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A concept describes the purpose, scope, and objectives of a potential funding opportunity.  Approved concepts are usually developed into Requests for Applications (RFAs), in which funds are set aside by the Institute to stimulate a specific program of research.  Concepts are being posted to give interested researchers additional time to plan for application submissions. The NACDA conducts most, but not all, NIDA concept clearances. Concepts may also be cleared through other public venues.  Concepts cleared through other public venues are marked with an asterisk (*). 

Please send questions regarding specific concepts to the program contact listed in the description. Please also note that to avoid any conflicting information, once a concept has been finalized as a published RFA (or similar funding announcement), it is deleted from this early notification, concept clearance list.

Concept Index:

Leveraging Big Data Science Approaches to Elucidate the Neurobiological Basis of Substance Use Disorder

Posted: February 15, 2019


The young field of big data science is providing computational tools, such as artificial intelligence and machine learning algorithms that can be used to mine data across levels of experimental analysis in innovative ways and extract new information to help elucidate the biological underpinning of substance use disorder. Additionally, combining large data sets from different sources can be used to answer research questions in a way that was not previously feasible. Computational approaches can be used to link changes in gene networks to neural systems and predict patterns of drug use and state changes that predispose to compulsive substance use or resilience to it. Drug addiction is a complex neuroadaptive process that begins with a molecular event that is amplified to cellular, circuit, and network changes that govern cognition and behavior, and changes in gene function produced by chronic drug administration may underlie the enduring behavior. Substantial data has been, and continues to be, generated by NIDA-funded studies regarding the effects of drugs of abuse at various levels of analysis, and the untapped power of data emerging from these studies lies in their mining, integration, and analysis.


This initiative will attract data and computational scientists to propose novel ways to integrate data from various levels to allow new types of analysis through big data science approaches. It is expected that with the development and application of novel computational, bioinformatics, statistical, and analytical approaches, previously inaccessible insights will reveal new aspects of addiction biology.  Some specific questions include:

  • How can neural data from the cellular level to circuits and behavior be integrated and mined using artificial intelligence/machine learning to help determine the pathways involved in drug addiction?
  • Are there novel data that can be integrated or novel ways of integrating existing data?
  • What predictions can be made about drug abuse, including treatment and prevention?

Roger Little, Ph.D. & Susan Wright, Ph.D. Division of Neuroscience and Behavior

Exploiting Precision Pharmacology Techniques to Understand Opioid Receptor Signaling in Specific Circuits, Cell Types, and Subcellular Compartments

Posted: February 15, 2019


Developing novel opioid analgesics devoid of limiting side effects, such as respiratory depression, tolerance and addiction liability, is a major goal for the field. Progress in this area requires a better understanding of how opiate receptors signal in time and space at a subcellular, cellular and systems levels.

Systemically-administered opioids engage a large variety of cells in the body to mediate their complex behavioral and physiological actions. Technological advances, such as single-cell transcriptomics and genetically-targetable sensors, which correlate opioid receptor cellular expression or subcellular signaling with their physiological effects, suggest that spatially and temporally restricting the action of opioid ligands to defined cell-types, circuits or even intracellular compartments may provide an effective way to dissociate their analgesic effects from adverse effects. However, testing such hypotheses and establishing a causal link between a physiological effect in vivo and a pharmacological action in a subset of cells or organelles remains a challenge, due to a lack of appropriate tools.


To address this gap, this FOA will support exploratory projects organized in 2 successive milestone phases that (i) develop and validate transformative pharmacological approaches to interrogate opiate receptor signaling in defined circuits, cell-types or subcellular compartments and (ii) apply these novel "precision pharmacology” approaches to understand the action of opiates in vivo.

The proposals sought under this FOA are expected to employ multidisciplinary approaches and leverage timely advances in chemical biology, chemistry, nanotechnology, molecular biology or other disciplines to achieve the targeted in vivo activation, blockade or quantification of opioid signaling in molecularly-defined organelles, subsets of cells, or circuits, through delivery of clinically-relevant opioid ligands. Of special interest are applications leveraging single-cell transcriptomics or imaging datasets, such as those emerging from the BRAIN initiative, to identify new cellular or subcellular targets and proposing to apply the developed tools to test novel mechanistic hypothesis susceptible of increasing the therapeutic window of opioid treatments.

An improved understanding of the cellular and subcellular substrates of opioid physiological effects is expected to inform and spur the development of novel pharmacotherapies that retain the beneficial effects of opioid analgesics while avoiding their detrimental effects.

Olivier Berton, Ph.D. Division of Neuroscience and Behavior

The Rat Opioid Genome Project

Posted: February 15, 2019


The goal of the Rat Opioid Genome Project is to identify genetic variation underlying individual differences associated with vulnerability to the stages and sequela along the opioid use disorder (OUD) trajectory, ultimately resulting in addiction. Each of these vulnerabilities most likely has multiple causes, including genetic and environmental components. These studies will facilitate discovery of the genetic architecture (e.g. genes, gene networks and genetic pathways) underlying OUD.

A major challenge in preventing OUD is to identify the underlying genetic variation that contributes to various phenotypes across the OUD trajectory. Parsing out the genetic and environmental components associated with these stages requires an animal model. The rat provides a sound behavioral and genetically tractable model to uncover the genetic pathways that contribute to susceptibility or resilience to discrete stages along the OUD trajectory. This proposal capitalizes on two complementary rat resources: the Hybrid Rat Diversity Panel and outbred animal model systems. The Hybrid Rat Diversity Panel consists of 91 distinct inbred strains that display divergent phenotypes related to substance use disorders. Users can identify strains with divergent phenotypes and map the phenotypes. These genetically identical animals facilitate longitudinal and repeated studies within the same strains, as phenotype data from one study can be analyzed in subsequent experiments. Outbred animals mimic human studies and any one cohort contains the genetic diversity of the starting population. Outbred animal studies facilitate quantitative trait locus (QTL) discovery. These complementary approaches facilitate gene discovery, with the Hybrid Rat Diversity Panel providing a strong understanding of how genetic variation influences phenotypes and behaviors underlying OUD and the outbred animals fostering gene discovery.


This project will provide a foundation for identification of genetic variants associated with vulnerability to specific stages along the trajectory of OUD and build a strong basis for cross-species comparisons of the genes and gene networks associated with OUD. It is designed to test hypotheses generated by human genetic studies and identify new genes involved in OUD using rat models. It will provide molecular targets for future therapeutics and interventions, as well as help tease out the molecular endophenotypes associated at early stages of OUD that can stratify an individual’s risk for OUD following initial use of opioids. This stratification can be used to inform human studies and cluster individuals with OUD based on predisposing genetic factors. This initiative takes a systematic approach from phenotype/behavior to genes to identify causal variants underlying the different stages of OUD and lead to the development of new therapies to identify at-risk individuals to halt opioid use at different stages along the trajectory.

Potential Research Questions: What are the genetic components of various stages across the OUD trajectory (e.g. tolerance, dependence, addiction) or adverse effects (e.g. respiratory depression, hyperalgesia)?

  • Are there different genetic components associated with the different stages? Can they be used to stratify different risk at the end stages of disease? Do these different genetic underpinnings represent distinct genetic and neural networks?
  • Are there sex differences in these behaviors and phenotypes?
  • What genes do single cell and tissue transcriptome studies implicate? What role do other factors (e.g. chromatin, genetic background, Gene x Gene, Gene x Drug, Gene x Environment) play in OUD?

