA, Ramey CT, Pungello E, Sparling J, Miller-Johnson S. (2002) Early childhood education: Young adult outcomes from the Abecedarian Project. Appl Dev Sci, 6(1):42-57. Catalano, R. F., Fagan, A. A., Gavin, L. E., Greenberg, M. T., Irwin, C. E., Ross, D. A., & Shek,D. T. L. (2012). Worldwide application of the prevention science research base in adolescent health. Lancet, 379, 1653-1664.Clark DB, Cornelius JR, Kirisci L, Tarter RE. (2005) Childhood risk categories for adolescentsubstance involvement: A general liability typology. Drug Alcohol Depend. 77(1):13-21. Conduct Problems Prevention Research Group. (2014). Impact of early intervention on psychopathology, crime, and well-being at age 25. Am J Psychiatry..Hale DR, Fitzgerald-Yau N, Mark Viner R. (2014) A systematic review of effective interventions for reducing multiple health risk behaviors in adolescence. Am J Public Health.104(5).Hawkins JD. (2006) Science, social work, prevention: Finding the intersections. Soc Work Res. 30(3):137-152.Hill KG, Bailey JA, Hawkins JD, et al. (2014) The onset of STI diagnosis through Age 30: Results from the Seattle Social Development Project intervention. Prev Sci.;15 (Suppl 1):S19-S32.O'Connell ME, Boat T, Warner KE, editors. (2009) Preventing mental, emotional, and behavioral disorders among young people: Progress and possibilities. Washington, DC: National Academies Press.Sloboda, Z. (2012) Substance Use & Misuse, 47:1557–1568, 2012.Western B, Pettit B. (2010) Incarceration & social inequality. Daedalus. 139(3):8-19,146-147. Woolf SH. (2008) The power of prevention and what it requires. JAMA 299(20):2437-2439
Faces & Voices of Recovery is pleased to provide input on the 2016- 2020 draft strategic priorities as well as general recommendations that will sustain recent advances and accelerate discovery in addiction recovery research over the next five years. The following response reflects the views of the organization and membership as a whole.Suggested changes or additions to the list of strategic priorities, including emerging research needs and future opportunities that should be considered in the planChanges (underlined)Basic Neuroscience: Improve our understanding of the basic science of drug use, addiction, vulnerability to addiction, and the recovery process and increase our knowledge of biological, behavioral, environmental, and developmental factors involved in risk, resilience and recovery for drug use and addiction.Neurobiological correlates of recovery: Focus on the neuroplasticity properties with treatment and recovery supports that facilitate neural responses in recovery. How do environmental supports for resiliency enhance neural development in recovery?Improve our understanding of the interaction between addiction and co-occurring conditions and its impact on the recovery process. (With the shame and stigma associated with both addiction and mental health, is there a way to assess the differences in public perception, and the effect of addiction being seen more as a “choice”? Also what are the environmental andcultural differences leading to relapse, such as the right to refuse medication, over-prescribing of narcotics, beer sales, etc.)Support the development of novel, evidence-based, targeted prevention, treatment and recovery support interventions including social, behavioral, pharmacological, vaccines, and brain stimulation therapies (e.g., transcranial magnetic stimulation, direct current stimulation, etc.)Improve training for the next generation of scientists – including training on the Science of Addiction and Recovery (SOAR).Promoting research that considers the impact of sex and gender on drug abuse, addiction and the recovery process.Addressing the treatment, prevention and recovery needs related to common co-morbidities including HIV/AIDS.Identify measures other than abstinence that can reliably assess SUD treatment and recovery support services outcomes Identify biomarkers of addiction, resilience, and recovery to enable personalized treatment.AdditionsAddressing the needs of people seeking recovery in areas bereft of recovery supports (ie rural areas) such as the efficacy of online resources where there is no significant recovery community.Measure the presence, depth, and effect of stigma as a barrier to treatment and recovery, including perceived shame for relapse within the recovery community.The effect of marginalizing some types of treatment or pathways to recovery (specifically medication assisted treatment) within the recovery community.Additional research needs to be conducted to build the evidence base about the effectiveness of peer-delivered support and peer-delivered support services in both the mental health and addictions fields.More research is needed on matching individuals with the type of peer-delivered recovery support that best fits with their stage of recovery and their personal goals to improve our understanding of the most essential types of support at different stages of recovery. Factors such as age group, gender, self-identity, motivation to change, health and mental health status, and spirituality should be considered.Explore qualitatively how peer support and clinical care can complement each other.Examine people in recovery’s responses to peer support and how it influences recovery over time.Examine how integrating peer support workers contributes to aspects of the environmental context of a behavioral health program.Improve the rigor of research on the effectiveness of training programs for peer support workers, using control or comparison groups, and whenever possible randomized controlled trials.The scientific rationale for the changes or ideas proposed and the anticipated impact on advancing the science of drug abuse and addiction. Why Study Recovery? Recovery from substance use is a reality for millions of people worldwide. Addiction is a chronic disorder; addressing addiction and recovery requires that clinicians and researchers adopt a long-term approach.We know a great deal about addiction, but very little about recovery. Recovery is a lifelong process that may involve a succession of “stages” making changing demands on the individual. Most research on substance use adopts an ‘acute’ perspective to addiction, typically using short follow-up periods (e.g., 1 to 24 months).Therefore, most available data bear only on recovery initiation, a period that is short relative to the lifelong challenges of recovery.Little is known about temporal patterns of recovery over time or about predictors of long-term recovery (recovery consolidation and maintenance).Few studies provide data on outcomes beyond abstinence. Other outcomes of interest might include: housing and work status, quality of life, functioning, mental health status, and support networks.Anticipated challenges that will need to be addressed to achieve these prioritiesThe evidence base for peer-delivered recovery support services in behavioral health is growing and demonstrates that these services have a salutary effect and are an important component of the continuum of recovery support. To strengthen this evidence base, it is critical to take steps to improve the quality and methodological rigor of the research. We propose developing a national research agenda to better understand the nature, contributions, effectiveness, and cost-effectiveness of peer- delivered recovery support services.Appropriate benchmarks for gauging progress toward each recommended priorityFuture research must include greater detail and description of the peer role and peer qualifications.Future research needs to include more complete descriptions of peer-delivered services including recovery coaching, recovery community centers, telephone-based peer support; and how of the service/support elements being delivered (e.g., “one-to-one contacts to accompany peers to critical appointments,” “group sessions focused on stigma”). This includes more complete descriptions of the peers delivering services, including the demographic characteristics of the peer support specialists/recovery coaches, their educational backgrounds, stage of recovery, and information about their experience, training, and credentials in delivering peer- delivered services.ConclusionIt is a critical time in the development of novel, evidence-based peer-based recovery support interventions. The Affordable Care Act (ACA) has afforded the opportunity for many recovery community organizations to explore funding from public and private insurers to provide peer-based recovery support services in community-based, non-clinical setting. Enhancing the scientific understanding of recovery and supporting the development and testing of interventions and services to reduce relapse and promote recovery from addiction will expand these opportunities for RCO’s. The key to this success is having the research that demonstrates positive outcomes of these interventions to meet funding eligibility requirements. This is a critical time for the field to have the evidence-base for peer support in addictions. Faces & Voices of Recovery also supports prioritizing research on cost savings and cost-effectiveness of recovery support services.Thank you for the opportunity to provide feedback on NIDA’s 2016 – 2020 Draft Strategic Plan

