National Advisory Council on Drug Abuse (NACDA) Approved Concept Clearances

A concept describes the purpose, scope, and objectives of a potential funding opportunity. Concepts are posted to give interested researchers additional time to plan for application submissions. Approved concepts are usually developed into Requests For Applications (RFAs), Program Announcements that include set-aside funds (PASs), or Program Announcements with special receipt, referral and/or review considerations (PARs). The NACDA conducts most, but not all, NIDA concept clearances. Concepts may also be cleared through other public venues.

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:

HEALthy Brain and Child Development (HBCD) Study

Posted September 2024

Background

This concept proposes a competitive renewal of the HEALthy Brain and Child Development (HBCD; https://hbcdstudy.org/) study and extend the program past the end of its current project period on June 30th, 2026. The study aims to follow approximately 7,200 pregnant persons and their children from the prenatal period through the first 10 years of life. Using a prospective longitudinal design, the study’s main objectives are to understand the genetic, neurocognitive, socioemotional, and environmental influences on developmental trajectories over the first decade of life, and how early life exposure to opioids, other substances, and/or other adverse environmental circumstances affect those trajectories. To accomplish these objectives, NIDA, the NIH HEAL Initiative, and other NIH ICOs established the HBCD Study Consortium that consists of three highly integrated components: 24 research sites, a coordinating administrative core (HCAC), and a data coordinating center (HDCC). Together, the consortium established a common protocol that includes in-person or virtual assessments that span multiple domains of child and caregiver outcomes, including measures of growth, medical and family history, activity and sleep levels, social, emotional, and cognitive function, socioenvironmental and cultural factors, and brain indices using MRI and EEG. Research sites began enrollment for the main study in July 2023 and the study’s first public data release is planned for early 2025. To date (08/28/2024), the study has enrolled 1,977 pregnant persons to the study.

Goal

The purpose of this concept is to renew all 3 integrated components of the HBCD study (the research sites, HCAC, and HDCC) for another project period to provide the Consortium with resources to complete enrollment of 7,200 pregnant persons and their children, and to extend study visits through the first decade of life. Research sites will continue to be responsible for subject recruitment and retention, and administering all study protocol elements. The HDCC will continue its responsibility towards data management and coordination across all research sites, and to ensure a yearly public data release. HCAC will continue to be responsible for overall study management, performance, and dissemination of Consortium-wide policies and procedures. 

Janani Prabhakar, Ph.D., Division of Neuroscience and Behavior

Cutting Edge Basic Research Awards (CEBRA)

Posted September 2024

Background

The Cutting-Edge Basic Research Awards (CEBRA) fosters highly innovative, conceptually creative, and/or transformative research that advances our understanding of the etiology, pathophysiology, prevention, and/or treatment of addiction and substance use disorders (SUD). The CEBRA program prioritizes research that if successful, could transform our understanding of addiction. The proposed research should: 1. develop, and/or adapt, revolutionary techniques or methods for addiction research or that show promising future applicability to SUD research; and /or 2. test an innovative and significant hypothesis for which there are scant precedent or preliminary data and which, if confirmed, would transform current thinking.

Goal

The goal of CEBRA is to support the generation of novel tools and concepts that have the potential to significantly impact the fundamental understanding and exploration of addiction biology. It is designed to take a “high risk-high reward” approach in facilitating research activities and providing critical tests of validity and/or capability for future application.

Tristan McClure-Begley, Ph.D., Division of Neuroscience and Behavior

Rapid and Drug-Agnostic Identification of Emerging Threats

Posted May 2024

Background

Emerging threats continuously evolve. Xylazine, nitazenes, and other future threats are making their way or are already in the drug supply. Understanding them requires analyzing real world samples. Typically, testing strips are used to detect drug for which such strip exists, as the strips are fast, sensitive, low cost and reasonably accurate. However, as there might not be testing strips for the new threats, the analysis must be performed via sensitive and sample agnostic methods. This is typically done via GC-MS or LC-MS, which has high selectivity (augmented by chromatography) and sensitivity (sub-nanogram/ml). However, this type of analysis is slow (it may include shipping to a specialized laboratory), requires specialized knowledge to run the instruments, and the cost of both the instrumentation and the analysis is high. This resource and cost-intensive method forces emergency departments in the hospitals, community centers that focus on harm reduction, etc. to collect, store and ship samples to a centralized location, which prevents detection of new threats in real time.

Goal

There are technologies that have the potential to offer sensitivity and selectivity similar to GC-MS or LC-MS but are significantly less resource- and time-intensive. These include air-pressure differential mobility spectroscopy, surface-enhanced Raman scattering, electrochemical detection, portable high-pressure liquid chromatography, etc. They are detection target agnostic. The only new development that would be needed in the case of the appearance of a new target is the inclusion of its fingerprint in the library, which can be distributed electronically. Some of them have been already demonstrated to work with drug of abuse at concentrations ~1 ng/ml. What has not been demonstrated, however, is an end-to-end system, that is rapid, requires low initial capital cost and low cost of operation, is highly accurate and requires minimum training and consumables.

Yordan Kostov, Ph.D., Office of Translational Initiatives and Program Innovations 

Discovery and Development of Natural Products to Treat Substance Use Disorders (SUDs)

Posted May 2024

Background

Natural products (NPs) and NP-like compounds represent a highly diverse and promising chemical space for discovering and developing medications to treat diseases, including central nervous system disorders. Despite considerable promise, the search for therapeutic candidates, particularly for addressing substance use disorders (SUDs) and their impact on cognitive, affective, sensory, motor, circadian, as well as behavioral changes, has been limited. Recent technological advances have facilitated processes for the discovery of novel bioactive NPs, including pre-fractionation and fractionation, NP-like and NP-inspired library generation, cell-free and cell-based screening, computational tools for rapid compound dereplication, the ability to isolate, identify, and re-supply active compounds rapidly. Moreover, the automatic processing of extracts, including the use of Artificial intelligence (AI) and Machine learning (ML) algorithms, are being tested across different stages of the NP drug discovery pipeline and encoded into molecular representations, molecular descriptors, likeness scores, chemical space, prediction of biological functions, and de-orphanization and generation of de novo NP-inspired compounds. Further development of these strategies is needed to accelerate NP-focused drug discovery and medication development efforts.

Goal

The goal of this concept is to leverage the recent technology developments in partnership with the National Cancer Institute, the National Center for Complementary and Integrative Health, and the National Center for Advancing Translational Sciences to encourage innovative NP-focused research involving lead discovery and drug development to address the challenge of SUDs. NP discovery and development research is technically demanding, inherently risky, and potentially highly rewarding. Thus, novel NP pipeline candidates for SUD drug discovery and development are needed to expand the targets and ligand chemical space. This concept will provide resources and opportunities for exploring NP-focused discovery research targeting SUDs.

Sample Research Questions

Research questions and areas that the concept will address.  

  1. What are the efficient strategies for high-throughput screening (HTS) of NP extracts to identify novel leads for clinically relevant SUD targets?
  2. What are the best approaches to deconvolute the hits from NP extract screening, isolate, purify, and elucidate the structures of active compounds? 
  3. What are the best approaches for testing potential NP candidates (specifically herbal formulations) in preclinical studies and clinical trials?
  4. How can traditional uses of botanicals and other NPs and sociocultural factors leverage ethnographic methods to facilitate the identification of novel leads for clinically relevant SUD targets?

Jia Bei Wang, Division of Therapeutics and medication consequences

Clinical Research on HIV-Associated Pain in the Context of Substance Use Disorders

Posted May 2024

Background

Chronic pain can be a significant burden for people who live with HIV (PLWH), especially those who use drugs, and is frequently associated with decreased quality of life and high disability.  Particularly relevant is the pain related to HIV neuropathy, a frequent complication of chronic HIV, but other types of pain syndromes such as musculoskeletal, rheumatic, headache, facial, and visceral are of concern. Pain is commonly complicated with depression, isolation, suicidal ideation, overdose, use of alcoholic beverages, malnutrition, etc. Comorbidities (obesity, diabetes mellitus, rheumatoid arthritis, etc.) often worsen the various pain syndromes in chronic HIV. Unfortunately, little is known about mechanisms and factors associated with pain in PLWH and SUD. Moreover, there is limited information about safe and effective treatments for this population.

Goal

The purpose of this concept is to support the development of a phased funding opportunity to support research that will help to elucidate the mechanisms and pathways of pain in PLWH and SUD and the development of safe and effective treatments (pharmacological, devices, and/or behavioral) to treat this important comorbidity and its medical and psychosocial consequences.

Raul Mandler MD, FAAN, FANA, Clinical Medical Branch; Division of Therapeutics and Medical Consequences; NIDA

Sustained Addiction Recovery: Mechanisms, Attributes, Process, and Persistence (STAR-MAPP)

Posted May 2024

Background

According to SAMSA’s 2022 National Survey on Drug Use and Health (NSDUH) “48.7 million people aged 12 or older (or 17.3%) had a substance use disorder (SUD) in the past year.” To address this public health crisis, these individuals ultimately need to be treated using therapy, medication, medication-assisted therapy, or other means to hopefully achieve a sustained addiction recovery. However, we know surprisingly little about the characteristics of the recovered brain, how long-term brain changes associated with recovery persist, or the mechanisms involved.

In the realm of basic addiction research, many NIDA projects focus on scientific questions surrounding brain alterations across the substance use trajectory, including but not limited to  drug consumption, withdrawal, abstinence, and relapse at the molecular, cellular, circuit, and/or behavioral levels. However, NIDA currently supports far less work investigating brain alterations associated with recovery at the molecular, cellular, circuit, and/or behavioral levels and virtually no research on the biobehavioral mechanisms underlying sustained recovery.  

Goal

To stimulate animal research projects that model important facets of sustained recovery in humans in the following areas:

  • Characterization of brain phenotypes associated with sustained recovery at the molecular, cellular, circuit, and/or behavioral levels
  • Temporal dynamics of sustained recovery phenotypes
  • Exploration of individual differences associated with successful sustained recovery
  • Illumination of the biobehavioral mechanisms associated with sustained recovery
  • Discovery of novel therapeutic approaches or strategies to help initiate, accelerate, or maintain sustained recovery

John Satterlee, Ph.D., Division of Neurobiology and Behavior, contact for Team Recovery (John Fedota, Nic Johnston, Hoang Le, Holly Moore, Sunila Nair)

Maternal Mortality from Drug Overdose: Causes, Mechanisms and Treatment

Posted May 2024

Background

Drug overdose deaths during pregnancy and in the postpartum period in the US have consistently increased in women aged 10 to 44 years with a dramatic increase of approximately 81% between the years 2017 and 2020. While several NIDA-funded projects focus on the effects of drug use during pregnancy, little is known about the factors that drive maternal mortality due to drug overdose during these vulnerable periods, the biological mechanisms that lead to increased vulnerability and mortality, and strategies that might enhance prevention and treatment quality during pregnancy and in the postpartum period.

Goal

To stimulate research targeted at understanding the causes of maternal mortality from drug overdose, the underlying biological mechanisms, epidemiology, and prevention and treatment strategies in this high-risk population. Areas of interest are as follows:

  • Identification of biological, social, environmental, epidemiological factors that increase vulnerability to drug overdose during pregnancy and in the postpartum period.
  • Identification of specific windows of vulnerability during the gestational and postpartum periods and the biological basis for increased risk within these windows.
  • Identification of biomarkers or signatures that may predict risk of drug overdose in pregnancy or in the postpartum period.
  • Actions of drugs on the maternal brain and/or maternal physiology and/or the placenta leading to overdose mortality. 
  • Influence of comorbidities such as postpartum depression and/or anxiety (or other mental health conditions), pain, sleep disorders or HIV and HIV-related infectious diseases (e.g., HCV) on the risk of maternal mortality from drug overdose and the underlying mechanisms.
  • Identify interventions and novel prevention and treatment approaches to mitigate against drug use and overdose during pregnancy and in the postpartum period.