Amy Lossie, Ph.D. Division of Neuroscience and Behavior

Exploiting Single Cell Technologies to Understand the Effects of Persistent HIV and Chronic Opioid Exposure on the Brain

Posted: February 15, 2019


Recent novel technologies have enabled researchers to molecularly characterize large numbers of single cells or nuclei.  These technologies can be used to identify the types of cells in a given brain region and understand how individual cells differ with respect to gene expression. 

People living with HIV are at higher risk for impaired executive or cognitive functions (e.g. HIV-Associated Neurocognitive Disorder or HAND) and often have higher levels of legal and illegal drug use.  Opioid use by HIV-infected individuals can diminish immune function and might exacerbate HIV-related CNS impairment.  At the molecular level, little is known about the effects of persistent HIV infection on the CNS and how chronic opioid use may exacerbate these effects.  Single cell technologies have the potential to shed light on these processes. 


The purpose of this initiative is to support generation of single cell datasets for one or more brain regions relevant to persistent HIV infection and opioid use disorder.  If fully successful, this project will:

  • Generate a cellular “parts list” for a limited number of NIDA-relevant brain regions
  • Reveal how cell types within these brain regions differ from one another with respect to gene expression
  • Reveal how HIV infection in the brain influences single cells, yielding potential targets for improving HIV-related CNS sequelae in patients
  • Reveal how cell types within these brain regions are altered by chronic opioid exposure, yielding potential novel therapeutic targets for opioid use disorder
  • Uncover potential synergistic effects of HIV infection and chronic opioid exposure and in the CNS

John Satterlee, Ph.D. Division of Neuroscience and Behavior

Data Coordination and Analysis Center for Single Cell and Other Molecular HIV/SUD Data

Posted: February 15, 2019


Recent novel technologies have enabled researchers to molecularly characterize large numbers of single cells or nuclei.  These technologies can be used to identify the types of cells in a given brain region and understand how individual cells differ with respect to gene expression. 

People living with HIV are at higher risk for impaired executive or cognitive functions (e.g. HIV-Associated Neurocognitive Disorder or HAND) and often have higher levels of legal and illegal drug use.  Opioid use by HIV-infected individuals can diminish immune function and might exacerbate HIV-related CNS impairment.  At the molecular level, little is known about the effects of persistent HIV infection on the CNS and how chronic opioid use may exacerbate these effects.  Single cell technologies have the potential to shed light on these processes. 


A data coordination/analysis/outreach center will be established to:

  1. Coordinate and help analyze single cell data sets generated by the above concept or other funded NIDA projects
  2. Coordinate selected previous and future molecular HIV/SUD data to make it FAIR (Findable, Accessible, Interoperable, and Reusable) and more readily accessible to the scientific community 

Harmonization of single cell and other HIV/SUD molecular datasets will enable:

  • Near term data mining by the scientific community for HIV and/or SUD biomarkers and potential pathways for therapeutic intervention
  • Future mining of these data sets as new and improved data science and information technology approaches are developed, maximizing NIDA’s original investment in the data generating activities

Susan Wright, Ph.D. Division of Neuroscience and Behavior

Assessing Effects of Cannabinoids on HIV-associated Neuroinflammation

Posted: February 15, 2019


Acute cannabis administration is proposed to alleviate HIV-associated immune and neurological complications, although concerns remain about the aversive effects and impact of prolonged cannabis administration.  The potential beneficial actions of cannabis towards HIV-associated disease is based on positive observations of anti-oxidative, anti-excitotoxic, and anti-inflammatory properties in the study of models for several other neurodegenerative diseases.  However, existing data about the protective effect of cannabis is largely observational without causal evidence.  We have limited knowledge about dynamic changes along with the time course and pattern of administration, or with the status of the endocannabinoid (endoCB) system at treatment.  The therapeutic potential/benefit of cannabis on HIV pathogenesis has not been systematically investigated.  Questions remain about the integrity of the endoCB system during HIV pathogenesis or under substance use disorders to inform how the preconditions may impact the therapeutic potential of cannabis.  Further, a longitudinal design is necessary to determine the limits of cannabis for this treatment purpose. 


This initiative supports research that will elucidate the roles or limits of using cannabis to mitigate HIV associated neuroinflammation.  It will be carried out with preclinical and clinical neuroAIDS models, to understand the interrelationships among cannabis, biomarkers of endoCB and neuroinflammation, and chronic neuroimmune complications.

Yu (Woody) Lin, Ph.D. Division of Neuroscience and Behavior

Targeting Inflammasomes in Drug Abuse and HIV

Posted: February 15, 2019


Neuroinflammation triggered by brain trauma, neurodegenerative diseases or other neurotoxicant-induced central nervous system (CNS) disorders including human immunodeficiency virus type-1 (HIV-1) infection initiates CNS innate immune responses.  HIV-1 penetrates the blood brain barrier, infects macrophages and microglial cells, and promotes a cascade of inflammatory responses including the formation of inflammasomes.

Inflammasomes are a complex of high molecular weight proteins within the cytosol of stimulated cells that mediate the activation of inflammatory cascades. In response to insults, Nod-like receptors (NLRs) recruit adaptor proteins and caspase-1 to assemble inflammasomes and process the release of pro-inflammatory cytokines IL-1b, IL-18 and IL-33. The NLRP3 inflammasomes are the most well-characterized that comprises NLRP3, apoptosis-associated speck-like (ASC) adapter protein, and the downstream effector protease procasepase-1.

Recent evidence suggests that chronic drug exposure, i.e., cocaine, methamphetamine and morphine, can induce inflammasome activation primarily mediated by NLRP3 within microglia. Additionally, emerging data suggest that HIV-1 infection can also prime inflammasome activation. Drug abuse, especially in association with HIV-1 infection, induces reactive oxygen species (ROS) production, impairs blood brain barrier integrity, and promotes monocyte transmigration. These upstream events exert synergistic effects that prime oligomerization and activation of inflammasome and release of pro-inflammatory cytokine IL-1b. Persistent inflammatory signaling pathways involved inflammasome formation and activation may lead to progressive loss of the functional capacity of the immune system. This could contribute to the pathogenesis that underlies HIV-associated neurocognitive disorders (HAND).


The scientific objective of this research is to delineate the role of inflammasomes in neuropathology produced by chronic drug exposure and HIV infection. Understanding the involvement of inflammasome in the immune activation may help identify molecular markers and CNS immune cells associated with HIV-1 infection or disease progression among substance abuse populations, as well as identify novel therapies to target inflammasome activation or suppression to treat neuroinflammation and immune dysregulation aroused in these processes.

Anne Tsai, Ph.D. Division of Neuroscience and Behavior

Cohort Studies of HIV/AIDS and Substance Abuse Populations

Posted: February 15, 2019


NIDA has been supporting HIV/AIDS cohorts among substance abusing populations which address emerging and high priority research on HIV/AIDS and related consequences of substance use. These are intended to serve as a resource platform for collaborative efforts to address HIV prevention and/or treatment in the context of substance abuse. The cohorts include historical studies like AIDS Linked to the IntraVenous Experience (ALIVE), recent cohorts established in key populations, and new cohorts. Some cohort samples include people living with HIV (PLWH) while others had been HIV-uninfected at enrollment, or a mix of HIV+/- at enrollment. The cohorts include relatively homogeneous populations (PWID, MSM) as well as samples that cut across key populations.