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 Subcommittee. Dr. Diana Fishbein, Chair. The 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 Transdisciplinary Translational – 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 medicine derivatives (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 area of 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-related exposures 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-occurring conditions particularly relating to marijuana and e-cigarettes. NIDA Priority: 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 promising universal 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 are successful 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 coalition functioning. 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 regarding these 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 prevention interventions 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 assess strengths 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 of timely 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 is the 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, Format

General CommentsI recommend: (i) consolidation of NIDA’s priorities to a reduced number of themes (~3) and goals (<10); and (ii) re-writing the priorities to enable an investigator to clearly understand their direction and intent. This will enable investigators to understand NIDA’s priorities and research directions, and will provide some direction as to what the expected outcomes are. The NIDA strategic plan has a very large list of priorities that covers diverse topics. Many of the individual components were poorly defined, which made it difficult to identify the key areas of focus and the goals that NIDA wants to achieve. For example, the basic science priorities alone had 12 of topics across a diffuse set of objectives, which ranged from cellular and animal models to evaluating the impact of mental health on addiction. I do not know why “evaluating the impact of mental health and HIV/HCV infection on addiction,” which is an epidemiological undertaking, is a component of basic neuroscience. The priorities are listed under 5 different themes, which further compounds the problem of having so many priorities. The diffuse and unclear description of many of the priorities adds to the numerical problem. For example, “Integrating animal models, behavior, genetics, epigenetics, and other molecular biomarkers for drug abuse and addiction” is a priority. Does this mean that NIDA wants to better understand drug abuse and addiction through the integrated analysis of data obtained from various sources? If so, it is important to specify what we hope to learn. Similarly, I was unable to interpret what was desired from the priority “Neural-glial, -immune, and neuroendocrine interactions.” Two different priorities ((i) Increase our knowledge of biological, behavioral, environmental, and developmental factors involved in risk and resilience for drug use and addiction and (ii) Improve our understanding of the interaction between addiction and co-occurring conditions) are probably the same. It is very difficult to do contribute progress metrics for a priority that begins with “increase our knowledge of” or “improve our understanding of.” Specific CommentsI believe that NIDA should prioritize funding research that will uncover fundamental mechanisms of neurodevelopment, factors affecting drug addiction, and the characterization of the interaction between environmental and genetic factors affecting drug addiction. These are very difficult areas to study in human populations; it is difficult to obtain samples from relevant tissues, and there are multiple confounding variables that cannot be controlled in human populations. However, there is now a huge opportunity to obtain new knowledge in these areas from analysis of mouse genetic models, and this could generate new therapeutic approaches to address the growing health problem caused by drug addiction. To do this, the findings from the mouse models must be coupled with two other areas: (1) functional analysis of pathways and (2) human translational studies. New methods for analysis of mouse genetic models can now be used to identify the underlying genetic factors. However, analysis of these models requires a different approach than those that were developed in the 20th century, when studies analyzed a very limited amount of genetic limited diversity present in intercross or recombinant inbred strains. Moreover, they analyzed SNP markers, which did not encompass all of the information about the pattern of genetic variation in the mouse genome. In contrast, 21st century methods require analysis of many inbred strains, which enables the strains with outlier phenotypes to be identified (i.e. the strains that represent susceptible and resistant populations). In addition, the analyses should use full genomic sequence data; and the use of integrated datasets. Thus, I believe that NIDA should prioritize funding for the following 3 areas:The development of mouse genetic models of the behaviors/responses that are key to NIDA’s mission, which is identify the genetic underpinnings that lead to addictive behaviors. Of particular importance, the endophenotypes that contribute to addictive behavior can be modeled under conditions where the environmental variables can be controlled (and the effect of environmental factors can be analyzed). This includes funding the analysis of the models developed across a large panel of inbred strains, which will enable them to be successfully genetically analyzed. To do this, teams of investigators should be formed, which will include those that develop the models and those able to analyze the models.This should be accompanied by funding of experimental analyses of the pathways identified by the genetic analyses in mice. This step is critical for understanding the effector mechanisms, which will enable human translation; and possibly the generation of new therapeutic approaches. The analysis of genetic factors affecting addiction often requires in vivo models. Thus, funding methods that use new methods for mouse genome engineering is critical for this, since it will enable the effect of allelic differences to be assessed.The 3rd component is funding for human translational studies. The 20th century concept of performing GWAS using SNP allele markers on existing arrays must be discarded for analysis of human cohorts. In contrast, targeted analysis of candidate regions using sequence is needed.