Sunila Nair, Ph.D., Division of Neuroscience and Behavior.
In collaboration with Keisher Highsmith, DESPR, Angela Lee-Winn DESPR, Tanya Ramey DTMC, Rita Valentino, DNB. 

Promoting Medical Device Development for the Youth Affected by Drug Addiction and Substance Misuse

Posted May 2024

Background

Over 3.6 million young people aged between 12 and 17 use illicit drugs in 2022 alone. Very often, adolescents who fatally overdose do not necessarily show the warning signs generally expected beforehand, such as problems with alcohol or other drugs or prior substance use treatment. Only 1 in 10 teens and tweens who died from a drug overdose had a history of treatment for a substance use problem, and only 1 in 7 had ever experienced a prior nonfatal overdose. Medical therapeutic and diagnostic devices offer promising means to monitor, diagnose, and treat youth suffering from substance misuse or substance use disorders (SUD). Digital Health Technologies, including digital therapeutics and wearables, present auspicious opportunities for young people, avid users of such technologies.  The recent progress and activities demonstrate that the time is ripe for boosting the development of medical products specifically designed for the youth, as innovative pediatric medical devices have yet to be developed promptly at the same rate as adult medical devices. Under the current paradigm, devices are designed for adults, limiting the potential for usability and acceptability by the adolescent population. Similarly, existing algorithms supporting medical devices are often based on adult data and are not optimized for adolescents.

Goal

The proposed concept invites research and development of novel medical devices, including software as a medical device, specifically designed and developed for the youth and adolescents. Examples of medical devices could include, but are not limited to:

  • Artificial intelligence-based algorithms aimed to collect, integrate, analyze, and visualize multimodal data related to the diagnosis or treatment of drug misuse and addiction in youth. 
  • Stand-alone or adjunctive digital therapeutics focused on behavioral health interventions to diagnose, treat, prevent, and mitigate drug misuse and addiction.
  • Wearables and connected digital therapeutics at a point-of-need intended to detect, diagnose, and treat opioid-induced respiratory depression.
  • Therapeutic devices (e.g., neuromodulation) intended to improve SUD treatment outcomes and recurrence prevention.

Leonardo Angelone, Ph.D., Office of Translational Initiatives and Program Innovations 

Engaging Loved ones in Recovery Processes to Enhance Recovery Capital and Outcomes

Posted May 2024

Background

Addiction impacts many people beyond the individual with a substance use disorder, including family members (parents, spouses, siblings, children), romantic partners, friends and peers. These loved ones and caregivers often provide instrumental and emotional support that are the foundation of a person’s recovery capital. However, these support persons have often experienced a multitude of negative effects related to their loved one’s addiction. These relationships impact recovery trajectories in myriad ways, yet few interventions address these influential relationships or include support persons as targets of intervention. Support persons are often desperate to engage their loved ones in care but may face significant challenges in navigating a complex treatment environment where effective treatments such as medications for opioid use disorder (MOUDs) are stigmatized and may be harder to access than treatments with limited effectiveness. Yet, outside of research with adolescents, there is a relative dearth of research on how to effectively leverage and support these relationships to improve treatment navigation, engagement and recovery outcomes. Furthermore, there is a pressing need to address misconceptions and misunderstandings about OUD and effective treatments among support persons, as these misunderstandings can lead to increased stigma or create barriers to their loved ones engaging in effective treatments such as MOUDs.

Goal

The proposed initiative would address this crucial research gap by supporting studies to improve engagement of support persons. This initiative would support pragmatic trials focused on scalable, sustainable adaptations to existing EBPs and service delivery frameworks that emphasize enhancing engagement of loved ones and support persons, thereby strengthening recovery capital and increasing the likelihood of stable recovery. Approaches of interest include testing adaptations or new interventions that: 1) reduce stigma toward addiction and MOUD among support persons; 2) provide assistance to support persons in navigating care options for their loved one; 3) formally engage support persons in services; 4) leverage support persons as lay interventionists; and 5) enhance well-being and coping skills among support persons.

Tisha Wiley, Chief, Services Research Branch, Associate Director for Justice Systems, DESPR

Fundamental Research into Mechanisms that Contribute to HIV-Associated Pain in the Context of Substance Use Disorders

Posted May 2024

Background

Pain is a complex physiological state that involves more than nociception in its manifestation. As a systemic pathology, the fundamental mechanisms underlying the incidence, severity, and impacts of pain in people living with HIV (PWLH) need to be investigated. For example, chronic inflammation in PLWH is common, even with adherence to combined antiretroviral therapy (cART), which indicates persistent challenges to immune function and pain need to be addressed for effective management of pain conditions. There may be a bidirectional relationship with respect to the physiological underpinnings of perceived pain and the clinical course of HIV and its comorbidities. Reported pain intensity in individuals who are on long term opioid therapy tends to correlate with features such as socioeconomic status and psychiatric comorbidity (e.g. major depressive disorder and other conditions where pain catastrophizing may feature and/or pain contributes to comorbidity and symptom severity). Additionally, the use of substances (e.g. cannabis, alcohol) as self-medication for pain in PLWH is associated with indicators of poor health management, such as reduced viral suppression on cART, intermittent adherence to cART, psychiatric comorbidities and substance use disorders (SUD). Together these observations indicate that the degree and type of pain experienced by PLWH are powerful predictors of longer-term treatment outcomes and challenges with maintaining a good quality of life. As the length of pain suffering increases, so does the likelihood of its unmanageability, and with HIV as a lifetime chronic condition, strategies to mitigate the incidence and severity of pain, and its chronification over time become ever more important.
To address the unique challenges associated with the manifestation of pain in PLWH, and against the backdrop of comorbidity of HIV and SUD, we must develop an improved understanding of the fundamental mechanisms by which HIV and cART alter the immunological and neurological signaling landscape.

Goal

This NOFO will support basic research into the mechanisms of pain and modification/modulation of pain as a chronic condition in the context of HIV infection with special emphasis on the identification of targets for therapeutic intervention to reduce the risk of SUD and their comorbidities.  This includes, but is not limited to, research examining mechanisms contributing to analgesic medication escalation and tolerance under long-term use. Model systems that capture key attributes of HIV infection, volitional drug consumption, and with translational relevance are favored in this regard.

Division of Neuroscience and Behavior Contacts:
Tristan McClure-Begley, Ph.D.; Kathleen Borgmann, Ph.D.; John Satterlee, Ph.D.; Hoang Le, Ph.D.; Yu Lin, M.D. Ph.D.; Holly Moore, Ph.D.; Sam Ananthan, Ph.D.

Neuromodulation Controllers in Substance Use Disorder

Posted May 2024

Background

One of the most attractive aspects of neuromodulation as a therapeutic intervention is the flexibility of its implementation. Stimulation parameters are almost infinitely adjustable, and can be adapted iteratively with target sites, offering the potential to overcome significant individual differences. There a numerous studies indicating the therapeutic potential for targeted neuromodulation therapy, drawing on a rich background of functional neuroanatomy. Currently, time is spent personalizing the intervention with clinician-in-the-loop iterations to find the combination of parameters necessary for efficacy in the individual, and even then, benefit is not guaranteed. A closed-loop system with a built-in controller can reduce the time and trial-and-error nature of neuromodulation, leading to broader potential for adoption and a greater likelihood of scaling to meet the needs of a large and diverse patient population. Since the crux of good feedback loop control depends on the quantitative nature of signals and their robust prediction of state functions, then the selection of those signals and their coupling to (or degree of abstraction from) the state under modulation is the single greatest determinant of the control system’s performance. Right now, the most inclusive models make use of multimodal activity reporters that are not possible in humans (e.g., optogenetics, chronic multichannel array implants), so research is needed to bring the high-content networks and features from biological model systems together with human functional neuroanatomy to generate hierarchical models of neural circuit activity and test those models for control system design and validation in multiple behavioral models to evaluate generalizability and translational value.

Goal

This NOFO will support research into the development of hierarchical control models of addiction circuits as enablers of closed-loop neuromodulation therapy for substance use disorders. It is expected that research will follow a design-build-test cycle explore the design and construction of model-based control systems for neuromodulation and then test performance in comparison with a current exemplar therapy.

Tristan McClure-Begley, Ph.D.; Division of Neuroscience and Behavior

Multisensory Integration, Interoception and Substance Use Disorder

Posted May 2024

Background

A basic science research gap to be addressed is how sensory stimuli and interoceptive processing of those stimuli can influence different stages of drug taking behavior. The sensory processing regions of the brain are intricately linked to the motor regions underlying the execution of complex behaviors, and multisensory processing of external and interoceptive signals influence complex behaviors at both conscious and unconscious levels. This effect may be particularly potent for unexpected, novel, and/or salient stimuli. For example, the experience of a sudden exposure to a particular smell or taste can evoke both an obviously identifiable interoceptive state (i.e., hunger) and one that is more ineffable (i.e., a craving), and this same sequence can occur in addiction. Novel sensory stimuli and neural responses to them are also gaining interest as key therapeutic elements. Conversely, addictive drugs can elicit interoceptive signals that become associated with positive reinforcing effects of their use and can also alter the processing of sensory information, contributing to the pathology of addiction. The neurobiological basis for the bidirectional relationship between substance use and sensory/interoceptive processing is thus an understudied area with strong potential for identifying novel targets or therapies for treating SUD.

Goal

How different drugs interact with multisensory processing and plasticity and how these interactions modify drug use at different stages of the SUD trajectory are critical elements of this research initiative. Additionally, it is important to apply tools and models that allow us to examine the contributions of sensory processing occurring at conscious and unconscious levels to the contextual effects of drug use and progression through different phases of addiction. 

Research support will include (but is not limited to):

  • Exploration of circuits linking sensory processing, interoception, and reward.
  • Mechanisms of sensory-evoked synaptic plasticity in circuits relevant to reward and/or addiction.
  • Behavioral models and quantitative assessment of subjective sensory experience and impacts on motivated behavior.
  • Integrative approaches addressing environmental context and modifying factors on sensory-evoked plasticity. 

Tristan McClure-Begley, Ph.D.; Division of Neuroscience and Behavior

Discovery and Characterization of Anti-Addictive Neural Circuits and Mechanisms 

Posted May 2024

Background

Neural signals encoding value and cost are key to the survival of every organism with a nervous system. These signals and the shift in interpreted balance between value and cost are also key components in the cycle of addiction. However, research into the neuroscience of reward and appetitive behaviors wrestles with an abundance of false dichotomies that has been limiting to the potential target space for therapeutic intervention. The circuit-level encoding of subjective drug effects is likely much more complicated than simple ratios of “feel good/feel bad”, and impairments in these circuits may underlie the progressive loss of control in drug intake seen in people with substance use disorder. These circuits may act to produce “drug satiety” analogous to the role that ventral nucleus of the hypothalamus plays in inhibiting feeding, or alternatively may increase cognitive control or provide more dynamic range for perceived effects. Neuromodulation to oppose addiction-related signals and behaviors has focused on interruption of nodes in neuroanatomical networks that are positively connected to correlates of addictive processes, but what has been lacking is direct interaction with the modulators of those core nodes (either parallel or convergent circuits). In other words, we see evidence for efficacy from interfering with the positive actuators of addiction, but there is a gap in identifying and modulating the anti-addictive actuator circuits, or the things that shift the balance of cost/value without producing perceived aversion or threat.  

Recent molecular neurobiology studies have identified the existence and modulatory influences of multiple discrete cell types using multiple signal types (neuropeptides, growth factors, etc.) that provide insights into how specialized subpopulations of neurons can impact different features of a complex subjective rewarding experience. These extended circuit components have shown the ability to “temper” elements of reward and cue-induced motivated behavior without eliciting aversion, indicating the potential for targeted modulation with specificity for aberrant activity. Research is needed to assemble these modulatory signals and their cells of origin into an expanded network of addiction-related neural circuitry that provides finer resolution on how such a spectrum of experiences and motivations to consume drugs exists.