This initiative will continue the data collection activities of the cohorts, while furthering the process of harmonizing and standardizing data collection protocols. It will increase the cohorts’ status as a national platform for basic, clinical, translational and behavioral research in HIV and substance use disorder. This will include steps to increase data sharing with other NIDA and NIH-funded cohorts, as well as increase collaborations with other established data and biospecimen banks. The overall objective of these efforts is to establish and further collaborations that will promote innovative research related to HIV and substance use.

This limited competition FOA will not support establishment of new cohorts.

Richard Jenkins, Ph.D. Division of Epidemiology, Services and Prevention Research  

PrEP for HIV Prevention among Substance Using Populations

Posted: February 15, 2019


Antiretroviral treatment (ART) as pre-exposure prophylaxis (PreP) has demonstrated efficacy in reducing new HIV infections in several studies, mostly among men who have sex with men (MSM). Less than daily use also has proven efficacious if sufficient blood levels of PrEP are present.

PrEP is recommended by CDC for those at high risk for HIV acquisition, including people who have injected drugs and shared needles/works during the past 6 months or been in drug treatment in the past 6 months. Even so, only one efficacy trial has evaluated PrEP among people who inject drugs (PWID). That trial recruited PWID from methadone clinics in Bangkok. It included no longitudinal data on drug use or injection, although these were collected in a follow-up study in this sample which found relatively low levels of drug use and injection. Other data regarding PrEP and substance users are lacking, even among populations like MSM, where substance use is common


This initiative will address important gaps in the implementation of PrEP among substance users. Specifically, it will enable a better understanding of substance use effects on PrEP effectiveness and clarify considerations for PrEP implementation among substance users. These steps will help identify ways to improve HIV preventive care with PrEP including optimization of PrEP monitoring and linkage to PrEP services.

Richard Jenkins, Ph.D. Division of Epidemiology, Services and Prevention Research  

Advancing the Study of Recovery Support Services for Those Treated with Medications for Opioid Use Disorder 

Posted: February 15, 2019


Numerous studies are examining how to improve access to effective treatment for individuals with opioid use disorder.  Few studies have rigorously examined recovery support services (RSS) that may aid stabilization and ongoing remission and recovery.  RSS include peer-based recovery support services, recovery community centers, education-based recovery support services, recovery housing, and clinical models of continuing care. These services have often been developed by individuals in recovery, suggesting needs that are insufficiently met elsewhere, and are disseminating rapidly. However, according to a recent expert panel meeting, systematic literature review, and review of federally-funded projects, substantial research gaps exist. States and other payers have begun to pay for these services to address the needs of those affected by the opioid crisis but need evidence to continue their investment.  At the same time, many of the available services are or are perceived to be unsupportive of individuals continuing on OUD medications.  Given that the recovery support services research field is relatively small, but the demand for these services is growing, now is an opportune time to rapidly strengthen the scientific base of research in this area.


To support activities that would lead to rapid, collaborative development and dissemination of scientific resources needed to develop meaningful, actionable research in this field.  Participants might include not only researchers, but other relevant stakeholders such as people in recovery, providers, payers, state personnel or others who would make use of the findings. Development of common, agreed upon scientific resources and methods and preliminary data that could be used to support R01-level research, are examples of the type of work that might be pursued under this initiative.  Absent a specific initiative, it is unlikely that these resources would be developed, missing an opportunity to advance methods and increase the efficiency of the research process when it is needed most. Because of the foundational yet timely nature of this work, participation from several other institutes and agencies with an interest in recovery will be pursued.

Sarah Q. Duffy, Ph.D. Division of Epidemiology, Services, and Prevention Research

Clinical Outcome Assessments for Clinical Trials of Substance Use Disorders as FDA-qualified Drug Development Tools

Posted: February 15, 2019


Development of novel Clinical Outcome Assessments (COAs) for Substance Use Disorders (SUDs), and most importantly for Opioid Use Disorder (OUD), is urgently needed to accelerate innovative clinical drug development and deal effectively with the Opioid Crisis. Existing COAs may not be fully reflective of what is truly important to patients from their point of view. The Opioid Crisis prompted a recent, April 2018, FDA-lead Patient Focused Drug Development (PFDD) OUD meeting where the regulators had an opportunity to hear directly from patients regarding their experiences, describe the main effects of OUD that are affecting their daily lives, and identify the most important symptoms that need to be effectively treated. Based on the outcome of this meeting new COAs will emerge, as well as a renewed focus on SUDs symptoms seen as key by the sufferers.

An expanded portfolio of COAs in addictions will be enriched with novel and/or additional improved clinical assessments. Furthermore, novel COAs will be especially significant if they go through the rigorous FDA Drug Development Tools (DDT) qualification process. The Center for Drug Evaluation and Research (CDER) reviews submitted data for a new DDT and qualifies it as such within specific Context of Use (COU). Qualified DDTs could be used as validated and reliable instruments for human laboratory early clinical trials and for phase 3 confirmatory studies with a high level of confidence.

A COA can be a Clinician-reported Outcome (ClinRO) that is based on a report from a trained healthcare professional and observation of patient’s health condition; or a Patient-Reported Outcome (PRO), where a report comes from a patient about the status of their health without additional interpretation by a clinician or anyone else; or a Performance Outcome (PerfO), where a patient is administered a standardized task and their performance is evaluated by a trained individual, or is independently completed; or an Observer-Reported Outcome (ObsRO) that is based on a report of observable signs, events or behaviors, related to a patients’ health condition by someone other than a patient or a healthcare profession (e.g., a family member).

A qualified COA should be: a) a measure that produces a score; b) a reliable assessment for the targeted construct; c) include defined methods and instructions for administration and well-documented methods for scoring, analysis and interpretation of the results in the targeted patient population; d) include a standard format for data collection. A COA is expected to be used across early and late drug development studies and related research.


This funding opportunity will serve to support the development of novel COAs and the optimization of existing COAs, including: psychometric scales, tasks and/or measures for any of SUDs, and/or as a measure/task for an RDoC construct that reflects functional aspects of behavioral, cognitive and affective processes of addiction. This announcement encourages submissions that will plan for and result in novel or improved psychometric scales, tasks and measures that demonstrate good validity, robust measurement properties and could be qualified as DDTs for a defined COU.

Tanya Ramey, M.D., Ph.D. Division of Therapeutics and Medical Consequences  

Digital Health Technologies to Address the Social Determinants of Opioid Addiction

Posted: February 15, 2019


Multiple initiatives to address the opioid crisis in the United States aim to improve pain management, access to medication-assisted treatment, and use of overdose-reversing drugs. Public health experts have also long recognized the impact of social determinants on health outcomes, such as socioeconomic status, education, and social support. According to the World Health Organization (WHO), the social determinants of health are the conditions in which people are born, grow, live, work and age. These circumstances are shaped by the distribution of money, power and resources at global, national and local levels. The social and economic factors can shape risk behavior, access to resources, and the health of drug users. Social risk factors directly and indirectly influence individual drug-use behavior and ability of the substance use disorder patients to recover their health. Moreover, social factors contribute to health disparities directly by affecting the availability of resources and access to social support systems in ways that increase marginalization and decrease compliance with treatment and medication.