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 max drinks 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 properties selective 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. Cannabidiol - Cannabidiol 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 cathinones. Effects 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 understudied psychoactive compounds contained in a street drug called ‘bath salts’. The abuse liability 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 use - Test 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 are immunosuppessive. 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

One thing that seemed to be missing from the basic neuroscience priorities (at least explicitly) was mention of development of animal models that more closely mimic the conditions of human drug use. There has been a considerable shift in the last 10 years or so toward "long-access" models of drug self-administration, which likely come closer than "short-access" models to mimicking human use; however, even these models likely fail to capture many important features of human drug use, particularly the adverse consequences of drug use and other factors that drive abstinence (as opposed to extinction). Another thought is that although there is considerable focus on the developmental trajectory of drug use from childhood to adulthood, there is much less known regarding drug use at advanced ages. Granted, this tends to be less of a concern from a population perspective (i.e., drug use is less of a problem at advanced ages compared to adolescence), but it is also likely that drug use in older adults has features and consequences that are distinct, and possibly more deleterious, compared to drug use in younger individuals.
Thank you for the opportunity to provide input as NIDA continues efforts to develop a revitalized Strategic Plan for 2016–2020. As the principal leadership organization for the field of college health, the American College Health Association members include over 800 institutions of higher education and 2,8oo individual college health professionals. Our members include prevention specialists as well as medical and mental health professionals involved in the prevention and treatment of drug abuse and addiction. We are pleased to provide input specific to the needs of college populations that may be helpful in NIDA producing an updated plan for the future.We offer the following observations for further consideration as you continue your work:1. We are hopeful that the plan will feature a focus on marijuana use in much the same way that the previous plan focused on prescription drugs. As an emerging public health issue, the legalization of marijuana deserves greater attention given that many states have either legalized or are considering legalization. As new evidence suggests that there are important effects of even casual marijuana use on young adult neurobiology and psychological well-being, additional research is critically needed. The plan should incorporate and encourage more scholarly input that informs the decisions of policymakers at state and federal level.2. We would like to see the plan address the need for additional research on the unique vocational rehabilitation needs of college students as part of treatment. In particular, the last few years have seen the rapid growth of on campus collegiate recovery programs. Research and evaluation of these programs is important to inform federal, state and institutional policy makers.3. We feel that it is also important to include content within the plan regarding the integration of technology and/or leveraging technological advances to advance treatment, intervention, or prevention initiatives. Promising evidence is emerging regarding delivery of prevention and treatment via on-line, smart-phone based, and virtually. These technologies are readily adopted by college student populations and could be more cost effective and accessible than traditional methods. 4. A final observation is that the proposed Strategic Plan appears to give less attention to the realm of public health when compared to neuroscience, translational science, and science infrastructure. We hope that a more balanced approach can be adopted. While the neuroscience-based approach entails a focus on individual factors and their role in substance abuse, public health brings an equally valuable focus and consideration of macro-level factors influencing substance use/abuse.We hope this input is useful in your important work, and that it will help produce a well-rounded, relevant, and comprehensive strategic plan that positions NIDA and its stakeholders for the important work that lies ahead.I thank you in advance for your interest in college students’ health and incorporating our insights into the plan development process. I stand ready to assist in any way possible
Legacy appreciates the opportunity to submit comments in response to the Request for Information (RFI) regarding the National Institute on Drug Abuse’s (NIDA) strategic plan for 2016-2020. We were encouraged that the Draft Strategic Priorities listed in the RFI contained a focus on public health. We were particularly pleased to see the emphasis on implementation science and “increasing readiness to respond to emerging public health priorities,” such as recent changes in marijuana legalization and emerging drug trends. Legacy wholeheartedly supports these efforts with regard to tobacco and nicotine products and their association to other drugs of abuse. Legacy appreciates NIDA’s emphasis on developing the next generation of scientists – a goal we share at Legacy as well.Legacy envisions an America where tobacco is a thing of the past, where all youth and young adults reject tobacco use. Legacy’s proven- effective and nationally recognized public education programsinclude truth®, the national youth smoking prevention campaign that has been cited as contributing to significant declines in youth smoking; EX®, an innovative public health program designed to speak to smokers in their own language and change the way they approach quitting; and research initiatives exploring the causes, consequences and approaches to reducing tobacco use. Located in Washington, D.C., the foundation was created as a result of the November 1998 Master Settlement Agreement (MSA) reached between attorneys general from 46 states, five U.S. territories and the tobacco industry.We understand that our partner organization, the Campaign for Tobacco Free Kids, has submitted comments to this RFI, and we fully support those comments and incorporate them by reference here. As was noted in those comments, tobacco use continues to be the number one cause of preventable death and disease1 and more needsto be done to end this epidemic. Legacy, through its research and programs, focuses its work on several critical populations that bear the brunt of tobacco’s toll. Smoking rates among minorities, the LGBT population, those with low education