Goal

This NOFO will support research that identifies neural substrates and circuits that act in opposition to processes engaged during stages in the trajectory of drug use. These studies are expected to identify and characterize components and effectors of neural circuits that modify the subjective experiences of addictive drugs as a roadmap towards therapeutic interventions. 

Tristan McClure-Begley, Ph.D.; Division of Neuroscience and Behavior

Data Integration to Reveal Biological Pathways Underlying SUDs

Posted May 2024

Background

Biomedical research aimed at understanding how addictive drugs alter brain biology and function to engender a state of physical dependence and/or promote the compulsive behavior that characterizes addiction is generating a substantial amount of data of various types (i.e., imaging, genetics, physiological, electronic health records, etc.) from different species. Data integration is the process of combining data from multiple sources into a single, unified view with the goal of making the data more useful and meaningful for analysis and decision making. Integrating multi-omic and multi-species data is critical to further our understanding of the biological pathways underlying substance use disorders. Data integration methods can be applied across any set of phenotypes, comorbidities, and SUDs; some examples are combining various types of multi-omic data to understand opioid addiction or combining animal model and human data to find actionable human mechanisms.

Members of the NIDA Genetics Consortium and NIDA Animal Genomics Program have made initial efforts to integrate human and animal data, including establishing phenotypic and cross-species genomics databases, forging collaborations, and publishing foundational papers demonstrating shared gene networks among human and animal studies of nicotine and alcohol use disorders. However, these studies would benefit greatly by concerted efforts using machine learning to understand SUD mechanisms, such as heterogeneity among different types of omics data (e.g. genomics, epigenomics, transcriptomics, proteomics), whereby affected individuals may contain genetic or other omics changes that converge into a phenotype or trait. Different parts of the mechanism can be explored by examining multiple omics layers. Genes that contribute to a complex phenotype should have significant topological connectivity in multiplex networks that represent genic interactions, which facilitates the ability to filter out noise and false positives among the gene sets. Moreover, such integrated analysis of multi-omic data could reveal novel, as yet unexplored targets that could be pursued for development of therapeutic approaches to address substance use disorders and addiction.

Goal

To address these challenges and maximize the opportunity offered by integrating various types of data, this NOFO would aim to address the following objectives:

  • develop innovative and generalizable computational methods for analysis of data from different species
  • explore the impact of gene regulatory and genetic variation on gene expression patterns across different substance use disorders
  • identify shared and unique gene regulatory and gene expression patterns across cells, tissues, species, and development
  • integrate data from different species to find actionable human mechanisms for substance use disorders
  • integrate imaging data across different modalities such as DTI, resting-state, fMRI, and integrate imaging data with behavioral, genetic, and survey data

By encouraging data integration, the supported projects will contribute to:

  • Approaches to integrate various types of data with the data that exists in publicly available databases 
  • Develop approaches to integrate data from the same individual and across individuals
  • Develop new methods that account for genetic diversity of gene regulation across developmental trajectories
  • Develop new approaches to make predictions about the functional relevance of genetic variants to gene regulation 
  • Explore methods to link multi-omic data sets for improved causal inference

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

Developing Medications and Devices for Comorbid Substance Use Disorders

Posted May 2024

Background

NIDA’s Division of Therapeutics and Medical Consequences (DTMC) invites preclinical and clinical research to advance the development of medications and devices to treat comorbid substance use disorders. We highlight this topic of interest because the number of overdoses involving multiple drugs of abuse has increased dramatically in recent years, comprising the majority of overdose deaths in the United States. Furthermore, polysubstance use is associated with worsened access to treatment and poorer outcomes. Effectively treating this complex clinical population will require new therapeutic targets and treatment strategies. This Concept expands the scope of previous Funding Opportunities for the development of medications to prevent and treat comorbid opioid and stimulant use disorders to encompass all permutations of polysubstance use, including benzodiazepines, cannabinoids, nicotine, opioids, stimulants, and/or other drugs of abuse.

Goals

  • Develop medications alone or devices alone or their combination to treat comorbid substance use disorders
  • Develop medications alone or devices alone or their combination to treat overdose due to concomitant use of multiple substances
  • Identify and understand the medical and psychiatric safety risks of concomitant us of multiple substances and study methods to treat them with medications and/or devices.

Drew Townsend, Ph.D., Division of Therapeutics and Medical Consequences

Fostering Lay Community and Community with Lived Experience Awareness on Biomedical Product Development for Substance Use Disorders

Posted May 2024

Background

Biomedical product development is a highly regulated, costly, long, and complex process that is largely unrecognized by the lay public. This is especially prominent in substance use disorders (SUD), leading to disenfranchisement of the affected populations. In an era of growing demand and emphasis on both quality and sustainability of healthcare, it is critical to address this major gap in perception and knowledge.

Raising societal awareness in the SUD product development area would significantly facilitate the acceptance of innovative interventions into high-quality care.  Indeed, well-informed patients and caretakers have a key role to play in the design of patient-centered clinical research strategies, approval processes and informing the future research agenda. Informing patients and caretakers about the stringent principles of SUD product development is critical to ensure the reliability of clinical trials and treatment adherence, as well as for the successful patient participation in defining the products tailored to patients’ individual needs.

Although several patient organizations, pharmaceutical companies and academic research organizations have developed successful information programs on drug development for specific diseases of interest, such effort in SUD is lacking. This NOFO offers a unique opportunity to bring together experts from the pharmaceutical industry, academia, patient organizations, health professionals, ethical bodies, regulatory authorities, and media to jointly work in an open and transparent way to improve the understanding of SUD biomedical research and development among patients, carers, and other interested lay people.

Goal

The successful application will build innovative education programs for patient awareness centered on the following themes:

  • The complex nature of biomedical research aiming at SUD biomedical breakthroughs (i.e. translational medicine), with emphasis on the respective roles of the different stakeholders involved and, on the processes, leading to regulatory approval.
  • Rational approach to product safety and risk benefit assessment of novel SUD products from the perspective of the various stakeholders involved.
  • The growing importance of pharmaco-economics and health technology assessment in modern medicine.
  • The design and objectives of clinical trials, with emphasis on the respective roles of the different stakeholders involved, in particular, SUD patients themselves.
  • The synergies between innovative medicines and other strategies to enhance patient-centered chronic disease management.

Jess Lukacs, MD, MBA, Office of Translational Initiatives and Program Innovations

In Vivo Research on the Effects of Methamphetamine Use on HIV Infection, Expression, and Persistence

Posted May 2024

Background

The effects of METH use on HIV latency, persistence, reactivation, and clearance are areas of great concern in the context of HIV cure research.  Since peripheral immune and neural cells express METH receptors, METH has been implicated in the seeding and persistence of the HIV reservoirs throughout the body by altering cellular epigenetic, transcriptional, and functional phenotypes.

Many in vitro mechanisms have been identified by which METH directly and indirectly affects HIV infectivity, expression, and persistence in cellular models.  While these studies have provided important insights, the effects of METH on HIV cure strategies, including broadly neutralizing antibody/anti-antibody responses, CRISPR editing therapies, latency inducing/reactivating agents, are understudied, especially in complex model systems that recapitulate the pathology of human disease.  Therefore, there is a need for confirmation and expansion of mechanistic research with in vivo models and clinical studies of METH use and HIV across the human lifespan. It is anticipated that In vivo and human studies are likely to provide a more complete assessment of the comorbid effects of METH use and HIV.

Goal

This initiative seeks to promotes research into the complex interactions between METH use and HIV disease biology in vivo. The initiative supports METH-relevant mechanistic studies and confirmatory research connecting in vitro research outcomes with in vivo models of HIV and clinical studies in people who live with HIV (PWH) across the human lifespan.

Da-Yu Wu, Division of Neuroscience and Behavior

Exploring the Roles of Endocannabinoids and the Effects of Exogenous Cannabinoids on Brain Development

Posted May 2024

Background

The endocannabinoid system plays a pivotal role in embryonic, fetal, and adolescent brain development, impacting neurogenesis, differentiation, axonal elongation and pathfinding, as well as synaptic growth, and neural circuit modulation.  Meanwhile, the growing evidence suggests that exposure to cannabis and its derivatives during critical windows of brain development can dysregulate the endocannabinoid system, resulting in adverse psychiatric, cognitive, and behavioral disorders.  Therefore, it is important to identify mechanisms by which exogenous cannabinoids affect developmental programming through their effects on the endocannabinoid system.  Research is critically needed to advance our understanding of specific genetic, epigenetic, molecular, and cellular mechanisms by which the endocannabinoid system regulates developmental processes, and how exposure to cannabis and derivatives during critical periods of brain development interact with these mechanisms.

Goal

This initiative seeks to foster studies of the roles of endocannabinoid system and the impact of exogenous cannabinoids exposure during brain development.  Specific program interests include, but are not limited to, the role of endocannabinoid system in genetic and epigenetic regulation, neural and glial proliferation, migration and differentiation, neural circuit formation and synaptic plasticity, as well as the effect and/or consequences of cannabinoid exposure in the developing brain.

Da-Yu Wu, Division of Neuroscience and Behavior

Building an Innovation Platform for the Repurposing of Medicinal Products for Substance Use Disorders

Posted May 2024

Background

Drug repurposing is the identification of new therapeutic uses for existing or investigational drugs. It can reduce development time (< 6 years) and costs (<$200 mil) compared with de novo drug discovery and development. However, drug repurposing faces several challenges and barriers, such as inadequate resources, trial data access and transparency, and expertise: uncertainty about the value of repurposing, liability risks, and intellectual property (IP) challenges. These challenges and barriers often discourage the industry from investing in drug repurposing.

Although basic drug addiction research is highly active, the transition to the clinic is seriously limited. The translational success of the neurobiology of substance use disorders can be enhanced through the application of diverse strategies and methodological approaches, including drug repurposing. Most drug repurposing efforts for SUD originate in academia, whose well-intentioned efforts are often jeopardized by the lack of experience and practical knowledge. Instead of supporting such fragmented energies in drug repurposing, NIDA could significantly increase its research efficiencies by creating a fully-fledged, multidisciplinary infrastructure for validated precision drug repurposing at every stage in the value chain – one that is open to all stakeholders for information, capacity building, matchmaking, and cooperation.

This NOFO seeks to establish a first-in-class coherent and innovative web-based platform for safe and efficient drug repurposing for substance use disorders (SUD), ensuring global medical impact. This platform will operate as a hub for key information, training resources, matchmaking, and cooperation in drug repurposing, providing extensive expertise throughout the whole value chain in drug repurposing: from freedom-to-operate analysis to intellectual property protection and business development, reimbursement assessment, ethics, and data governance considerations.

Goal

The successful application will build an innovative platform for repurposing medicinal products for SUD centered on the following themes:

  • Design and set up a platform supporting an innovative repurposing model for SUD. This model should integrate the scientific, methodological, financial, legal, regulatory, and intellectual property aspects of the repurposing approach.
  • Provide robust and transparent selection mechanisms for prioritizing already approved medicinal products or investigational products for repurposing. 
  • Leverage, pool and share existing high quality SUD data assets, also by using pharmacogenomics, in silico, and artificial intelligence (AI) approaches, innovative preclinical human in vitro cellular/multi-organ validation methods, and deliver new computational tools.
  • Resolve the fragmentation and lack of ownership of the repurposing approach that greatly impedes the efficient exploitation of its potential, networking existing projects and initiatives in the field. Particular attention should be given to supporting and strengthening academic-driven research.

Saravanan Karuppagounder, Ph.D., Office of Translational Initiatives and Program Innovations

Effects of HIV on Drug-Seeking and Impulsive Behavior

Posted May 2024

Background

Substance use and HIV are highly comorbid disorders. While substance abuse exacerbates HIV disease, emerging evidence also suggests that viral proteins may potentiate the rewarding effect of some addictive substances. The key question is whether HIV increases the severity of drug use and addiction.  Understanding whether HIV infection alters drug-seeking behavior and impulsivity is important for better managing the treatment of SUD and HIV infection. 