Through this FOA, NIDA solicits the commercializable digital health concepts that aim at positively affecting the fundamental social and environmental conditions that are risk factors for the populations affected by opioid crisis. The grant proposals, which may focus on transforming family, housing, employment, criminal justice and educational determinants of opioid addiction, should offer the most far-reaching and promising opportunities for state, federal and community leaders to meaningfully contribute to addressing the opioid crisis.

Illustrative topics could include, but not limited to:

  • Develop and validate the best approaches for employer education and support to allow employers to hire, retain, and facilitate treatment for employees seeking help for substance use disorders;
  • Research, design and validate novel tools and approaches to address food and housing insecurities;
  • Research and design of novel tools to enable housing programs that co-locate employment, education, and behavioral health services;
  • Design and validation of curriculum for “soft skills” development for addiction treatment providers;
  • Research and design of preventive systems for families to promote healthy behaviors, social skills, community opportunities, and pro-social involvement;
  • Design and validate technologies that help create and enhance pro-social support networks that facilitate recovery, engagement with care, and/or access to needed services;
  • Research and design tools and technologies to help facilitate continuity of care, access to services, and successful community reintegration for people re-entering communities following a period of incarceration;
  • Research, design and validation of novel approaches for job training (e.g. in entrepreneurship, financial literacy, IT skills), delivered in recovery housing or while incarcerated.

Elena Koustova, Ph.D., M.B.A. Office of Translational Initiatives and Program Innovations

Blockchain Technology to Improve SUD Care

Posted: February 15, 2019


Recently, there has been lots of excitement about the role that blockchain technology might play in the long-term transformation of U.S. healthcare. The problems that are common to the U.S. healthcare (e.g. misaligned incentives, lack of accountability and transparency, and multitude of stakeholders) are further exacerbated when it comes to the care of the patients suffering from substance use disorders (SUD).

SUD care space is excessively fragmented, suggesting that blockchain could be ideal for ensuring data integrity while decentralizing control. Blockchain is a new way of storing data in a distributed ledger that allows various stakeholders to securely access the same information. The technology could make the biggest impact in SUD healthcare in enabling health outcomes that take a 360° view of the patient’s genetic profile, their demographic and socioeconomic status, the behaviors that impact their health, and their response to different treatments or combinations of treatments.


The goal of this funding opportunity announcement (FOA) is to test the implementation of blockchain technology to address specific inefficiencies within the SUD ecosystem. Some example of studies to be conducted, includes, but is not limited to:

  • Using blockchain in combination with AI and machine learning to predict relapse;
  • “Blockchain-as-a-service (BAAS)” products for SUD;
  • Using blockchain to ensure the integrity of the medical records;
  • Using blockchain for patient recruitment and engagement;
  • Tracking the prescription drugs in the pharmaceutical supply chain to the patient;
  • Validation of payments or claims

Elena Koustova, Ph.D., M.B.A. Office of Translational Initiatives and Program Innovations

Rapid Assessment of Drug Abuse: Smart City Tool

Posted: February 15, 2019


Given the prevalence of drug abuse there is a growing need for a comprehensive approach to assess trends in drug use, understand the effectiveness of prevention and treatment programs, and compare usage data across cities and/or states.  However, the current methods of the drug use surveillance using surveys and data on incidence have limitations including lack of geographic resolution, coverage of the selected population, exclusion of the large portion of drug-using community, and involvement of multiple stakeholders.

Municipal wastewater testing is a relatively new strategy that can provide a more rapid and objective measure of drug use than traditional methods. A panel of experts from Mathematica’s symposium on “The Potential of Wastewater Testing for Public Health and Safety” (Washington, DC, May 16, 2017) recommended Wastewater-based Testing Methods because they are readily scalable, anonymous, can eliminate self-reporting surveys, map drug consumption, and provide an early warning in the ever-changing landscape of substance abuse for proactive responses. Currently technologies can detect various illicit drugs and opioids in the waste stream and can differentiate between drugs that were discarded and drugs that were metabolized. Large-scale coordinated studies using wastewater methods have already been successfully conducted in Europe (http://www.emcdda.europa.eu/topics/pods/waste-water-analysis. In USA the wastewater-based studies were initiated in few states (Nevada, Utah, South Carolina, Nebraska, and New York).

However, the current methodologies require labor-intensive sample collection, multiple resources for sample analysis, involve calibration complexities, and lack multi-indicator monitoring and alert systems. Thus, the utilization of wastewater testing for illicit drugs and granularity in the data could be increased by developing novel sampling analyzers or robotic devices with a broad spectrum of drug sensitivity.


This FOA aims to support small businesses to advance knowledge and address technological gaps to adopt wastewater testing for routine monitoring of illicit drugs.                    

Through this initiative, prominent research opportunities could include but are not limited to:

  • Improving existing technologies or developing new sensing devices that can consistently detect illicit drugs and opioids in wastewater.
  • Optimizing sample collection for wastewater testing.
  • Increasing the wastewater signal specificity and sensitivity for highly potent but less common illicit drugs.
  • Determining the stability of many of the new synthetic opioids to assess whether these samples can be detected in wastewater.
  • Testing device placement at upstream sewer pipes where different subcatchment areas merge.
  • Determining operational feasibility and developing a model for working collaboratively with existing infrastructure and community stakeholders.

New wastewater testing technologies could provide a widespread and objective picture of drug use that would be consistent, scalable, cost-effective, and complement other epidemiological studies. This could benefit multiple stakeholders providing opportunities to test effectiveness of new programs and reinforcing use of the best practices.

Irina Sazonova, M.S., Ph.D., Office of Translational Initiatives and Program Innovations

Preventing Opioid Use Disorder in Older Adolescents and Young Adults (ages 16–30)*

Posted: February 15, 2019


An estimated 11.4 million people misused opioids in 2017, of which 11.1 million misused prescription opioid analgesics. Opioid drugs, including opioid analgesics, heroin and illicit synthetics, accounted for more than 60% of overdoses in 2016. There is need to develop preventive strategies that can decrease the incidence and prevalence of opioid misuse and Opioid Use Disorder (OUD), particularly in at-risk populations.

Currently, evidence-based interventions exist to prevent substance use broadly, that predominantly target children and adolescents. However, there is a gap in the evidence for interventions and strategies to prevent non-medical use of opioids and OUD in the transition from adolescence to young adulthood.


The goal of this project is to develop, adapt and test interventions and strategies to prevent initiation of opioid misuse and development OUD in at-risk older adolescents and young adults (ages 16-30). Given the target population of older adolescents and young adults, research will likely take place in health care settings, justice settings and other systems and settings opportune for accessing and engaging at-risk older adolescents and young adults. This project aims to support research to develop strategies for identification, reach and engagement of at-risk older adolescents and young adults; development, adaptation and testing of interventions and strategies to prevent initiation and misuse of opioids and OUD; development and testing of strategies to facilitate implementation and sustainability of prevention interventions and strategies in health care, justice and other systems and settings opportune for engaging and providing interventions or services to at-risk older adolescents and young adults; and, conduct economic evaluations to quantify programmatic costs and cost-effectiveness of interventions and strategies developed and tested.