and low income levels are much higher than that of the general population.2,3 Further, our research on the children of smokers has shown that parental smoking influences their children’s smoking. The research also found that when parents quit smoking, it also influences their children’s behavior – the children of smokers who quit were less likely to smoke or develop into regular smokers.4 To end the tobacco epidemic, more must be done to explore the causes of tobacco use in all these at-risk populations. We encourage NIDA to increase its research on tobacco use, particularly among those groups disproportionately affected by tobacco.Additionally, while strides have been made in reducing some forms of tobacco use, much work needs to be done to reduce not only cigarette use, but also other forms of tobacco use, including cigars of all sizes, smokeless tobacco and emerging products that do not necessarily contain tobacco, but contain tobacco- derived nicotine. In recent years, the use of new and emerging tobacco products, like e-cigarettes, little cigars/cigarillos (LCCs), and hookah has been on the rise among young adults,5-8 despite a modest decline in cigarette use.9 Rising trends in the use of new and emerging tobacco products are of concern, as evidence suggests that some of these products portend similar negative health consequences as regular cigarette smoking.10-12 We encourage NIDA to support research to better understand more about the causes, consequences, and pathways to nicotine addiction as it differs across a variety of tobacco products.Further, Legacy urges NIDA to strengthen its focus on (a) understanding the connection between tobacco, marijuana use, and other addictive substances; (b) exploring the links between drug use and abuse to the use of new and emerging tobacco products (e.g., e-cigarettes, hookah); (c) developing new methods and models to understand the progression from initiation to regular use among youth and young adults; (d) developing and testing novel modalities of assessment and intervention to deter rates of tobacco product use in young people and to help current users quit; and (e) recognizing the complex interplay between tobacco use, drug use, and HIV/AIDS. These issues are outlined below in more detail.Very little research exists with regard to the impact of nicotine exposure on the adolescent brain and subsequent development. Most of what we know about how nicotine effects youth brain development comes from fetal studies or animal studies.1 Because nearly 90% of adult smokers begin smoking during the critical period of adolescent brain development,1 more research is needed to determine nicotine’s role in this phenomenon. Some questions that warrant further exploration include: Are adolescents and young adults more susceptible to nicotine addiction relative to older adults? What is the threshold of nicotine exposure at which youth and young adults become addicted to nicotine? Does the threshold for nicotine addiction differ across tobacco products? Legacy strongly encourages NIDA efforts to find the answers to these questions.This is important not just for nicotine addiction and could have implications that touch many areas of NIDA’s work. Our own work at Legacy, and that of others, indicates that tobacco use, including the use of new and emerging tobacco products, is highly correlated with alcohol and marijuana use.13-16 Animal research studies have found connections between nicotine addiction and addictions to other substances, some of which indicate a causal sequence of tobacco use leading to other drugs of abuse.17,18 The potential influence of marijuana use on tobacco use is particularly noteworthy given recent state-level changes in the legalization of marijuana. It is unclear how marijuana and other drugs of abuse are differentially related to the spectrum of new and emerging tobacco products (LCCs, hookah, e-cigarettes), but preliminary findings from Legacy indicate that marijuana use was significantly associated with use of these products in a national sample of young adults (study under review). Further, cigars (and use of cigar wrappers in particular), which remain unregulated by the FDA, are associated with marijuana use.20-23 Thus, while we know about usage patterns from epidemiological studies, more research is needed to understand the interaction in the brain between nicotine, marijuana, and other substances. Legacy is encouraged by NIDA’s interest in links between tobacco use and marijuana use as a priority topic and encourages NIDA to allocate more of its budget to this area.Legacy supports NIDA’s focus on HIV/AIDS in the 2016-2020 strategic plan and we want to highlight the complex interplay between tobacco use, drug use, and HIV/AIDS as an important area for research. While a main focus of HIV prevention has been on harm reduction related to injection drug use, current smoking is also associated with increased all-cause mortality compared to non-smoking in persons living with HIV/AIDS.24 As treatment improves and HIV is managed as a chronic disease25,26, there is an increasing need to understand and tailor tobacco prevention and treatment services to those with HIV and those at greatest risk for HIV.27-29Finally, Legacy applauds NIDA’s work with the Food and Drug Administration (FDA) in its tobacco regulatory science program. While that work is absolutely critical to improving cessation rates among current smokers and reducing the overall morbidity and mortality associated with nicotine addiction, we encourage NIDA to devote funds to studies that seek to translate research into policy and practice. For example, the FDA Center for Tobacco Products has indicated that setting tobacco standards that reduce the appeal and addictiveness of tobacco products is a priority. NIDA’s research into factors that trigger tobacco addiction and make nicotine and tobacco products appealing are critical to achieving this goal. Funding from FDA alone in this area is not sufficient to develop this line of research and Legacy urges NIDA to continue and expand its research to support tobacco and nicotine regulation. Similarly, we encourage NIDA to prioritize further exploration of novel modalities of assessing mechanisms that impact tobacco use and nicotine addiction, and developing and pilot testing innovative platforms for deploying targeted prevention and interventions aimed at reducing tobacco use and co-existing substance use conditions. Some work by our investigators indicates that use of non-traditional assessment platforms significantly adds to our understanding of the factors that impact tobacco use and nicotine addiction.30-33 Additionally, our past and ongoing work supports that innovative platforms for delivering prevention and treatment interventions can have broad reach and impact.34-36 More research is needed to develop and test these novel methodologies for assessment and intervention delivery.Legacy appreciates NIDA’s consideration of these recommendations as it develops its strategic plan for 2016-2020. If you have questions or need additional information, please contact [PII Redacted]. We look forward to working with you in implementing the plan in the coming years.ReferencesU.S. Department of Health and Human Services. The health consequences of smoking – 50 years of progress: a report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health,;2014.Agaku IT, King BA, Dube SR. Current cigarette smoking among adults - United States, 2005-2012. MMWR. Morbidity and mortality weekly report. Jan 17 2014;63(2):29-34.Lee JG, Griffin GK, Melvin CL. Tobacco use among sexual minorities in the USA, 1987 to May 2007: a systematic review. Tobacco control. Aug 2009;18(4):275-282.Mays D, Gilman SE, Rende R, Luta G, Tercyak KP, Niaura RS. Parental smoking exposure and adolescent smoking trajectories. Pediatrics. Jun 2014;133(6):983-991.Barnett TE, Smith T, He Y, et al. Evidence of emerging hookah use among university students: a cross-sectionalcomparison between hookah and cigarette use. BMC public health. 