Goal

  1. What is the effect on drug-seeking behavior and impulsivity in improved animal models that express the correct cellular and spatial expression of HIV protein or the HIV virus?  Specifically, how does the HIV viral protein or HIV virus affect sensitization, conditioned place preference, self-administration, ICSS thresholds, motivation to seek a drug, extinction, and drug and cue reinstatement of drug-seeking behavior?
  2. Does infection with HIV or the expression of HIV viral proteins in specific nuclei and pathways increase drug-seeking pathway by making mesolimbic dopamine system more sensitive to the drug or by suppressing an anti-reward pathway?
  3. Does infection with HIV or the expression of HIV viral proteins alter the aversive properties of drugs?
  4. Does infection with HIV or the expression of HIV viral proteins change impulsive behavior in the presence or absence of drug?
  5. How does the temporal pattern of drug use and HIV infection affect drug-seeking behavior?
  6. What are the mechanisms by which HIV exposure produces changes in drug-seeking behavior and impulsivity?

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

Annual Conference in Therapeutics Development for Substance Use Disorders

Posted May 2024

Background

The body of research on therapeutics development for substance use disorders (SUDs) and the scientific community working in this area have grown substantially in recent years. As a result, multiple research questions and challenges have emerged. For example, new tools to identify compounds, validity and predictability of pre-clinical models, clinical trial designs, outcome measures, regulatory requirements, etc. Currently, a forum where investigators from all sectors (industry, NIDA, and academia) can interact and share knowledge focusing specifically on relevant scientific issues of therapeutics development for SUDs does not exist. Most CNS conferences tend to neglect SUDs and most SUD conferences tend to emphasize basic mechanistic studies or clinical applications. Consequently, investigators developing treatments for SUDs often find themselves working in isolation or with limited access to peers and industry partners to discuss and advance their treatments. Therefore, there is an urgent need for a specialized forum to discuss relevant scientific and practical issues in the development of therapeutics for SUDs.

Goal

The Goal of this concept is to support a Conference Award to develop and implement an annual scientific meeting that involves participants from academia, industry, and NIDA to advance the development of therapeutics for SUDs to:

  • Facilitate knowledge sharing.
  • Encourage communication by identifying and addressing common challenges faced by all sectors and leveraging each other’s expertise to find solutions.
  • Foster collaboration (e.g., developing joint projects).
  • Facilitate transactions (e.g., licensing of compounds).

The ultimate goal is to accelerate the development, FDA-approval, and commercialization of safe and effective treatments for SUDs by fostering communication and collaborations among industry and academic investigators, and NIDA staff.

Ivan Montoya, Division of Therapeutics and Medical Consequences.

Mechanisms of Cell-Cell Interactions and Communication in CNS HIV Replication

Posted February 2024

Background

CNS resident cells interact with different cells to promote and protect the homeostatic functions of neuronal cells. Although increasing studies suggest brain microglia may serve as a HIV reservoir and ignite rebound viremia following repeated antiretroviral therapy (ART), CNS hosts several resident immune cell populations other than microglia. Recent studies also have demonstrated that HIV infection of astrocytes is via the cell-to-cell contact mechanism. Although the reactivated HIV in the astrocytes exert poor viral productivity, they can conduct efficient cell-to-cell viral transfer to neighboring cells and thus support high viral replication. Productively infected cells are capable of spreading the bystander cell death into neighboring uninfected cells by a cell-to-cell contact-dependent mechanism. However, the exact mechanism in this regard is still unknown. Since HIV infection in the brain is tightly regulated via cell-cell interaction, and HIV-induced inflammation can cause neuronal death by direct or indirect cell-cell interactions and the release of inflammatory cytokines, understanding the mechanism of cell-cell communications under the influence of substance use is essential for HIV cure.

Goal

The majority of the HIV studies focuses on a specific CNS cell type; however, the CNS reservoirs are dynamic. Understanding the cellular characteristics and viral dynamics in CNS reservoirs is critical, it is essential to investigate at the level of cell-cell communications, as well as the underlying mechanisms in the context of substance use and HIV infection.

This initiative will support research in the following areas:

  • Crosstalk between neurons and CNS resident cells– mechanisms of bystander effect and their impact on brain development and neurodegenerative processes (HIV associated NCD and other aging related comorbidities).
  • Functional changes of circuitry arise from specific cell-cell communications in brains of people aging with HIV and using addictive substances and ART.
  • Identifying cell-cell contact mechanisms required for viral transmission in HIV infection and substance use.
  • Bi-directional signaling between astrocytes-neurons, microglia-neuron, and glia-glia. How substance use mediates viral transmission and activation in neighboring cells and consequences of HIV propagation.
  • Studies to understand prevalence and identity of directly transferred proteins and the cellular specificity of transfer at cell-cell junctions using cutting-edge techniques. 
  • Characterization studies using 3D tissue models and mircophysiological systems, animal models, and imaging tools.

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

Waste Not, Want Not: Exploring interactions between brain waste clearance and renewal systems with HIV and addiction

Posted February 2024

Background

The brain has a waste clearance and renewal system that refreshes the parenchyma by driving cerebral spinal fluid (CSF) into the brain along periarterial spaces and removes waste as interstitial fluid (ISF) drains out of the brain along perivenous spaces. These drain to the brain meningeal lymphatic system to the cerebral lymph nodes. While these processes are highly dependent on sleep, the waste clearance and renewal system is likely affected by other physiological mechanisms. Dysfunction in the brain’s waste clearance and renewal system has been described as a consequence of aging, which may play a pathogenic role in various neurological pathologies. However, the mechanisms regulating waste removal and renewal in the context of substances with addiction potential, substance use disorders and people aging with HIV are largely unknown.

Stimulants, opioids, and HIV have been shown to dysregulate cerebral blood flow, aquaporin-4 (AQP4) expression, aggregation, and polarity - impairing fluid exchange and promoting gliosis in various brain regions. Cerebrospinal fluid metabolomics revealed altered waste clearance and aging-related markers in people living with HIV associated neurocognitive impairment. Further, AQP4 deficiency significantly reduced heroin-induced self-administration, morphine-induced behavioral sensitization, and restored cocaine induced impairment of neural cell proliferation in animal models. Studies have also shown that stimulants, opioids, and HIV disrupt the normal functioning of the blood-brain barrier (BBB), increase BBB permeability, induce neuroinflammation, and reactive oxygen species, while dysregulating glutamate signaling in the brain. These changes can lead to damage to neurons and astrocytes, impaired fluid exchange, and altered expression and activity of genes and proteins that are involved in waste clearance and renewal system function.

Significance: Targeting the glymphatic-lymphatic system could have a translational impact on regulating drug-related behaviors and mitigating neurological damage from substance use, addiction and HIV-associated brain injury, presenting a promising avenue for the development of new therapeutic interventions.

Goal

Despite potential roles in regulation of sleep, brain health, and neurodegeneration, the mechanisms regulating waste removal and renewal in the context of substances with addiction potential, substance use disorders and HIV are largely unknown. This funding opportunity will support research into the mechanisms regulating the waste clearance and renewal system and the roles that the fluid exchange system plays in regulating addiction and HIV-associated neurological impairment. Understanding the interplay between the waste clearance and renewal system, HIV and SUDs may provide new insights for developing interventions.

Kathleen Borgmann, Ph.D., Division of Neuroscience and Behavior

Research to Address Systemic and Structural Barriers and Facilitators to Improve the HIV Pre-Exposure Prophylaxis (PrEP) Care Continuum for People Who Use Substances

Posted February 2024

Background

Pre-exposure prophylaxis (PrEP) is a safe, highly effective medication for preventing transmission of HIV from sex or injection drug use. More recently, the US Preventive Services Task Force released their updated Recommendation on PrEP that called for more research on increasing PrEP uptake and adherence, particularly among people who inject drugs. Despite PrEP’s high efficacy and its availability for over a decade, the awareness, uptake, and adherence of PrEP, especially among people who use substances remain suboptimal, suggesting the need to address access at a systemic, rather than solely individual level. The introduction of long-acting injectable PrEP after its FDA approval in December 2021 provides a new tool for enhancing the PrEP care continuum among people who use substances. However, successful implementation of that tool will require careful attention to the barriers and facilitators of access with specific systems. Innovative strategies that focus on unique contexts, challenges, and preferences of end users, with an intersectional lens to address socio-structural determinants of health that contribute to the PrEP care continuum (i.e., awareness, uptake, and adherence) are needed to address the persistent PrEP disparities.

Goal

The goal of this concept is to examine and address systemic and structural factors that impede or facilitate the PrEP care continuum among people who use substances. Projects will support the development, implementation, and evaluation of effective strategies to improve the PrEP care continuum. Intervention strategies will be expected to meet the needs of people who use substances, particularly among populations who have been understudied in the past, including women, adolescents and young people, transgender people, people who inject drugs, and sex workers.

Angela Lee-Winn, Ph.D., Division of Epidemiology, Services, and Prevention Research

Pilot Health Services and Economic Research on the Treatment of Drug, Alcohol, and Tobacco Use Disorders 

Posted September 2023

Background

NIDA’s Services Research Branch (SRB) supports rigorous research to optimize the efficient delivery of high-quality substance use treatment and related services when and where patients need them and wherever they are on the substance use disorder recovery trajectory. Research is needed to ensure that effective substance use disorder (SUD) services are delivered and sustained at scale, maximizing access to such services by the people who could benefit from them. Maximizing access includes identifying novel settings where services can be delivered and attending to the needs of vulnerable populations. Engagement with key stakeholders and patients are critical to connecting research to practice and achieving these goals.

Goal

The goal of this concept is to support pilot and preliminary health services research that will assess the feasibility, acceptability, and utility of a wide range of approaches designed to optimize the efficient delivery of high-quality substance use treatment and related services that meet the needs of individuals with SUD on the substance use disorder recovery trajectory. Relevant trials may test interventions, practices, and policies designed to optimize SUD treatment and related services accessibility, quality, effectiveness, affordability, and utilization. Relevant approaches may include both those that are novel, and those that are commonly used in practice but lack an evidence base. Investigators supported will identify hypothesis-driven research questions in the context of a broader conceptual model, which should follow through to the envisioned subsequent larger-scale services research trial. 

Keisher Highsmith Dr.PH, Division of Epidemiology, Services and Prevention Research

Mechanistic Studies on Social Behavior in Substance Use Disorder

Posted May 2023

Background

Social behavior, an umbrella term that spans multiple cognitive and emotional processes, is mediated by a complex, distributed network of brain regions. Substance use and substance use disorder (SUD) are associated with myriad differences in social processing, including but not limited to social threat processing biases and emotion recognition deficits. While substance use likely contributes to these differences, studies have identified social behavioral risk factors for SUD that predate substance use and potentially influence the substance use trajectory. There has been increasing recognition of the need to further develop research on how social behavioral processes influence the onset and trajectory of SUD. Current research gaps include:

  1. Limited data on social behavioral phenotypes that impact the SUD trajectory and, conversely, on understanding the impact of substance use on social cognition and behavior
  2. Limited understanding of social processing differences that may be specific to SUD and not manifested with substance use in the absence of SUD; for example, studies have revealed social behavioral impairments, such as impaired theory of mind processing, that may be more specifically linked with SUD and not observed with recreational or medical use.
  3. Paucity of research aimed at elucidating neural circuit mechanisms underlying social behavioral function in the context of SUD risk, particularly with respect to neurocognitive development

The above gaps can be addressed through development and application of novel behavioral paradigms aimed at assessing social cognitive function in people diagnosed with, or at risk for, SUD, and by building computational models that can leverage data from both human and animal studies. Through clinical research that leverages existing datasets (e.g., ABCD) and with original experimental studies, we can achieve mechanistic insights that incorporate the broader socioenvironmental context in our understanding of social behavior. Complementary animal models of social cognitive processes, informed by mechanistic research in humans, are also needed to address gaps in our understanding of psychosocial and neurocognitive causal mechanisms. Importantly, there is an unprecedented opportunity to advance translational research on SUD by leveraging the rapid advancement of technologies for continuous, high-resolution, holistic behavioral data from humans and animals as they interact in naturalistic settings (e.g., BRAIN Initiative Brain Behavior Quantification and Synchronization Program).