The ultimate goal of this project is to develop efficacious and effective interventions and strategies to prevent opioid misuse and OUD in older adolescents and young adults that will be adopted in health care systems, justice systems and other systems and settings.

Jacqueline Lloyd, PhD, Division of Epidemiology, Services and Prevention Research

The Trans-NIH baby Brain Cognitive Development (bBCD) Study*

Posted: September 26, 2018


There has been a dramatic increase in the number of babies who have been prenatally exposed to opioids due to the opioid crisis. Between 2004 and 2014, the number of infants born with neonatal opioid withdrawal syndrome (NOWS; also known as neonatal abstinence syndrome [NAS]) increased 433% from 1.5 to 8.0 per 1000 hospital births which translates into one neonate born with NOWS every 15 minutes. As this crisis continues to escalate, these numbers will also increase, and we do not know what the long-term implications of early exposure to opioids (or to medications used to treat opioid use disorder) will be. In addition, other drugs continue to be used during pregnancy and afterwards when many women are breastfeeding. The National Survey on Drug Use and Health indicates that in 2016, 6.3% of pregnant women used an illicit drug (Center for Behavioral Health Statistics and Quality, 2017), and many use more than one drug. A large and growing body of evidence indicates that early exposure to substances, including pre- or perinatally, is linked to greater risk for developing substance use disorders. Moreover, prenatal exposure is also associated with other behavioral problems, including ADHD, conduct disorder, anxiety, etc. However, a causal link is difficult to establish due to confounding factors such as socioeconomic, environmental, and genetic influences.


The goal of this project is to understand the long-term impacts of pre- and perinatal drug and adverse environmental (e.g., parental neglect, physical abuse) exposures on brain development and social/behavioral/academic achievement and how these in turn impact risk for substance use and mental illness.  We propose to establish a large cohort (e.g., 7,500) of pregnant women from regions of the country significantly impacted by the opioid crisis and follow them and their newborns through childhood. The cohort will also include non-exposed children, which will establish normative brain and behavioral development trajectories for socioeconomically and environmentally matched children, to which altered trajectories can be compared. This prospective approach will allow us to investigate prodromal changes in brain and behavioral development resulting from early exposure to opioids, other substances, and associated adverse conditions that might predict emergence of substance use disorders and other mental illness. 

Key research objectives include, but are not limited to:

  • Understanding variability in individual developmental trajectories (e.g., brain, cognitive, emotional, social, academic) from birth through childhood.
  • Understanding the impact of pre- and postnatal exposure to opioids, opioid treatment medications, cannabis, alcohol, tobacco, other prescription or illicit substances (alone or in combination) on developmental trajectories.
  • Investigating the role of sex, genetic, epigenetic, social and other environmental factors on risk/resilience related to structural and functional brain development, social/behavioral/academic achievement, and future substance use and mental disorders.

Gaya J. Dowling, Ph.D., Director of the Adolescent Brain Cognitive Development (ABCD) Project

Renewal of the Adolescent Brain Cognitive Development (ABCD) Study*

Posted: September 26, 2018


 The ABCD study (ABCDStudy.org) is the largest long-term study of brain development and child health in the United States. It is structured as a cooperative agreement involving multiple NIH Institutes, 21 recruitment sites, a coordinating center, and a data analysis and imaging center.  The consortium has been recruiting approximately 11,900 children ages 9-10, with plans to follow them through adolescence into early adulthood.  A common protocol is used at all sites, involving biological, social, behavioral and neuroimaging measures. The primary goal is to create a diverse and well characterized cohort to understand how experiences in childhood interact with each other and a child’s changing biology to affect brain development and social, behavioral, mental and physical health outcomes.  All data (with PII removed) will be shared widely with the research community through the NIMH Data Archive.


This initiative would renew the ABCD Consortium so that the cohort of children in this nationwide sample can be followed into young adulthood. The study was designed to address the following overarching research objectives, which are inherently interdependent and mutually informative: 

  • Describe individual developmental trajectories (e.g., brain, cognitive, emotional, academic), and the factors that can affect them.
  • Develop national standards of healthy brain development.
  • Investigate the roles and interaction of genes and the environment on development.
  • Study how physical activity, sleep, screen time, sports injuries, and other experiences affect brain development.
  • Examine the factors that influence the onset, course, and severity of mental illnesses.
  • Understand the relationship between mental health and substance use.
  • Study how use of different substances (caffeine, nicotine, alcohol, marijuana) affects developmental outcomes, and vice versa.

This initiative is supported by the Collaborative Research on Addiction at NIH (NIDA, NIAAA, NCI) and the following NIH Institutes and Centers (ICs), NICHD, NIMHD, NINDS, NHLBI, ORWH, OBSSR, and NCI on this initiative.  

Bethany Deeds, Ph.D., Deputy Director of the Division of Epidemiology, Services, and Prevention Research

Virtual Reality Tools to Enhance Evidence Based Treatment of Substance Use Disorders

Posted September 6, 2018


There are numerous existing evidence-based behavioral treatment approaches for substance use disorders. A significant proportion of patients who receive treatment using evidence-based behavioral therapies relapse, suggesting that additional adaptations are needed to enhance the effectiveness of these therapies. Technology driven approaches (e.g., cell phone based applications, text messaging interventions, ecological momentary assessment) to improving evidence-based treatments have shown some success.

Virtual reality (VR) is unique among other technological enhancements in that it can recreate some elements of the social situations and physical environments that typically trigger relapse, allowing patients to practice skills they will need when they encounter such situations in real life. The potential for VR to enhance treatment effects has been demonstrated in domains outside of substance use, such as comorbid depression, anxiety, posttraumatic stress disorder, obesity, and acute and chronic pain (e.g., Fodor LA et al., 2018, Tarrant J et al., 2018, Manzoni et al., 2015, and Pourmand A et al., 2018). In addition to the potential to increase the potency of interventions by allowing patients to practice skills in realistic virtual settings, VR also has the potential to extend access to treatment outside of clinical settings, and generate digital markers/digital phenotype tools for Clinical Research (Bourla A et all., 2018).


This initiative aims to support small businesses to develop VR-enhanced technologies that will:

  1. Support SUD treatments and recovery,
  2. Provide treatment alternatives for chronic pain,
  3. Serve as next generation Clinical Research Tools which leverage data from the VR experience and model SUD and comorbid mental illnesses disorders.

Numerous evidence-based substance abuse treatments may lend themselves to VR adaptation. Examples include, but not limited to:

  • Cognitive Behavioral Therapy
  • Contingency Management
  • Motivational Interviewing/Motivational Enhancement Therapy
  • Multisystemic Therapy
  • Multidimensional Family Therapy
  • The Matrix Model
  • 12-Step Facilitation Therapy
  • Behavioral Therapy

Irina Sazonova, M.S., Ph.D., Challenges and Prize Competitions, Educational Programs, Office of Translational Initiatives and Program Innovations, NIDA

Laboratories for Early Clinical Evaluation of Pharmacotherapies for Substance Use Disorders

Posted September 6, 2018


A significant challenge in the development of medications for Substance Use Disorders (SUDs) is the need for specialized laboratories that have the knowledge and expertise to timely and efficiently conduct FDA-defined Phase I and Phase II clinical trials. For example, Phase I clinical trials in addiction must evaluate the medical safety of compounds, that may involve the evaluation of safety of the interaction with a drug of abuse, or pharmacokinetic or pharmacodynamic studies. Such studies require an inpatient unit where subjects can feel comfortable and have adequate medical monitoring and other safety protection measures in place. They also require pharmacy support with a set of licenses and permits to allow the storage and administration of some substances, potentially including DEA scheduled drugs. These laboratories must have the ability to recruit participants with SUDs who are not motivated to receive treatment. Moreover, they must be able to conduct Good Clinical Practice (GCP) quality studies that satisfy the FDA requirements to accept the data for approval purposes.