2013;13(1):302.Cobb C, Ward KD, Maziak W, Shihadeh AL, Eissenberg T. Waterpipe tobacco smoking: an emerging health crisis in the United States. American journal of health behavior. 2010;34(3):275-285.Smith JR, Edland SD, Novotny TE, et al. Increasing hookah use in California. American journal of public health.Oct 2011;101(10):1876-1879.Richardson A, Williams V, Rath J, Villanti AC, Vallone D. The Next Generation of Users: Prevalence and Longitudinal Patterns of Tobacco Use Among US Young Adults. American journal of public health. 2014;104(8):1429-1436.Agaku IT, King BA, Dube SR. Current cigarette smoking among adults-United States, 2005–2012. MMWR. Morbidity and mortality weekly report. 2014;63(2):29-34.Akl EA, Gaddam S, Gunukula SK, Honeine R, Jaoude PA, Irani J. The effects of waterpipe tobacco smoking onhealth outcomes: a systematic review. Int J Epidemiol. June 2010;39(3):834-857.American Lung Association. An emerging deadly trend: Waterpipe tobacco use. 2007.Nonnemaker J, Rostron B, Hall P, MacMonegle A, Apelberg B. Mortality and Economic Costs From Regular Cigar Use in the United States, 2010. American journal of public health. Jul 17 2014:e1-e6.Villanti A, Cobb C, Cohn AM. Correlates of hookah use and predictors of hookah trial in young adults aged 18 to 24. Am J Prevent Med (2014, accepted for publication).Cohn AM, Cobb C, Richardson A, & Niaura R. The Other Combustible Products: Prevalence and Correlates of Little Cigar/Cigarillo Use among Cigarette Smokers (accepted for publication). Nicotine and Tobacco Research.Cohn AM, Villanti A, Richardson A., Rath J, Williams V, Stanton C, Mermelstein R. The association between alcohol, substance use, and new and emerging tobacco products in a young adult population (revise and resubmit). Addictive Behaviors.Cohn AM, Villanti AC, Rose SW, Pearson JL, Johnson AL, Kirchner TR, Williams VF, Rath JR. Support for marijuana legalization among U.S. young adults: Tobacco use and other risk-related correlates. Abstract submitted to the Society for Research on Nicotine and Tobacco annual meeting, Philadelphia, PA, 2015.Kandel ER, Kandel DB. A Molecular Basis for Nicotine as a Gateway Drug. New England Journal of Medicine.2014;371(10):932-943.Kandel D, Kandel E. The Gateway Hypothesis of substance abuse: developmental, biological and societal perspectives. Acta paediatrica (Oslo, Norway : 1992). Feb 2015;104(2):130-137.Office of National Drug Control Policy, The White House. Marijuana resource center: State laws related to marijuana. 2014; http://www.whitehouse.gov/ondcp/state-laws-related-to-marijuana. Accessed August 20,2014, 2014.Richardson A, Rath J, Ganz O, Xiao H, Vallone D. Primary and dual users of little cigars/cigarillos and largecigars: demographic and tobacco use profiles. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. Oct 2013;15(10):1729-1736.Delnevo CD, Giovenco DP, Ambrose BK, Corey CG, Conway KP. Preference for flavoured cigar brands among youth, young adults and adults in the USA. Tobacco control. Apr 10 2014.Sifaneck SJ, Johnson BD, Dunlap E. Cigars-for-blunts: choice of tobacco products by blunt smokers. Journal ofethnicity in substance abuse. 2005;4(3-4):23-42.Everett SA, Malarcher AM, Sharp DJ, Husten CG, Giovino GA. Relationship between cigarette, smokeless tobacco, and cigar use, and other health risk behaviors among U.S. high school students. The Journal of school health. Aug 2000;70(6):234-240.Pines H, Koutsky L, Buskin S. Cigarette smoking and mortality among HIV-infected individuals in Seattle, Washington (1996-2008). AIDS and behavior. Jan 2011;15(1):243-251.Siegel K, Lekas HM. AIDS as a chronic illness: psychosocial implications. AIDS (London, England). 2002;16 Suppl 4:S69-76.Vidrine DJ. Cigarette smoking and HIV/AIDS: health implications, smoker characteristics and cessation strategies. AIDS education and prevention : official publication of the International Society for AIDS Education. Jun 2009;21(3 Suppl):3-13.Benard A, Bonnet F, Tessier JF, et al. Tobacco addiction and HIV infection: toward the implementation of cessation programs. ANRS CO3 Aquitaine Cohort. AIDS patient care and STDs. Jul 2007;21(7):458-468.Niaura R, Shadel WG, Morrow K, Tashima K, Flanigan T, Abrams DB. Human immunodeficiency virus infection, AIDS, and smoking cessation: the time is now. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. Sep 2000;31(3):808-812.Reynolds NR. Cigarette smoking and HIV: more evidence for action. AIDS education and prevention : official publication of the International Society for AIDS Education. Jun 2009;21(3 Suppl):106-121.Cohn AM, Cobb C., and Ehlke SJ. Disentangling “the chicken and the egg”: Do risky drinking smokers have stronger implicit motivations to drink or so smoke? Abstract submitted to the 38th annual Research Society on Alcoholism conference; San Antonio, Texas, 2015.Ehlke SJ, Cohn AM, & Cobb C. Self-efficacy to quit smoking and implicit cognitions: Does temptation matter among risky drinkers? Abstract submitted to the 38th annual Research Society on Alcoholism conference; San Antonio, Texas, 2015.Cohn A, Brandon T, Armeli S, Ehlke S, Bowers M. Real-time patterns of smoking and alcohol use: an observational study protocol of risky-drinking smokers. BMJ open. 2015;5(1):e007046.Cohn AM, Cobb C, Hagman BT, Cameron A, Ehlke S, Mitchell JN. Implicit alcohol cognitions in risky drinking nicotine users with and without co-morbid major depressive disorder. Addictive behaviors. Apr 2014;39(4):797-802.Cobb NK, Graham AL. Health behavior interventions in the age of facebook. American journal of preventive medicine. Nov 2012;43(5):571-572.Cobb NK, Jacobs MA, Saul J, Wileyto EP, Graham AL. Diffusion of an evidence-based smoking cessation intervention through Facebook: a randomised controlled trial study protocol. BMJ open. 2014;4(1):e004089.Graham AL, Cobb NK, Papandonatos GD, et al. A randomized trial of Internet and telephone treatment for smoking cessation. Archives of internal medicine. Jan 10 2011;171(1):46-53