Goal

We propose to leverage ongoing momentum in these interacting fields by supporting mechanistic research in humans and animal models to advance our understanding of social processing in SUD. The proposed initiative will catalyze collaboration among experts in addiction science, social and cognitive neuroscience, cognitive psychology, sociology, neurobiology, neuroethology, intervention science, computational modeling, artificial intelligence, and lived experience with SUD to guide design and interpretation of innovative studies. Supported studies are expected to be relevant to the development of preventative and therapeutic interventions.

Topics of interest include, but are not limited to:

  • Development of novel behavioral paradigms towards investigation of SUD-relevant behavior and neural circuitry (e.g., application of machine learning approaches to quantify human behavior)
  • Application of existing behavioral paradigms (e.g., virtual reality, hyperscanning using fMRI or fNIRS, pupillometry, speech or electronic media analysis) towards uncovering social processing differences associated with SUD
  • Teasing apart differences in social behavior that predate substance use vs. those that are induced by substance use
  • Differentiating impairments in social behavior specific to SUD from those observed more broadly in recreational or medical use
  • The impact of social threat or disruptions of social bonding on social behavior in the context of SUD (e.g., biasing the animal toward choosing drug over a social interaction), and the neural mechanisms underlying these effects
  • Identification of social behavioral predictors of susceptibility to drug-seeking and/or the impact of drug use on social function using computational approaches
  • How communication of negative or positive affective states can influence drug-seeking or other SUD-relevant behavior and related brain function in the receiver
  • Neural circuit targets for increasing the sensitivity to affiliative social behavior and its impact on behavior at different stages of the SUD trajectory, e.g., slowing or preventing the transition to compulsive drug-seeking, accelerating voluntary abstinence, reducing the probability of cue- or stress-induced reinstatement of drug-seeking

Mary Kautz, Ph.D., Holly Moore, Ph.D., Vani Pariyadath, Ph.D., Division of Neuroscience and Behavior

Studying the Neuroplastic Effects of Addictive and Therapeutic Substances Using Next Generation Quantitative Readouts of Synaptic Connectivity

Posted May 2023

Background

Many, if not all psychoactive drugs affect synaptic connectivity. Both the addictive and therapeutic properties of substances have been attributed to their ability to modify neural circuitry through remodeling of synapses. However, to what extent different drugs impress unique or shared “fingerprints” on the distribution and composition of synapses, across brain regions, circuits, and cell types, remains an unresolved question. Studies that have addressed these questions in the past have often been conducted in cultured cells and have been limited in their robustness for synapse identification, and resolution scale, sampling.

Goal

This concept aims to support research to comprehensively and quantitatively map the effects of psychoactive drugs (addictive and/or psychedelic) on synapse distribution and nanostructure in intact molecularly resolved circuits. Conducting these studies with improved scale and granularity is essential to rigorously test whether synaptic connectivity encodes drug action, and how different “types” of synapses contribute to complex drug effects on physiology and behavior. The program will aim to promote the implementation of next-generation quantitative readouts of synaptic connectivity to address SUD related questions, by enabling collaborations between technology developers and addiction neuroscience experts.

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

Taking the First Step in Translating New SUD Research Ideas: Centers to Support Early Technical Development for Pharmacotherapeutics and Digital Therapeutics

Posted May 2023

Background

There are multiple hurdles in translating new ideas from the lab into a clinically viable commercial product. Specifically, many academic researchers are unaware of the initial steps needed to transition a discovery out of the lab and into a commercialization pathway and often do not have the resources to investigate these pathways while maintaining a productive lab. Training in the principles of defining a product, the first step in translating a promising new idea, is limited for academic researchers. Researchers with ideas for new SUD products do not understand the resources available to support early product development, leading to a loss of potential new treatments for SUD if these ideas never move beyond the lab bench.

NIDA currently supports the entrepreneurship and business development aspects of early-stage product development through the UE5 centers at MIT, Babson, and Johns Hopkins. However, more support is needed for aspects of technical development in the context of translation to enable the transition of these novel ideas into tangible biomedical products. Based on previous NIDA-supported initiatives in early translational research, addiction researchers have a strong desire to learn formal product development skills and gain access to technical expertise and support. Therefore, this concept aims to establish a center (or centers) of excellence intended to support technical needs in the emerging product development stage for early discoveries to transition them to a product development pathway. Specifically, this funding will support centers capable of technical leadership in novel pharmacotherapeutics and digital therapeutics for SUD.

Goal

Establish a technical development center (or centers) to assist researchers to develop new pharmacotherapeutics and digital therapeutics for SUD. These centers will provide idea developers with technical development support to prepare the PI for a future Phase I STTR/SBIR submission. The technical development assistance will include support from experts in “idea to product” translation activities including the following:

  • target product profile development
  • clinical need assessment
  • project plan development with timeline and milestones
  • prototype development
  • proof-of-concept study design
  • preliminary safety assessments
  • assistance in understanding current and future regulatory requirements
  • data generation to support future Phase I STTR/SBIR application

Stacie Gutowski, Ph.D., Sara Lioi, Ph.D., Tam Nguyen, Ph.D., Office of Translational Initiatives and Program Innovations

Artificial Intelligence-Enabled Translation of Interconnected Targets into New Pharmacotherapeutics for Substance Use Disorders (SUD)

Posted May 2023

Background

Drug discovery and development is a costly, high-risk, and time-consuming endeavor where the failure rate in clinical trials is 90% and are due to a lack of clinical efficacy (45%), unmanageable toxicity (30%), poor drug-like properties (15%), and lack of commercial need (10%). In recent years, drug developers have embraced artificial intelligence (AI) technologies to reduce clinical failure rates, speed drug discovery, and enable precision medicine. These AI methodologies can design new molecules and conduct virtual preclinical studies, allowing companies to refine, reduce and potentially replace in vitro and ex vivo experiments as well as in vivo studies in animals. As the COVID-19 pandemic raged, Pfizer was in a race to find a new treatment drug and relied on AI technologies to accelerate the discovery of its anti-covid drug, paxlovid. However, AI-enabled drug discovery for substance use disorders (SUD) has lagged. One main reason is that AI technologies are traditionally built around the lock-and-key mechanism that involves the identification of a drug that can target a single receptor to modulate the disease condition. Although single target-based AI drug design may be adequate for some indications, SUD can be caused by complicated mechanisms and can be outside of the traditional drug discovery paradigm. Novel AI technologies that are trained for polypharmacology could significantly improve the research and development of new medications to treat SUD. Such AI tools can assess the effects arising from binding multiple targets (beneficial polypharmacology), and thus improve potential clinical efficacy, as well as identify the pathways and mechanisms that can lead to side effects caused by drug binding to unwanted off-targets (adverse polypharmacology), and thus reduce unmanageable toxicity. Such AI tools can identify the best target combination, design effective multi-targeting agents, and inform the in vitro and in vivo assays to characterize the effects of these compounds on multiple targets and functions. To deliver proof-of-concept, there is also a need for assays utilizing more cell-free, cell-based, and animal models that can simultaneously assess the effects of compounds on multiple targets or functions. Since animal models are usually complex, costly, and time-consuming, the use of simple organisms such as C. elegans and zebrafish may be a path to proof-of-concept studies. AI trained in complex mechanisms should lead to remarkable discoveries.

Goal

Develop artificial intelligence tools and experimental assays to identify pharmacotherapeutics with desirable pharmacological properties for substance use disorders (SUD). Areas of interest include but are not limited to: 1) the development of AI tools to identify potential target combinations, design new molecules, and conduct virtual preclinical in vitro and in vivo studies to efficacy and toxicity, and polypharmacology and 2) the development of assays to determine the effects of compounds on multiple targets or functions.

Tam Nguyen, Ph.D., Office of Translational Initiatives and Program Innovations

Combined Neuromodulation and Behavioral Treatment Algorithm Development for Stimulant Use Disorder (StUD) Enriched for Vulnerable Phenotype

Posted May 2023

Background

Neuromodulation technologies (e.g., TMC, tDCS, focused ultrasound, and others) are being examined across SUDs (alcohol, nicotine, opioid use disorders). However, there is a paucity of information across different patient populations, e.g., in StUD- vulnerable with cognitive dysfunction, and compulsive and impulsive traits. To neuromodulate impulsivity and to improve decision-making we propose to develop combination approaches of neuromodulation and existing and/or novel behavioral treatments, such as CBT, and mindfulness-based. Developing neuromodulation combined with behavioral treatment modalities that will help to maintain use decrease and prevent relapse would be of great value, especially in the absence of FDA-approved StUD treatments. Randomized controlled trials are needed to develop treatment algorithms.

Goal

  • Determine which brain areas for neuromodulation methods to target and for how long in terms of session duration, number of sessions, and when (timing-wise) to add the behavioral treatment follow-on
  • Characterize the functional imaging brain activity changes that would be characteristic of response and with what clinical symptoms
  • Focus on how to modulate impulsivity and enhance decision-making in the StUD vulnerable phenotype
  • Determine what could be an effective behavioral treatment paired with neuromodulation methods, especially as a remote version
  • Elucidate interactions with behavioral therapy to examine timing, extent, and cumulative effects

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

Psychedelic Treatment Research for Alcohol and/or Substance Use Disorder (ASUD)

Posted May 2023

Background

Psychedelic treatments are currently in clinical development for a range of mental disorders. Therapeutic areas undergoing active clinical research include alcohol and substance use disorders (ASUD). The exploration of psychedelics purported beneficial outcomes requires our urgent attention.

In a recent Workshop on psychedelics, NIDA mapped its opportunities, challenges, and gaps. Among the latter, the topics of set and setting, and whether the subjective mystical experiences are needed for the clinical effect were debated. The psychotherapeutic component of the treatment administration, the role of an expectancy and placebo effect for the total treatment effect are also important questions. Such key barriers to patients' engagement in treatment as lack of insight, and interoception impairment have a significant negative impact on all treatment options currently available.

This concept supports clinical studies applications to study psychedelic treatment administration paradigms, assess the role of psychotherapy in its administration, and describe and assess the range of clinical outcomes, including downstream functional effects, that are evidenced as the result of this treatment. The concept also invites applications that test novel endpoints and the changes that occur with the psychedelic treatment, such as insight and interoception improvements and their downstream effects on response and relapse rates.

Goal

  • To explore what psychedelic treatment administration approaches are best suitable and developed for ASUD.
  • To elucidate the role of the psychotherapy component in treatment administration and its optimal type, content, the timing of administration, and its duration.
  • Impacts of the set and setting with the current psychedelic administration paradigm and what are their key characteristics to retain.
  • The role of an insight changes and/or interoception as potential mediators/moderators of decreased substance use and relapse rate.
  • Potential novel endpoints discovery that could emerge from psychedelic treatment.

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

National Drug Abuse Treatment Clinical Trials Network - Node Infrastructure

Posted May 2023

Background

NIDA’s National Drug Abuse Treatment Clinical Trials Network (CTN) was established in 1999 to bridge the gap between research and practice to improve addiction treatment. Through the collaborative partnership of scientists and treatment providers, the CTN seeks to address critical research questions with direct relevance to clinical practice and the needs of patients. Over the last two decades, the CTN’s research infrastructure and agenda have evolved to reflect the changing landscape of the SUD treatment community, transformation of health care systems, and emerging technologies and scientific advances.

The CTN currently is comprised of 16 Nodes, a data and statistical center, and a clinical coordinating center. The CTN program is administered within NIDA through the Center for the Clinical Trials Network (CCTN). The award period for the existing CTN Nodes ends February 28, 2025.