Phase II studies mainly focus on the evaluation of the safety and early efficacy of medications. These studies can be conducted in outpatient settings in treatment-seeking populations with strict inclusion/exclusion criteria and specific treatment outcomes. The settings where Phase II studies are conducted must have the knowledge and expertise in the area of research, the ability to recruit study participants, and the clinical services necessary to attend to the needs of participating patients.   Also, they must possess the necessary licenses and certificates to conduct these types of trials and the ability to follow GCP guidelines. The data collected from these studies must also satisfy the FDA quality requirements to support the approval of the compound.


Given the high level of specialization and strict regulatory requirements needed to conduct early clinical trials of medications for SUDs, it is critical to increase the availability of laboratories that can perform these types of studies. It is expected that each laboratory will be GCP-compliant, have access to an Institutional Review Board (IRB) to perform timely and efficient review and oversight, possess a track record of success in operational aspects of drug development, have successful clinical study initiation and recruitment, and the demonstrated ability to complete clinical studies with standards and timelines comparable to the pharmaceutical industry.

The purpose of this Funding Opportunity Announcement (FOA) is to accelerate the clinical development of medications to treat Substance Use Disorders (SUDs) by supporting laboratories with the expertise and resources to timely and efficiently conduct early (Phase I or Phase II) clinical trials of potential pharmacotherapies for SUDs.

Some examples of studies to be conducted in the laboratories may include:

  • Early clinical studies with a potential medication candidate, such as First time in Humans (FIH), Single Ascending Dose (SAD), Multiple Ascending Dose (MAD) or SAD-MAD combination, food effect
  • Drug-Drug interaction (DDI) studies, including safety interaction studies of medications with drugs of abuse and other studies related to aspects of formulation development (e.g., bioavailability)
  • Translational Phase 2A proof-of-mechanism (POM) studies. It is expected that neuroimaging and other technologies will be used where appropriate.
  • Phase 2B dose-ranging and/or Early Signal of Efficacy (ESoE) type of trials
  • Proof of Concept (POC) efficacy and safety clinical trials

Tanya Ramey, M.D. PhD, Medical Officer, Medical Clinical Branch, Division of Therapeutics and Medical Consequences (DTMC)

The Helping End Addiction Long-Term (HEAL)-ing Communities Study*

Posted June 13, 2018


Despite the availability of multiple effective evidence-based practices and programs, most Americans at risk for or with an opioid use disorder (OUD) do not receive effective prevention and treatment services, particularly in an integrated and coordinated manner. Simultaneously, opioid overdose rates continue to increase.


This initiative will support a new cooperative agreement multi-site national research effort to develop approaches for the systematic implementation and sustainability of effective interventions to address the opioid crisis in highly-impacted communities. Findings from this study will contribute to our understanding of how an integrated array of evidence-based prevention and treatment services can decrease rates of overdose deaths and events, the incidence of OUDs and HCV, and increase the number of individuals receiving medication-assisted treatment and retained in treatment beyond 6 months. In addition, the study will yield best practices for replication in other communities impacted by the opioid crisis including metrics for evaluating outcomes.

The HEALing Communities Study will address the following key questions:

  1. What is the individual and public health impact of implementing an evidence-based integrated OUD care delivery system in highly-impacted communities? 
  2. What factors (organizational, community, policy-level) contribute to successfully implementing an integrated care delivery system?
  3. What analytic tools, resources, and strategies are most useful to help communities rapidly respond to the opioid crisis?
  4. What is the cost and cost effectiveness of designing and implementing a coordinated and integrated response in a highly-impacted area?

Redonna K. Chandler, Ph.D., Director, NIDA AIDS Research Program

The Justice & Community Opioid Innovation Network (JCOIN)*

Posted June 13, 2018


Opioid addiction and opioid misuse consequences exist at the intersection of health and justice systems. Thus, the justice system represents a critical target in addressing the current opioid crisis. Illicit opioids, including fentanyl and heroin, accounted for more than 60% of opioid-related overdose deaths in 2016. More than 9 million people pass through the justice system each year and the average daily population of U.S. jails and prisons is 2.5 million. Most (70%) people who encounter the justice system have used drugs; 25% have used heroin—roughly 100 times the community-level rate of use. While medications for addiction treatment (MAT) increase connections to care and reduce mortality and recidivism, fewer than <1% of U.S. jails and prisons offer MAT. Recent data suggest that implementing MAT in jail and prison settings can dramatically decrease overdose deaths of justice-involved populations and even translate into substantial reduction in community-level mortality. 

Collaboration between justice and public health systems is critical to an effective response to the opioid epidemic. Siloed approaches lead to fragmented, low quality care for patients, increased mortality, and increased costs to communities. A services cascade framework is a powerful and flexible tool that can help facilitate collaborations between justice systems and community-based organizations (Belenko et al., 2017). Flexible study designs are needed to systematically and rapidly evaluate the effects of existing and emergent innovations to enhance community capacity to effectively respond to the opioid crisis.


JCOIN will provide a nimble, coordinated infrastructure. Components and key activities that will be supported under JCOIN will include: rigorous multisite studies, national surveillance and survey activities, data infrastructure, training, rapid response trial mechanisms, and dissemination and implementation science. The overarching goal of JCOIN will be to facilitate effective justice-community partnerships that enhance outcomes for justice populations and the communities in which they reside and to rapidly translate these findings for broader dissemination.

Tisha Wiley, Ph.D., Assistant Director for Criminal Justice Research, Division of Epidemiology, Services, and Prevention Research

Responding to Opioid Use Disorders (OUD) in Tribal Communities in the Context of SAMHSA Tribal Funding

Posted May 15, 2018


American Indians and Alaska Natives (AI/AN) have been disproportionately affected by the opioid crisis, second to or equal to Whites in the rate of overdose deaths and diagnosis for OUD. AI/AN had the highest drug overdose death rates in 2015 and the largest percentage change increase in the number of deaths from 1995 to 2015. Despite this health burden, few studies of the prevention or treatment of OUD have been conducted with AI/AN.

Tribes and tribal organizations have both unique opportunities for and barriers to responding to the opioid epidemic. The status of tribes as sovereign nations uniquely positions them to use tribal policymaking in response to the opioid crisis. This provides an opportunity for research and practice partnerships to showcase how tribal responses, including those focused on prevention, treatment or multi-level, community wide responses, can address the risks for opioid use, improve treatment outcomes and reduce overdose deaths and addiction. Some unique barriers exist as well, particularly related to the implementation of medication assisted treatment (MAT), such as no published outcome studies of MAT nor studies indicating the availability of this treatment for AI/AN, the concern that using MAT is substituting one drug for another, the cultural incongruency of standard treatment approaches, distance to treatment, insufficient funding, and stigma. Many treatment programs do not reflect the AI/AN value for a holistic approach to recovery that includes bringing mental, emotional, physical and spiritual aspects of health into balance, nor do they incorporate traditional practices or other culturally appropriate strategies.