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, Unifying Themes

RE: NIDA Strategic Priorities – 2016-2020. The strategic priorities that I believe will have the greatest impact on NIDA’s goal of reducing drug abuse are: Increase our knowledge of biological, behavioral, environmental, and developmental factors involved in risk and resilience for drug use and addiction. Understand the developmental trajectory of addiction and individual heterogeneity. Normal development/function across the lifespan including mechanisms of reward, self-control, and conditioning. Improve our understanding of the interaction between addiction and co-occurring conditions. Although research over the past 5-10 years has clearly shown that environmental enrichment and exercise can significantly alter the reinforcing effects of drugs, relatively little is known about how the types of foods and chemicals we consume on a daily basis (e.g., fats, sugars, caffeine, etc.) impact one’s vulnerability to abuse drugs. Preliminary data from our laboratory and others has provided compelling evidence that feeding animals high amounts of fat, or allowing them to consume caffeinated water can dramatically increase their sensitivity to behavioral effects of cocaine. Moreover, the impact of these nutritional manipulations appears to be greatest when the consumption occurs during adolescence, a period of development that is already associated with increased risk for developing a substance abuse disorder. While many think of the consumption of fat and/or caffeine as benign, if not unavoidable in modern western society, the fact of the matter is that the past 10 years has seen unprecedented levels of childhood obesity, driven in large part by the fact that western diets tend to be high in fat and sugar, and skyrocketing numbers of highly caffeinated “energy drinks”, which are primarily marketed towards adolescents and young adults. To address these issues, I think it is imperative that we invest in basic scientific research aimed at identifying and understanding how environmental, nutritional, and pharmacologic history impacts (1) the likelihood of initiating drug use during adolescence, (2) the rate at which drug use transitions to drug abuse/addiction, and (3) individual vulnerability to resume drug taking after a period of abstinence. In addition to improving our basic understanding of how the choices we make for ourselves, and our children, can impacts drug effects, the results of such studies would have practical implications that are “relatively” easy to implement. For instance, with only slight modifications to the types, amounts and/or timing of meals and snacks that we feed our children, we could substantially reduce their sensitivity to drugs of abuse. Another area that I would like to see emphasis placed is on dose and drug selection. In reading the drug abuse literature, I am consistently struck by how many studies include a single dose of a single drug, often cocaine. As a pharmacologist I believe that the only way to accurately assess how a condition (e.g., candidate medication, behavioral intervention, etc.) impacts the abuse-related effects of a drug is to evaluate the full dose-response curve. While there are situations in which a single dose might be advisable, I would like to see NIDA push their investigators to employ a more rigorous approach, particularly in basic drug abuse research. A third area that would benefit from additional emphasis is the intersection of injury/pain and vulnerability to drug abuse. In particular, given the more than decade’s long War in the Middle East, as well as the increased awareness of concussions resulting from contact sports, it is vitally important that we gain a better understanding of how traumatic brain injury, chronic pain and post-traumatic stress disorder impact individual vulnerability to drug abuse.Lastly, although there are currently many great animal models of drug abuse, I think the field would benefit from the development, and adoption of more sophisticated behavioral assays. For instance, while the use of the food-drug choice procedure has proven to be a powerful tool for evaluating candidate medications, relatively little work has been done using self-administration procedures in which multiple drugs are concurrently available. In addition to allowing for studies of commonly co-abused drugs (e.g., caffeine and nicotine, alcohol and THC, benzodiazepines and opioids, etc.), such poly-drug abuse procedures would strengthen our ability to accurately model the human condition in which drug abusers commonly use more than one substance. In addition, while traditional reinstatement procedures have been instrumental in identifying the neurobiology of relapse, implementing more sophisticated procedures (e.g., progressive ratio, choice, etc.) to study the strength relapse-related behaviors would greatly improve not only our understanding of the factors that contribute to abstinence and relapse, but also our ability to accurately assess the effectiveness of candidate medications to maintain abstinence/prevent relapse.