NIDA sees value in continuing to support the CTN research infrastructure to build on the broad portfolio of research previously conducted in the CTN (https://nida.nih.gov/about-nida/organization/cctn/clinical-trials-network-ctn). Support for both new Nodes and renewals of existing Nodes can be considered. MPI collaborations to form regional consortia are especially encouraged.

Goal

The proposed initiative seeks to continue to support CTN Nodes and bolster the CTN enterprise’s capacity to accelerate the translation of science into evidence-based practices for addressing SUD that can be readily and sustainably adopted by providers and patients. This network of Nodes aims to support core scientists and clinicians with expertise and experience in leading multi-site effectiveness and implementation clinical trials; a demonstrated history of clinical or research collaboration with health systems and/or clinical research networks; and the ability to conduct timely and tailored research with the potential to influence SUD management practices and policies. Desirable features of participating Nodes include the following: 1) ability to engage diverse patients in areas highly impacted by substance use, 2) ability to develop and test interventions that address the complex challenges that patients face, including polysubstance use, co-occurring disorders, and social and environmental determinants of health and well-being, 3) ability to conduct health data science and information technology research using digital technologies and platforms such as mobile health tools and electronic health record (EHR) systems, 4) ability to conduct point-of-care research that leverages existing clinical resources and staff and evaluates pragmatic, sustainable interventions, strategies, and implementation models, and 5) ability to actively engage community partners and address research questions focusing on health equity and inclusion.

Betty Tai, Ph.D., Center for the Clinical Trials Network

National Drug Abuse Treatment Clinical Trials Network - Clinical Coordinating Center

Posted May 2023

Background

NIDA’s National Drug Abuse Treatment Clinical Trials Network (CTN) was established in 1999 to bridge the gap between research and practice to improve addiction treatment. Through the collaborative partnership of scientists and treatment providers, the CTN seeks to address critical research questions with direct relevance to clinical practice and the needs of patients. Over the last two decades, the CTN’s research infrastructure and agenda have evolved to reflect the changing landscape of the SUD treatment community, transformation of health care systems, and emerging technologies and scientific advances.

The CTN currently is comprised of 16 Nodes, a Data and Statistical Center, and a Clinical Coordinating Center (CCC). The CTN program is administered within NIDA through the Center for the Clinical Trials Network (CCTN). The award period for the existing Clinical Coordinating Center ends in summer 2024.

NIDA sees value in continuing to support the Clinical Coordinating Center to support the broad portfolio of research conducted in the CTN (https://nida.nih.gov/about-nida/organization/cctn/clinical-trials-network-ctn).

Goal

The proposed initiative seeks to provide continued support for a CTN Clinical Coordinating Center that will support and provide resources to the CTN in management and conduct of trials in substance abuse treatment research. The CTN conducts clinical trials in sites located across the nation, including studies of behavioral, pharmacological, and integrated behavioral and pharmacological treatment interventions in rigorous, clinical trials to determine efficacy, effectiveness, practicality, and feasibility across a broad range of treatment settings and diversified patient populations and to transfer research results to physicians, clinicians, providers, and patients. These studies are typically Phase III clinical trials, but can also include Phase I, Phase II, Phase IV, and/or registry trials or surveys. Desirable features of the CCC include the following: 1) ability to coordinate and support protocol development, 2) ability to review and monitor protocol implementation requirements, 3) ability to provide research and study training to research staff, 4) ability to provide study pharmaceutical services and clinical support, 5) ability to provide and coordinate drug testing and analytical laboratory services, 6) ability to support trial regulatory functions and requirements, and 7) ability to participate in and contribute to CTN committee discussion and task force initiatives.

Ron Dobbins, MBA, Program Officer, Center for the Clinical Trials Network

National Addiction & HIV Data Archive Program (NAHDAP)

Posted February 2023

Background

The National Addiction & HIV Data Archive Program (NAHDAP) is a National Institute on Drug Abuse (NIDA)-funded data archive program that acquires, preserves, and disseminates data relevant to drug addiction and HIV research. By preserving and making available a library of electronic data on drug addiction and HIV research in the United States, NAHDAP offers scholars the opportunity to conduct analyses of existing data on major issues of social and behavioral sciences and public policy. NAHDAP provides an end-to-end service to data depositors and data users, including but not limited to, technical assistance for data deposition and education and training support on how to use the data made available in NAHDAP. 

The establishment of NAHDAP in 2009 was based, in part, on the increasing emphasis that has been placed on the importance of data sharing in general, and specifically in the social sciences where sharing has not been standard practice. Data sharing has been increasingly encouraged or required by government and other funding agencies, including the National Institutes of Health (NIH), which will be implementing the new data management and sharing policy effective January 25, 2023. Additionally, data sharing has been identified as a necessary component of collaborations aimed at solving society’s most urgent health challenges and is integral to facilitating the development of transdisciplinary science. By establishing this archive, NIDA demonstrated the priority it places on facilitating the sharing of social and behavioral sciences data on drug addiction, including that collected by NIDA funded investigators. Since its launch in 2009, NAHDAP has made over 500 studies available to the research community. Many are HHS-supported studies, such as the Monitoring the Future (MTF) Study, Research on Pathways to Desistance, and the Population Assessment of Tobacco and Health (PATH) Study. 

Goal

The goal of this proposed concept is to support the continuation of NAHDAP to archive drug addiction scientific data and data that intersects HIV research and drug addiction, primarily in the social and behavioral science field. Specific goals include:

  • Maintain, develop, and expand NAHDAP, including the provision of all tools necessary to maintain a cutting-edge data archive focused on drug addiction, and provide technical assistance to investigators depositing data.
  • Develop a system to prioritize datasets, apply the appropriate level of curations, follow the data standards for data archive and disclosure, and implement procedures to securely protect data.
  • Facilitate sharing of archived data, including distributing data and documentation and providing data user support, technical services, and trainings to the drug addiction field. 

Janet Kuramoto-Crawford, PhD, MHS, Division of Epidemiology, Services, and Prevention Research

American Indian and Alaska Native Collective Research Effort to Enhance Wellness (AI/AN CREW): Addressing Opioid/Drug Misuse, Mental Health and Pain

Posted February 2023

Background

Through Tribal Consultations in 2018 and recently in 2022, Tribal leaders have shared that addressing the opioid public health crisis is a high priority. American Indians and Alaska Natives (AI/AN) experienced the highest rate of drug overdose death relative to other racial or ethnic groups in 2021. Despite the numerous strengths of AI/AN people, culture and communities, and the significant innovation that communities have brought to responding to the opioid crisis, health disparities for AI/ANs persist in substance use outcomes, due largely to historical trauma and long-standing structural barriers to good health. Though Tribal leaders have called for more research funding for Tribal-led research to combat the opioid crisis, there remain few funded studies in this area. Additionally, Tribal leaders have shared that available data to support response to the opioid crisis is lacking. Funding Tribes to conduct locally-prioritized research and data expansions has the potential to accelerate the development of culturally grounded, effective, and sustainable strategies to prevent or treat opioid addiction and related factors within Tribal communities, and ultimately reduce health disparities. The AI/AN CREW program is part of NIH’s Helping to End Addiction Long-term (HEAL) initiative.

Goal

The AI/AN CREW program is proposed as an innovative, agile program that can adapt as new solutions emerge in real time to accomplish goals. The program will respond to themes that emerged in Tribal Consultation, which highlighted gaps in current substance use related research, particularly on topics that require AI/AN cultural expertise and knowledge of local community conditions. These include:

  • a need for understanding the role of traditional medicine, ceremony, physical activity, spirituality, holistic conceptions of health, strength-based perspectives, and other approaches important within AI/AN communities
  • the need to invest in research that accounts for the root causes of disparities and social determinants of health (e.g., historical trauma, housing, access to high-quality health care)
  • the importance of founding NIH programs on Tribal sovereignty and relying on the principles of AI/AN research, including, when partners are needed, close partnerships and engagement.

The program will support:

  • Tribes and American Indian/Alaska Native Serving Organizations (T/ASOs) to conduct locally prioritized research to address the opioid public health crisis, including related factors
  • Expansions in research capacity and infrastructure, as identified by T/ASOs
  • Improved surveillance data to characterize factors related to opioid/drug misuse/overdose
  • Comprehensive, ongoing technical assistance to respond to capacity, infrastructure, and other needs  

Kathy Etz, PhD, Epidemiology Research Branch, Division of Epidemiology, Services and Prevention Research

Engaging Survivors of Sexual Violence and Trafficking in HIV and Substance Use Disorder Services

Posted February 2023

Background

Sex trafficking survivors are a critical, but underserved, target population for addressing the HIV epidemic. Sex trafficking, defined by the United Nations as “forced, coerced, fraudulent or deceitful entry into sex work, entry by abduction, or entry into such work as an adolescent, teenager, or young adult”, affects 4.8 million victims annually, 90% of whom are women and girls. People with SUD, migrant workers or refugees, survivors of violence or abuse, unhoused youth, and sexual or gender minorities are among the populations most at risk for sex trafficking. Sex trafficking survivors experience violence, coercion, and multiple high-risk behaviors, including sexual risk behaviors (e.g., high volume of clients, no condom use) and injection drug use, greatly increasing risk of HIV and STI infection. Additionally, a complex sequelae of behavioral health impacts may remain as they seek to cope and recover from their traumatic experiences, including substance use, PTSD, depression, and anxiety.

Sex trafficking survivors often experience challenges in engaging in the healthcare system and have an unmet need for HIV and SUD care continuum, as they have experienced many violations of trust. Trauma-informed and survivor-centered care that integrates specific education on how to identify potential “Red Flags”, awareness of stigma and biases toward sex trafficked patients, and supportive care are necessary to best engage them in the healthcare system. Innovative approaches are necessary; interventions may require targeting multiple parties (e.g., survivors, police, harm reduction organizations) to successfully deliver effective services.

Goal

The goal of this concept is to support exploratory research and preliminary interventions to address the interrelated and compounding contextual factors that contribute to substance use and HIV risk among sexual trafficking survivors. This would be accomplished through research that builds new interventions and models of care that can effectively engage ST survivors in care for SUD, HIV, trauma, and other mental health outcomes and addresses key structural and social determinants of health that contribute to risk for ST as well as barriers to and facilitators of escaping continued exploitation. 

Minnjuan W. Flournoy Floyd, PhD, Division of Epidemiology, Services, and Prevention Research

Addressing HIV in Highest Risk Sexual and Gender Minorities

Posted February 2023

Background

Nearly three-fourths of new HIV cases in the US are among members of sexual and gender minorities. This proportion has increased during the past two decades, with an increasing percentage of these cases among members of ethnic/racial minorities. Existing HIV prevention and adherence interventions for sexual and gender minority populations insufficiently address substance use despite research documenting the large, identifiable attributable risk of substance use for HIV acquisition. Similarly, HIV interventions for prevention and adherence often have yielded poor results among persons with problematic levels of substance use in clinical trials. There also is accumulating evidence that substance use patterns previously not associated with HIV acquisition (e.g., cannabis) may be risk factors among sexual and gender minorities. Drug use has been evident among recent HIV outbreak clusters among men who have sex with men, but there is little recent research regarding how substance use settings and substance use networks contribute to HIV risk among sexual minorities in ways that can inform outbreak investigations.

Goal

This concept crosses prevention and care interventions, as well as epidemiologic research and will better represent sexual and gender minorities in the NIDA research portfolio. The epidemiologic focus will include drug use patterns and HIV prevalence/acquisition among sexual/gender minority persons from ethnic/racial minority backgrounds, with particular attention to stimulant use, giving consideration to syndemic production and social determinants of health and other factors that can inform novel interventions. Research related to new interventions will be expected to provide models that explicitly address substance use components to common interventions for HIV care/adherence or prevention among sexual and gender minority persons. Better models for addressing substance use in new HIV outbreaks also will be supported. In addition, modeling research will be supported that helps estimate the role of substance use in limiting the efficacy of prevention and care interventions on a population basis. Investigators will be asked to include end users of research findings as collaborators such as local or state HIV program planning activities and will include collaborations with service delivery organizations (CBOs/ASOs, health systems, FQHCs) that can implement effective interventions in their settings. 