Recent funding to the Substance Abuse and Mental Health Services Administration (SAMHSA) addresses one barrier for AI/AN communities; insufficient funding for strategies to combat OUD. In their 2018 budget allocation, SAMHSA is required to provide $50,000,000 for Tribes and Tribal organization to respond to OUD, including prevention and treatment; an FOA is in development.


The goal of this FOA is to solicit applications from researchers partnering with AI/AN communities, tribes or tribal organizations to use community based participatory research approaches to develop and assess culturally appropriate interventions supported within the context of expanded SAMHSA funding. This research will help to identify the most efficacious strategies for preventing and/or treating OUD in tribal communities, where unique culture, structures for and access to health care, and beliefs about treatment all impact OUD outcomes. Specific to treatment, this research will help to identify and address barriers to appropriate treatment and hasten the availability of clinically appropriate MAT and other relevant strategies. Further, it will help to elucidate how cultural grounding or adaptation can improve treatment efficacy. Given that unique barriers to treatment for this population include distance, this research could test whether the use of long acting MAT (Sublocade, Vivitrol, Probuphine) helps in making MAT available to remote communities, helps reduce stigma, or otherwise improves treatment use and outcomes for AI/AN.

Kathy Etz, Ph.D. and Sarah Q. Duffy, Ph.D., Division of Epidemiology, Services, and Prevention Research

Community Resource:  Post-Mortem Brain Resources for Exploring HIV Compartments in Individuals with Opioid Use Disorders

Posted May 15, 2018


Latent HIV infection can occur in a variety of cell types and tissues.  The brain is one of these compartments, but the extent to which substance use impacts the establishment and maintenance of latent HIV infection is poorly understood.   Post-mortem brains are needed to make valid comparisons for the effects that HIV has on the brain epigenome as well as determining how drugs affect HIV latent infections in the central nervous system.  Thus, Control brains (HIV minus, with (100) Opioid+/HIV-  and 100 Opioid +/HIV+ per year are proposed to be collected as part of this initiative.   Emphasis will be placed on collecting post-mortem brains from infected and uninfected subjects who suffered from OUD.


The proposed research resource will help support research into:

  • How do drugs of abuse affect the establishment and maintain latent HIV infection in different cell types and compartments of the central nervous system.
  • How HIV infection together with drugs of abuse affects epigenetic changes such as methylation, chromatin modifications, eQTLs, and the 3D genome.  The use of control tissue allows investigators to distinguish the effect of HIV infection from those produced by drugs of abuse.

Jonathan Pollock, Ph.D., Division of Neuroscience and Behavior


Modeling HIV Neuropathology Using Microglia from Human iPS Cells and Cerebral Organoids

Posted February 6, 2018

HIV-associated neurological disorders (HAND) persist in up to 50% of HIV-patients even when HIV replication is suppressed by cART. HIV does not infect neurons, but infects microglia and macrophages in the brain, causing HAND associated neuropathology. How microglia affect neurons and glia in human brains are not understood. Currently there are no effective approaches for live human brain studies or realistic HIV animal models for HIV neuropathology.

Recent technological advancements have allowed generating microglia and cerebral organoids from human iPSC lines. These microglia have been shown to be fully functional, secreting cytokines and phagocytosing neural debris, when introduced into cerebral organoids. 

This initiative will support studies using human iPSC to generate cerebral organoids and microglia to study HIV neuropathology. This includes the following:

Establish iPSC lines from HIV-patients and HIV-free controls, and use these cells to generate cerebral organoids and microglial cells. Microglia can then be infected by HIV and introduced into the organoids.
Characterize and compare the morphology, neuronal composition, oligodendrocyte and astrocyte differentiation, synaptic density and other basic measures of neurodevelopment in HIV-latent, HIV-infected, and HIV-free organoids.
Study how HIV-infected microglia alter neuronal structure, physiology, and function in the brain.
Answer questions such as: How do substances of abuse impact these processes? Can genetic and genomic editing alleviate neuropathology in HAND?

Da-Yu Wu, Ph.D., Division of Neuroscience and Behavior

Respiratory Stimulants to Reverse Drug-Induced Respiratory Depression (RD)

Posted February 6, 2018


The National Institute on Drug Abuse (NIDA) has an interest in reducing the impact of drug addiction on the health and well-being of the American people. At the current time, we are in a wave of mortalities based on drug-induced respiratory depression (RD). This disorder occurs when a high dose of an opioid or other sedating drug / combination, activates receptors in the brain stem, which serve to respiratory circuits. The effect is to weaken the respiratory drive to an extent that either the patient ceases to breathe, or the drive is insufficient to prevent aspiration of vomit into the lungs.

The current best pharmacological practice to counter drug-induced RD is to administer naloxone, an opioid receptor antagonist that occupies receptors, making them unavailable for opioids to activate. Until recently naloxone has proven to be an effective strategy, but today, inexpensive, high-potency opioids such as fentanyl and carfentanil are becoming commonplace in the illicit drug supply. The pharmacology and physiochemistry of fentanyl differs from morphine; it provides a very rapid onset of effect, and is both more potent and efficacious than morphine. Given that the end user of illicit opioids is frequently unaware of the exact composition of their drug purchase, these pharmacological differences are key drivers of the current wave of opioid overdoses and mortalities.

Naloxone is a competitive antagonist, it can only act to block vacant receptors and many synthetic opioids only slowly unbind from receptors. This means that to treat high potency opioid overdoses, naloxone must be provided at a high enough dose for a long period. Unfortunately, naloxone is eliminated rapidly from a patient’s circulation and so responders must remain observant and ready to repeatedly administer increasingly high doses in order to counter RD caused by synthetic opioids. In dependent opioid users, large doses of naloxone may unfortunately precipitate immediate withdrawal.

Given the assumption that economics will continue to drive the inclusion of (potentially increasingly) potent opioids in the illicit drug supply, NIDA wishes to facilitate the development of agents that can safely reverse RD without engaging opioid receptors. Pharmacologies have been demonstrated that can reverse opioid-induced RD by stimulating non-opioid sensitive components of the respiratory system. By facilitating the full exploitation and development of such agents, NIDA hopes to reduce morbidity and mortality associated opioid use, without regard to whether opioid receptors are occupied with potentially lethal concentrations of potent agonist.


To develop a lead compound and potential backup molecule (ideally from distinct structural classes) in a formulation that acts to reverse RD by mechanisms other than antagonizing the mu opioid receptor.

To demonstrate the efficacy of the lead compound in preclinical models of RD that include opioid-induced RD and / or RD induced by drugs or drug combinations that frequently cause life threatening RD in the real world. This can include alcohol, when in combination with other drugs such as benzodiazepines or opioids, or combinations of drugs that demonstrably cause significant risk of mortality in post-operative settings.

Project Activities and Expected Deliverables

The project may include medicinal chemistry to optimize the efficacy or other drug-like features of the lead compound, provided that a suitable assay system exists that both models real world situations adequately and provides sufficient through-put to allow for successful optimization.

The project may also include other studies that advance a molecule and at least one back up molecule with demonstrated efficacy, towards establishing the level of evidence of safety and efficacy required by FDA to allow clinical testing. Such studies might include preclinical efficacy and pharmacokinetic studies in a rodent and non-rodent species, manufacturing scale up chemistry, cGMP synthesis and formulation, toxicology and final formulation stability studies.