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, Public Health, Basic Science, Unifying Themes

Here are the areas that I believe are important priorities:Not on the list:Novel delivery methods for treating brain disorders: The development of non-invasive routes of delivery of compounds or genes to the CNS should be considered a top priority. Educate the public about addiction and how it is a disease: This is very important as drug addicts do not receive the proper care or support from their families and communities. They are treated as criminals. From the list:Better define 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: There is a huge opioid epidemic in the United States and experts believe that this is due to an increase in the prescription of pain medications. Most opiate abusers start using prescription meds in order to combat pain associated with injury or surgery. Therefore it is important to understand the mechanisms involved and to better define the interactions between pain and addiction. Increase readiness to respond to emerging public health priorities (opioid overdose epidemic, potential consequences of marijuana legalization, changing healthcare landscape, emerging drug trends, etc.): Same as above.Promoting research that considers the impact of sex and gender on drug abuse and addiction: More studies are highlighting that there are differences between the genders. Therefore we can not use the same approach and therapies to treat males and females. There needs to be more funding focused on gender differences. Improve our understanding of the interaction between addiction and co-occurring conditions: The number of co-occurring mental health disorders together with addiction issues is very high. We need to better understand how the two are related and what leads to drug use.Support the development of novel, evidence-based, targeted prevention and treatment interventions including social, behavioral, pharmacological, vaccines, and brain stimulation therapies (e.g., transcranial magnetic stimulation, direct current stimulation, etc.)Identify measures other than abstinence that can reliably assess SUD treatment outcomes Identify biomarkers of addiction, resilience, and recovery to enable personalized treatment: Without biomarkers we will not be able to predict how a therapy is working or whether or not it is effective.

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 benefits. Re-engineer the pipelines for med development with human laboratory studies and alternative early Phase II clinical trial designs. Characterize the use of electronic cigarettes for treating nicotine use disorders. Determine 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-abuse. Use 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 possible. Strongly support more efforts to promote research that directly examines the impact of sex and gender on drug abuse and addiction. In 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 community. Develop a central forum at NIDA for IND's that can be accessed by grantees. Develop a more active interaction between NIDA and the DEA and FDA with regard to drug scheduling.

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 of substance 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 Neuroscience - APA proposes additions to the draft priorities in this area. Neurobiological Correlates With regard to the improvement of understanding of brain circuits related to drug abuse and 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 Diseases. APA requests NIDA bolsters its attention to the comorbidity of substance use disorders and medical illnesses. Thanks to previous NIDA research, it is well recognized that substance use disorders are a significant contributor to the severity, morbidity, and mortality from many illnesses, including cardiovascular disease, gastrointestinal disorders, HIV/AIDS, and pain disorders. APA recommends that NIDA expand its support for collaborative research between psychiatry and general medicine to further address these comorbidities and develop an array of effective interventions.4DiversityDrawing on one of the aforementioned unifying themes of diversity, it also is important to 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 Science APA would like to suggest augmentation to NIDA’s vision in this area. Bidirectional Research, Functional Measures, Animal Models and Complex Addictions We recommend that NIDA consider supporting the translation of bench findings to clinical research in humans, as well as research on strengthening bedside to bench applications (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 concentrate on 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 Research- APA 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 These activities 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 as on 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 currently without 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 and safety. 7 Comorbidities 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 living with substance-related disorders, HIV, and the hepatitis C virus. Translational science such as this will be critical to ensuring that clinicians, substance abuse counselors, and others have effective tools to curb the HIV epidemic. As research continues to show promising HIV-prevention interventions in drug abuse treatment settings, a cascade continues 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 a substance-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 use disorders 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 of treatments would be helpful to the field.Publicizing NIDA ProgressGreater dissemination of NIDA progress, initiatives, research, and education to outlets with 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 Settings Implementing public health strategies for substance use disorders necessitates improvement 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 cannabis use in Washington State and Colorado. There has been an emergence of sales outlets located in communities of color. The APA suggests that NIDA consider assessing patterns 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 unique vantage 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 and offers 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 and underrepresented 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 who have 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. Difficult decisions 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 the beginning 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 critical and 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 our nation 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 on the brains of individuals vary at different stages of development, including late childhood, early adolescence, middle and late adolescence, young adulthood, and late life. 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, Basic Science, Unifying Themes

Suggested changes or additions to the list of strategic priorities, including emerging research needs and future opportunities that should be considered in the plan:We believe the future priorities of NIDA should take into account the increased level of legalization of cannabis, the continued abuse of prescription medications, and the potential problems associated with e-cigarettes in teenagers.An emerging research topic that is not stressed enough in the current outline is the role of the neuro immune system in the development of substance use disorders. The majority of the literature concerning neuroinflammation in drug addiction has appeared after the last strategic plan was published by NIDA. Contemplated in the past plan of strategic priorities, but we didn’t see in the present outline, is the study of specific populations, specifically, military personnel, where there is an increased abuse of prescription drugs compared to the civilian population. An example of this type of research could be the study of how post-traumatic stress disorder influence the development of drug addiction. Also, NIDA should promote research that consider the incarcerated population. In the prison system, a 65% of prisoners meet the medical criteria for substance abuse addiction, but the study of this population is not mentioned in the current outline. Lastly, behavior and environment are big components of the susceptibility and vulnerability to drug addiction. NIDA should prioritize studies that address the interaction between psychiatric diseases like major depressive disorder, anxiety disorder and the development of drug abuse.Anticipated challenges that will need to be addressed to achieve these priorities. A first step towards elucidating the pathophysiology of psychiatric disorders in addiction should include a deep knowledge of the participating neuronal circuits, the cell types, and the molecules in each neuronal population involved, and how these structures are interacting and influencing each other.