Richard A. Jenkins, PhD, Division of Epidemiology, Services, and Prevention Research

Research to Address SUD in the Criminal-Legal System

Posted February 2023

Background

NIDA has a long and productive history of conducting services research to address SUD among individuals involved in the criminal-legal system. Work in the CJ-DATS, JJ-TRIALS, and JCOIN initiatives identified effective interventions to assist adults and youth transitioning between detention, community supervision, and post-release; demonstrated the value of research-practitioner partnerships; and accelerated the shift from effectiveness to implementation research. Given recent shifts in both epidemiology and public policy, new research is needed to take effective interventions to scale in jails, courts, and community corrections, and to rigorously test new and emerging models for effectively addressing the complex needs of individuals with SUD at earlier points of the sequential intercept model. 

Goal

This proposed initiative has multiple interrelated goals:

  • Support hybrid effectiveness-implementation trials on SUD services delivered at early intercept points (e.g., crisis response/911 calls; overdose response teams; police deflection programs)
  • Support implementation research with the goal of scaling up evidence-based interventions in criminal-legal systems across states or regions
  • Develop and test interventions to address stigma toward addiction, addiction treatments, and persons involved in the criminal-legal system
  • Support research on technological tools to facilitate continuity of care during transitions between community and carceral settings
  • Conduct survey, geospatial, simulation, and other modeling studies to address high priority questions for practitioners
  • Provide training and technical assistance to build the capacity of practitioners and early stage investigators to form productive research-practice partnerships
  • Translate and disseminate research findings for practitioner and lay audiences 

Tisha Wiley, PhD, Division of Epidemiology, Services and Prevention Research

Resource Networks to Advance the Impact of Addiction Services Research Through Researcher/Decision Maker Collaborations

Posted February 2023

Background

Decision makers at the state and local levels routinely make critical decisions affecting access to and the availability, cost, quality, and effectiveness of services to prevent, reduce harms from, and treat addiction and support recovery.  In most places, the scientific research enterprise does not adequately serve the needs of these decision makers, such as Public Health Commissioners, Clinical Directors of Prisons, or other leaders who allocate or manage state and federal funds. Research is neither sufficiently timely nor designed to generate the practical real-world information that could best inform decisions, or to leverage innovative approaches developed in local jurisdictions. This stymies the reach of promising advances in addiction services quality and effectiveness because they are not adequately tested in the contexts in which they will be delivered, findings are not disseminated in a way that can inform broader implementation, or because state and local decision makers need to know the potential impact in their own populations to justify allocation of resources or changes in regulations or policy.

Goal

The goal of the proposed program is to seed and propel the development of multi-jurisdictional collaborative researcher-decision maker networks where needed to advance the impact of addiction services research in advancing the quality and effectiveness of these services. These networks would ultimately be focused on the generation, dissemination, and application of research findings in real world settings.

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

Research on the Neuro-Immune Axis in the Context of HIV and Substance Use

Posted February 2023

Background

Research on the modulatory effects of substances on the function of immune and neuronal cells have identified several targets and pathways of interest. Nonetheless, our understanding of the complex interactions between the immune and nervous systems, especially in the context of substance use disorders and HIV infection remains limited. The neuro-immune axes contain multiple orphan and atypical receptors and receptor-coupled systems with poorly or un-annotated endogenous and exogenous ligands and downstream effectors. The neuroinflammatory responses that accompany HIV infection and substance use include unique inflammatory processes along with changes in neuronal function at both the single cell and circuit levels. These phenomena occur via a diverse panoply of mechanisms involving the migration of HIV-infected cells across the blood–brain barrier while affecting key biological processes including neurocognitive function. Substances as single entities or as combinations (poly-substance) while having independent effects on immune function add a level of complexity to cellular and pro-inflammatory changes that are further exacerbated by HIV. Overall, the neuro-immune axes and their targetability in the context of HIV and substance use present themselves as a major opportunity for exploratory research and for basic drug discovery.

Goal

The goal of this concept is to encourage research for identifying biological targets and pathways that regulate neuroimmune interactions that are at the intersection of HIV and substance use. Research supported via this concept will help gain a fundamental understanding of transmission pathway networks and mediator and trafficking processes that are regulated by the neuro-immune axes. The concept will also encourage research towards the discovery of novel chemical entities that are effective in mitigating conditions associated with HIV and substance use, including HIV-associated neurocognitive disorder, pain, and aging.

Kiran Vemuri, PhD and Tristan McClure-Begley, PhD, Division of Neurosciences and Behavior

Chemical Probes and Drugs for Modulating HIV Transcription in People with Substance Use Disorders

Posted February 2023

Background

HIV infection and substance use are comorbid conditions that bidirectionally and synergistically influence the deleterious outcomes in people who suffer from substance use disorder (SUD).  Despite effective control of viremia by combination antiretroviral therapy (ART), people with HIV develop neurodegenerative and behavioral dysfunctions. The use of substances such as cocaine, methamphetamine, and opioids has been implicated in persistence of HIV in latent reservoirs. The persistence and transcriptional reactivation of HIV in the CNS leads to the development of neuropathological complications. While a practical cure for HIV remains elusive, strategies to address viral latency through permanently silencing HIV transcription or through activation and clearance are being intensively explored. Recent studies have revealed that a significant fraction of HIV infected cells that persist and proliferate in vivo have transcriptionally active HIV even after long term ART, and currently available antiretroviral agents do not suppress HIV transcription. HIV transcription can be inhibited by several mechanisms including epigenetic modulation, transcriptional interference and sequestration of transcription factors that regulate viral transcription. Inhibition of viral proteins such as Tat and Tar as well as inhibition of several host factors have emerged as potentially promising approaches for suppression of HIV transcription, thus providing a strong rationale for pursuing inhibition of viral transcription as a strategy to address HIV persistency and HIV-SUD comorbidity.

Goal

The goal of this initiative is to support research aimed at (1) identification of targets and pathways by which transcriptional activity of HIV can be suppressed in HIV reservoirs including the CNS in people with SUD, and (2) application of emerging small molecule drug discovery approaches to identify novel compounds that can be utilized as pharmacological probes and as drugs to suppress HIV transcription in people with HIV-SUD comorbidity.

Sam Ananthan, PhD, Division of Neuroscience and Behavior

ABCD Study® Data Sharing Platform

Posted February 2023

Background

The Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is the largest longitudinal study of brain development and child health in the U.S., having enrolled nearly 12,000 youth beginning in 2016, ~98 percent of whom have been retained in the study 6 years later. The ABCD Study® has embraced an open science model where data are made publicly available to the broader scientific community on a regular basis. The ABCD Study dataset includes a wide array of data from physical, cognitive, social, emotional, environmental, and behavioral assessments, as well as multimodal neuroimaging and biospecimen collection. As a result, approximately 500 scientific papers have been published using the data to date.

As data collection has progressed, however, the amount, types, and complexity of data included in the dataset (e.g., neuroimaging, genomics, behavioral data, actigraphy data) have significantly increased. Similarly, the needs of the scientific community have evolved such that an integrated cloud-based analytic platform is critical to facilitate the use of the data by scientists from different backgrounds. The current ABCD Study data sharing platform can no longer meet these needs or scale as the ABCD dataset continues to grow. 

Goal

The ABCD Study® needs a data sharing platform that is optimized for large datasets, including neuroimaging, genomics, and other complex data, and is flexible by design so that users with different levels of analytic expertise and differing analytic requirements can accomplish what they need. The platform also must provide multiple ways to access and analyze the data – in the cloud, or on prem. Finally, it must be responsive to evolving data sharing needs in a rapidly changing landscape.

This concept proposes to advance data sharing capabilities for the ABCD Study by supporting customization of a platform with an infrastructure and databasing system well-suited to sharing neuroimaging data, and that provides data ingestion, integrated data analytics, customized user experience, and flexibility to ensure ABCD data continuity for the future, as well as a homogenous solution for harmonizing with planned data from the Healthy Brain and Child Development Study.

Elizabeth Hoffman, PhD, Division of Extramural Research

Patient Engagement Resource Centers

Posted September 2022

Background

Only 1 in 10 people who need SUD treatment ever receive it. When asked, patients and families note that available treatment options are unacceptable, undesirable, inconvenient, and inadequate to address their needs. For example, in responses to the 2020 NSDUH, individuals who met diagnostic criteria for SUD but did not receive treatment indicated the following most common reasons:  uninsured/could not afford; could not find a program that offered what they wanted; feared negative opinions of others; felt treatment wasn’t needed/could handle the problem on their own; did not have time. This NSDUH response pattern has been largely the same for two decades. Compounding these concerns are widely held perspectives (reinforced by popular media) that treatment comes in only one form: highly structured, largely institutionalized programs that are lengthy, expensive, and stigmatized. This means that efforts to implement new treatments into existing systems of care are unlikely to reduce the treatment gap. Likewise, recent efforts to integrate addiction services into general medical settings either have not permeated public awareness, or are not the solution patients are seeking.

Goal

The goal of this concept is to support the development of Patient Engagement Resource Centers that can effectively engage patients (including prospective patients, families of individuals with SUD, and persons in recovery) in meaningful dialogue to inform the design and delivery of high-quality treatment services that are responsive to their needs and preferences. Projects would take a user-centered design approach to identify and articulate patient perspectives on treatment and their desired structures and outcomes, and inform the development of new models of care that better align with these preferences. Projects would also be encouraged to test dissemination strategies to better educate the public about the full array of evidence-based treatment options available.

Lori Ducharme, Ph.D., Division of Epidemiology, Services, and Prevention Research

Leveraging Inpatient Medical or Surgical Hospitalizations to Improve Outcomes for People Who Use Drugs

Posted September 2022 

Background

In the United States, a relatively small number of high-need patients account for a disproportionately high level of healthcare utilization, including hospital admissions and costs. Having a substance use disorder (SUD) increases the risk of an individual falling into this high-risk, high-need population. Individuals with SUD can experience worse outcomes for their medical or surgical hospitalizations because of stigma or because their SUD may complicate the treatment in other ways (for example, poor venous access in people who inject drugs). At the same time, individuals being treated in medical or surgical wards may not receive evidence-based treatment for SUD or be linked to outpatient SUD treatment on discharge.

There are existing models for initiation of SUD treatment during general inpatient hospital stays, some of which involve linkage to care post-discharge (e.g., addiction consult services, consultation liaison psychiatry referrals, care coordinators, patient navigators, bridge clinics, etc.). Some of these have been studied formally for short time periods and/or at limited scale, with far more focus on the emergency department initiation and linkage than the inpatient components. There is literature to support the idea the hospital may be an appropriate place to screen for and assess SUDs, that SUDs may complicate or extend the hospital stay, and that initiation of treatment during hospitalization with linkage to continued outpatient care can be beneficial in reducing hospital readmissions.

Goal

The goals of this initiative are:

  • to identify the best inpatient screening, treatment initiation, and linkage models for different hospital and service systems, such as rural vs urban, large vs small hospitals, and safety net systems, including cost impacts and economic evaluations
  • to identify strategies to support the successful implementation, sustainability, and scalability of effective and cost-effective inpatient initiation and linkage interventions
  • to identify strategies to assure that patients can continue appropriate substance use disorder care after hospital discharge
  • to evaluate the impact of inpatient-to-outpatient linkage of substance use disorder care on hospital readmissions and long-term patient outcomes including morbidity, mortality, and substance use outcomes

Marcy Fitz-Randolph, DO, MPH, Division of Epidemiology, Services, and Prevention Research.

Marijuana Farm and Analytics to Support the Availability of Consistent, High-Quality Material to Facilitate Cannabis Research

Posted September 2022

Background

A contract to grow marijuana has existed since 1968, when it was under NIMH, and was established to ensure a pesticide/herbicide-free source of marijuana for scientific research.

Since the initial award, the contract site has been University of Mississippi, with Mahmoud ElSohly, becoming the project director in 1981.