By the end of phase 1 sufficient data must exist to indicate that the medication can be administered via a route known to be safe and reliable in an unconscious individual.

The medication should reach efficacious concentrations at the site of action within a time period commensurate with the indication, i.e., to save the life of an RD patient discovered by a first responder shortly after RD has set in.

The persistence of the pharmacological action should exceed that of currently available alternatives, i.e., it should be able to reverse RD for more than four hours following a single administration.

The Phase I application must include:

  • Go/no-go decision tree with quantitative, milestones
  • Objective measures that demonstrate efficacy of the molecule against RD induced by several pharmacological mechanisms.
  • Objective measures that demonstrate the mechanism of action (unless previously established) of pharmacological agent.
  • Studies designed to address project-specific questions of feasibility.
  • Detailed discussion of potential pitfalls, side effects and safety issues and how these concerns are to be mitigated.

Phase II Activities and Expected Deliverables

  • Phase II involves execution and completion of studies on lead/backup molecule required to form a Drug Masterfile (DMF) sufficient to satisfy FDA IND requests for clinical testing.
  • Development, submission and acceptance of the DMF by FDA CDER.

Aidan Hampson, Ph.D., Division of Therapeutics and Medical Consequences

Pre-Exposure Prophylaxis for HIV Prevention and Treatment for Substance Using Populations

Posted February 6, 2018

Antiretroviral treatment (ART) used prophylactically in the form of pre-exposure prophylaxis (PreP; e.g., emtricitabine and tenofovir disoproxil fumarate [Truvada®]) is recommended for populations at high risk for HIV acquisition,, including individuals who have injected drugs in the past 6 months and have shared needles or works or been in drug treatment in the past 6 months.  The seminal trial to date on the efficacy of PreP among injecting populations is the Bangkok Tenofovir Study, in which there were 17 HIV infections among the 1,204 participants taking tenofovir, compared with 33 infections among the 1,207 participants taking placebo (49% reduction in risk of HIV acquisition among those receiving tenofovir).  The sample was recruited from methadone clinics and no data were reported on drug use or injection behavior, and no drug testing was performed (Choopanya K. et al. 2013).  Consequently, the actual efficacy of PreP for active injectors, adherent methadone users or even non-injectors who actively use opiates and other drugs is unknown. 

NIDA has funded surprisingly little research on the several key question related to PreP use among substance using populations The primary goal of this RFA is to examine the role of PreP in substance use trajectories and or treatments, including:

  • To what degree do substance use or HIV providers recommend or adopt PreP for substance using patients at risk for HIV (e.g., injection drug use)?  
  • To what degree does substance use affect access and adherence to PreP?
  • How does drug use interact with PrEP efficacy, including injection as well as polydrug use with substances that independently affect immune function?
  • Where does PreP fit within a comprehensive program for prevention of HIV acquisition?

This concept is squarely in line with high overarching HIV/AIDs priorities (NOT-15-137):

  • Reducing Incidence of HIV/AIDS, including:  developing and testing pre-exposure prophylaxis candidates and methods of delivery, especially those that mitigate adherence issues; and developing, testing, and implementing strategies to improve HIV testing and entry into prevention services.
  • Next generation of HIV therapies with better safety and ease of use including:  developing and testing HIV treatments that are less toxic, longer acting, have fewer side effects and complications, and easier to take and adhere to than current regimens. Additionally, implementation research to ensure initiation of treatment as soon as diagnosis has been made, retention and engagement in these services, and achievement and maintenance of optimal prevention and treatment responses.

Shoshana Y. Kahana, Ph.D., Health Scientist Administrator, Services Research Branch, Division of Epidemiology, Services and Prevention Research

Identifying Neural Mechanisms Linking Psychosocial Stress to Pain and Opioid Use Disorder

Posted September 6, 2017

Psychosocial stress, defined as socioenvironmental demands that tax the adaptive capacity of the individual, is a major risk factor for opioid use disorders (OUDs). Psychosocial stress may impact OUD risk by altering cognitive and affective function and facilitating the development of affective disorders. Stressful environments have been associated with pronounced negative affect and affective disorders, and impairments in reasoning, memory, inhibitory and cognitive control. In addition to cognitive and affective outcomes, exposure to psychosocial stress has been shown to modulate pain perception and tolerance to opioid analgesics, which can also contribute to the potential for opioid abuse and addiction. For example, adverse childhood experiences such as verbal and sexual abuse, low family income, and early parental loss, have been associated with an increase in pain-related medical conditions during adulthood.

OUDs show high comorbidity with affective disorders such as major depression and anxiety. Further, opioid misuse rates among chronic pain patients are influenced by negative affect. Neurobiological changes in overlapping brain areas, circuits and neurochemistry have been implicated in chronic pain, depression, anxiety, and substance use disorders. Initial findings suggest that individuals with affective disorders exhibit blunted endogenous opioid function, which is associated with altered pain sensitivity and response to opioid medications. Furthermore, healthy individuals with lower endogenous opioid release are more likely to develop chronic pain and report more pain in laboratory assessments of pain, suggesting that natural variations in the endogenous opioid system produce individual differences in pain severity and processing. Collectively, these data suggest a complex multidimensional relationship between psychosocial stress, cognitive/affective processing, pain, and OUDs. However, important questions remain regarding the underlying mechanisms related to behavior, genetics, epigenetics, neural circuitry, and endogenous opioid function. 

The goal of this initiative is to promote basic and clinical research directed at: (1) elucidating the neurobiological and behavioral mechanisms by which psychosocial stress alters pain sensitivity or cognitive/affective processes, biases opioid use, maintains opioid seeking and increases the risk of relapse; and (2) identifying the factors and the associated mechanisms of action underlying resilience or vulnerability to psychosocial stress-induced alterations in pain sensitivity or affective/cognitive functioning as it relates to OUD.

Vani Pariyadath, Ph.D. and Shelley Su, Ph.D., Division of Neuroscience and Behavior

Medications Development to Prevent and Treat Opioid Use Disorders and Overdose

Posted February 15, 2017

Description:  Given the current opioid use and overdose crisis in the country, the purpose of this Funding Opportunity Announcement is to support research that accelerates the discovery and development of medications to prevent and treat opioid use disorders (OUD) and overdose.  This project is part of the NIH initiative to establish a public-private partnership to address the opioid crisis via more effective and safe ways to prevent and treat opioid use disorders and overdose (https://www.nih.gov/opioid-crisis)

Application may include preclinical or clinical research studies that will have high impact and quickly yield the necessary results to advance closer to FDA approval medications that are safe and effective to prevent and treat OUDs and overdose. 

The compounds to be evaluated can be small molecules or biologics.  They can be tested in pre-clinical models and/or for the clinical manifestations of OUDs such as withdrawal, craving, relapse, or overdose. Applications may focus on the development of new chemical entities, new formulations of marketed medications available for other indications, or combinations of medications that hold promise for the treatment of OUDs and overdose.

Through this FOA, NIDA seeks to fast-track the discovery and development of medications to prevent and treat OUDs or opioid overdose and to advance them in the FDA's drug development approval pipeline.

Ivan Montoya, M.D., Division of Therapeutics and Medical Consequences