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. Successfully 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 organizations 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

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, 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 meetings The College continues to be a strong advocate for the work of NIDA, and we greatly appreciate the opportunity to address this Plan.

Public Health, Basic Science, Clinical and Translational Science

Below you will find my comments for consideration for inclusion in the forthcoming Strategic Plan;1. As an overall comment to be included under the Public Health Strategic Priority:Recreational use of substances of abuse has been pervasive throughout history across cultures and societies. Driving forces for its continued existence are much more than physiological and behavioral; deriving much of its persistence to socio-economical factors that maintain and perpetuate its existence. While the mission of NIH certainly is consistent with the focus for this five-year strategy on the basic science and clinical treatment of individuals with SUD; what is missing is the commitment of NIH, and in this case NIDA, to play a prominent role in addressing the proliferation of addiction by attacking the problem at its roots; and that is the “inoculation” of our children through innovative early educational programs that would include strong prospective outcome studies to examine their impact during preteen and adolescent years. Resources could be shared with SAMSHA for a concerted effort and integrated within the educational curriculum through ‘caring for our brain” initiatives just as we are doing with traumatic brain injury and the successes that we have achieved with the use of helmets. To not include such an objective in this Strategic Plan within the NIH as a way to encourage the active support of our scientists in the implementation of such efforts would be a mistake; since it is the excitement of the science and progress in brain research that must be the foundation for the design of such addiction prevention programs and will ultimately lead to success and differentiation from just another pedagogical program by departments of education. 2. Comment to be included in the Basic Science Strategic Priority (within bullet #9):There should be an effort to highlight a focus of research into an improved understanding of descending brain pathways for modulation of both chronic neuropathic and visceral pain. Such research efforts should incorporate and support a more thorough understanding of placebo response and its importance to clinical research design for alternative treatment strategies for pain. Such research will impact clinical trials well-beyond the therapeutics of pain.3. Comment to be included in the Clinical and Translational Science Strategic Priority:One of the key issues facing the discovery and development of new treatments for addiction is the translation of basic neuroscience research into the clinical setting. To this end I would reinforce the need for valid biomarkers including novel provocative tests that would increase our success in translation to clinical trials, but also might serve to identify individuals at particular risk for addictive behaviors and provide opportunities for preventative interventions.I will look forward to following your progress.
al Institute on Drug Abuse, National Institutes of Health;As the Executive Director of the Greater Lowell Health Alliance of CHNA 10 (GLHA) and representing GLHA's Substance Use and Prevention and Maternal Child Health Task Forces, I would like to respectfully submit the following written comments for the 2016-2020 Strategic Plan:Suggestions-Continue research on whether some people are genetically predisposed to becoming addicts.More research on why children with behavioral problems early in life become substance abusers later in life.Children between the ages of 3-6 do not have access to services. Early intervention ends at age 3 and the public school system takes over at age 6. The children between this age group need some intervention too. It is possible that they end up abusing substances later on in life as a way to self-medicate .There is an increase in Ritalin being given to preschoolers. Research needs to be conducted on whether these children later become substance abusers as they have been on an addictive substance for so long.More research needs to be conducted to produce more non-addictive options for detox as has been done for ADHD.More research should be conducted on cannabidiol (CBD).There is need for tighter legislation on Suboxone. There is no follow-up of clients using it. Clients should be mandated to attend group sessions . Physicians should also do follow-up of their patients. With methadone, clients have to go for counseling but there is no such requirement for clients on Suboxone .Suboxone is being misused and clients are buying it in the streets. Those clients who are unable to get hold of Suboxone end up using Percocet's or heroine.It takes several days to receive drug test results and most do not test for Suboxone.Transportation should be provided for clients who are in treatment. Drug dealers deliver to their clients but treatment centers do not provide similar services.There should be a policy change that allows DCF to get involved when pregnant women are abusing substances. Currently DCF can only get involved if there are other children in the household or when the baby is delivered, by that time it is too late for the newborn as he/she is born with an addiction .Doctors should be mandated to report to the hospital if a pregnant woman is abusing substances. This way she can receive detox services sooner.More work needs to be done to ensure pregnant women who ab use substances have access to Early Intervention Partnerships Programs (EIPP).1ChallengesSynthetic drugs are frequently changing and evolving, it is difficult to catch up. A recent case of a youth overdosing in Chelmsford on "smileys". Law enforcement had no knowledge what that substance was.Clients with a dual diagnosis (comorbid conditions e.g., mental illness, chronic pain). Half-way houses will not accept them if they have a prescription for a narcotic. This needs to be addressed as these clients are left with no treatment options. Re-imbursement rates from insurance companies are low and some insurance companies are not paying for detox.Detox centers will not take in women who have just left the hospital after delivering a baby. They require that the client must first test positive for a substance in order to be admitted. If the client uses, they get into trouble with DCF.There was little preparation for the legalization of medical marijuana. This has created problems, for example, law enforcement is not able to arrest someone buying marijuana if they have a Medical Use of Marijuana Program ID card.More detox options should be made available for people who are in jail but have not been sentenced yet, for example methadone, Suboxone . Currently this population has no services and is at highest risk of overdosing once released.Permission must be obtained to test adults for substances.Thank you for the opportunity to provide input on the research priorities to be included in the NIDA Strategic Plan. These comments were gathered at a special meeting held by the Greater Lowell Health Alliance, a coalition that is comprised of public, non-profit and private sectors working together to build healthier communities through community-based prevention planning and health promotion . Please let me know if you need further clarification.

February 11, 2015