The contract was the first federally legal source of cannabis for research and until recently, was the only DEA-approved manufacturer of bulk cannabis, although now there are five DEA-approved sites that can grow marijuana.

NIDA needs a continuous, standardized supply of cannabis and placebo material for research and clinical trials.  The existing contract also provides all the analytic services to determine content and purity of product produced by the Farm and from DEA and state agencies. 

Goals 

The purpose of this contract is to support the availability of consistent, high-quality material to facilitate cannabis research

  • Grow, harvest, and process cannabis plant material to produce standardized marijuana with different potencies for research.
  • Manufacture and distribute marijuana cigarettes to researchers.
  • Develop very low potency materials (almost no THC) to be used as a placebo for clinical trials.
  • Isolate and characterize different cannabis components for pharmacological studies.
  • Screen cultivars of different chemical profiles (THC, CBD and THC/CBD) for research purposes.
  • Prepare bulk quantities of specific cannabinoids (for example, THC, CBD, CBN, CBC, and CBG) as research-grade materials.
  • Ship cannabis materials to researchers throughout the U.S.
  • Follow good manufacturing practices of the US Food and Drug Administration (FDA) in preparing materials for clinical trials.
  • Initiate, maintain, and support Drug Master Files (DMF)s with the FDA.
  • Analyze confiscated cannabis products from DEA/State Agencies.

Jane B. Acri, Ph.D., Division of Therapeutics and Medical Consequences

Exploratory Clinical Neuroscience Research on Substance Use Disorders

Posted September 2022  

Background

According to The National Survey on Drug Use and Health, in 2017, approximately 19.7 million people aged 12 or older had a substance use disorder (SUD) in the past year, including 7.5 million people who had an illicit drug use disorder. Increased negative health consequences from opioid use are a leading public health problem in the US. In addition to this ongoing opioid crisis, the substance use landscape has witnessed several other recent developments: an increase in the use of psychostimulants, the growing popularity of e-cigarette consumption, and the legalization of medical and recreational marijuana. Together, these factors have renewed attention to the need for novel approaches to understanding the mechanisms underlying SUD, including clinical research studies that illuminate the neurobiological underpinnings of the disease.

Goal

This concept continues NIDA’s interest in exploratory clinical neuroscience research on SUD to support clinical research applications that are in early and conceptual stages of project development and focus on understanding the neurobiological mechanisms underlying SUD, including fundamental brain function relevant to substance use. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research. Another example could include the unique and innovative use of an existing methodology to explore a new scientific area. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of biomedical, behavioral, or clinical research.

Topics that would be appropriate for this concept include, but are not limited to:

  • Investigation of individual differences in neural circuitry underpinning SUD-related behavior and outcomes, including studies to understand the neurobiology underlying important risk factors for drug use and addiction
  • Testing of environmental, behavioral, or pharmacological manipulations that leverage potential treatment or prevention targets in all phases of drug taking behavior seen in the progression to development of SUDs, and identification of mechanisms of action
  • Development of computational models of network-level neural function and connectivity in the context of SUD
  • Investigation of neurobiological mechanisms related to transdiagnostic factors shared by SUD and other psychiatric disorders
  • Studies characterizing the interactions of substance use and HIV/AIDS

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

Remote Assessment 1: Identifying and Addressing Barriers to Participant Engagement

Posted September 2022

Background

While recent technological advancements have allowed for greater use of remote assessments in neuroscience research, there has yet to be universal acceptance of these assessments across broad, diverse communities. Barriers to acceptance include, but are not limited to, the technological divide between geographic regions and access to digital spaces, lack of engagement with under-resourced communities, and historic mistrust of healthcare and academic institutions. Acceptance of remote interactions facilitated by technology will help reduce geographic and social barriers to research participation and access to clinical care. Importantly, greater use of remote platforms for research and clinical purposes will provide safety to highly vulnerable participants by removing them from a hospital or high-risk or traumatized setting.

Goal

This concept proposal is designed to investigate and address barriers to help NIDA investigators find avenues to increase participant engagement and retention through remote platforms. Bringing traditionally laboratory- or clinic-based assessments to remote settings requires adequate knowledge of the sociocultural environment within which these assessments are given. As such, this concept emphasizes an interdisciplinary approach to bring together researchers, epidemiologists, statisticians, clinicians, and community collaborators to not only increase inclusion of traditionally underrepresented groups in biomedical research, but to also develop tools that are sensitive to the geographic, social, economic, and organizational components that contribute to participation barriers and SUD outcome disparities. The overarching goal is to build effective community collaboration to ensure that development and deployment of validated virtual assessments adequately serve the community.

Janani Prabhakar, Ph.D. and John Fedota, Ph.D., Division of Neuroscience and Behavior

Remote Assessment 2: Validation and Expansion of Remote Assessments of SUD‐Relevant Behaviors

Posted September 2022

Background

An opportunity exists to leverage the advancement, acceptance, and ubiquity of personal technology to extend the clinical research environment beyond a laboratory-based setting and deeper into a wide range of community settings that better reflect the diversity of the nation.  The COVID-19 pandemic forced the vast majority of ongoing human clinical SUD research to shift rapidly towards some degree of remote data collection.  However, it remains unclear what measures collected outside of the traditional laboratory environment yield robust, reliable data, and how such remotely collected data can be compared and combined with traditional laboratory collected data.  This concept proposes the development of validated measures for low burden home and virtual assessments of SUD relevant data (e.g. subjective clinical instruments, cognitive tasks, environmental characterizations) as well as a concentrated effort to increase the temporal resolution of this data collection.  The exponentially higher temporal resolution over extended durations possible via remote assessment coupled with the use of validated measures and other passive environmental and behavioral characterizations deepens the characterization of SUD relevant phenotypes and better characterizes the interactions between individuals and their environment. 

Goal

The robust, remote data can be employed to better model the relevant behaviors of individuals across society in the natural environment in service of the next generation of SUD interventions.  To achieve this, the current concepts seeks the validation of remote assessment measures by comparing the data collected in laboratory settings to that collected remotely and the integration of data across multiple measures/sensor types to deepen the characterization of interactions between individuals and their natural environment.

John Fedota, Ph.D. and Janani Prabhakar, Ph.D., Division of Neuroscience and Behavior

NIDA International Program

Posted September 2022

Background

Substance use disorders are a global health crisis requiring trained scholars and clinicians around the world. NIDA seeks to contribute to the development of international researchers to collaborate on research and to conduct related activities to facilitate international research to address the problems of drug use, abuse and addiction in the United States and abroad. In past decades, this NIDA contract has supported Hubert H Humphrey Drug Use Research Fellowship, INVEST Postdoctoral Drug Use and Addiction Research Fellowship, and the annual International Forum (in conjunction with CPDD).

Goal

The goals of this program include (1) supporting substance use disorder research, (2) training international postdoctoral or senior researchers, (3) information dissemination, and (4) international policy development.

Lindsey Friend, Ph.D., Health Science Administrator, Office of Research Training Diversity and Disparities

Ending the HIV Epidemic: Focus on Justice Populations with SUD

Posted May 2022

Background

The US cannot end the HIV epidemic without attending to the risks and service needs of justice-involved populations who use drugs. Initiatives aimed at ending the HIV epidemic in the US have largely ignored justice settings, which serve populations at substantially elevated risk for HIV. Injection drug use, one of the key risk factors for HIV transmission, is common among justice involved individuals. Thus, addressing the confluence of HIV and injection drug use among justice involved individuals is critical to ending the HIV epidemic. NIDA has a long and productive history of conducting addiction services research in justice settings. A robust toolkit of clinical interventions to prevent and treat HIV exists, but implementation science is needed to address significant service delivery gaps at all points of the HIV care cascade.

Goal

This goal of this initiative is to focus on HIV prevention and treatment implementation research in justice populations with substance use disorders. The proposed initiative would focus on creating national research capacity targeted to geographic regions where there are spikes in HIV cases. Through this initiative, studies would be conducted that systematically identify individuals at most risk for acquiring or transmitting HIV as they come into contact with the justice system and connecting this population with relevant HIV and substance use prevention and treatment services. 

Tisha Wiley, Ph.D., Division of Epidemiology, Services, and Prevention Research

Leading Addiction, Diversity, and Discovery in Education and Research (LADDER)

Posted February 2022

Background

The purpose of this program is to create new partnerships and collaborations between under-resourced universities (including Minority Serving Institutions) and the National Institute on Drug Abuse (NIDA) T32 funded institutions to jointly train substance use disorder researchers.  To achieve this goal, support will be provided to eligible domestic institutions that historically serve underrepresented and underserved populations or are in (IDeA)-eligible states (referred to as the home institution) to provide high quality training and mentoring that will prepare and empower scholars to lead the nations’ future substance use and addiction research workforce. Home institutions will partner with one or more NIDA funded T32 programs which would provide summer research experiences. In turn, T32 institutions can use this opportunity to diversify their T32 appointments as well as student body and research programs at large. The proposed research training programs will incorporate didactic, research experiences (in-person and/or virtual), mentoring, and career development elements to prepare trainees to transition to next career stage in substance use and addiction research. 

Goal

  • The purpose of this program is to provide funding for research resources to under-resourced universities for equipment and related costs;
  • Ensure that there is a diverse pool of undergraduate and graduate students who complete their degree, and successfully transition into substance use and addiction research-focused programs (e.g., Ph.D., or M.D./Ph.D., or postdoctoral fellowships) at NIDA funded research intensive institutions;
  • Promote the creation of new partnerships and collaborations between under resourced universities with NIDA T32 funded institutions. 

Albert Avila, Ph.D., Director, Office of Diversity and Health Disparities

Actionable Data to Inform Research‐Driven Decisions (HEAL Initiative Data2Action)

Posted September 2021

Background

Over the last year, the US saw a 30% increase in overdose deaths, totaling the largest number of annual overdoses in history, with 62% linked to synthetic opioids like fentanyl. While overdoses are rapidly increasing, lags in data availability (months or years) hamper efforts to proactively prepare for – or even nimbly react to – overdose surges. There is a need for actionable data to provide a precise picture of trends in opioid use and overdose in communities. Even if data lags are addressed, there are questions of who and how these data will be used to facilitate responses at national, state, and local levels. Enhanced methods of collection, new tools, technologies, or strategic access could offer data sources to inform implementation, to enhance available resources, or reduce opioid use and overdoses.

Goal

The goal of this concept is to attract researchers who have data in hand and new or existing tools or methods to conduct predictive analyses to 1) use data sources that accessible and analyzed on a timescale allowing for predictive and proactive responses and 2) leverage partnerships with key stakeholders to turn research results directly toward decisions and implementation.

Tisha Wiley, Ph.D., Division of Epidemiology, Services, and Prevention Research

NIDA Abuse Liability Testing Initiative

Posted February 2021

Background

The NIDA Abuse Liability Testing Program predates all current NIDA employees, and it is not known when the program was initiated. The activities of the program likely predate the establishment of NIDA (in 1974) and may have been supported by NIMH at one time. The Controlled Substances Act of 1970 (Public Law No: 91-513) placed a large number of abused drugs under special controls, and the law also describes the process by which the Department of Health & Human Services and the Drug Enforcement Agency (DEA) should work together to review pharmacological and toxicological data and make decisions regarding the possible control of new drugs. While the law requires data review for each drug under consideration for possible scheduling, it does not address the question of who should generate the necessary data. If a new drug is a potential medication, the FDA requires the relevant pharmaceutical company to generate the data. However, in the case of a new “street drug,” the NIDA Abuse Liability Testing Program usually generates the necessary data. The DEA is responsible for either providing the newly identified street drugs to NIDA or providing funds to support their synthesis, and NIDA has had the primary responsibility for conducing the necessary in vitro and in vivo preclinical testing. Current trends in drug abuse dictate the specific compounds that require testing, and data from DEA street encounters and pathology testing guide compound prioritization. Planning for this testing is a regular topic of discussion at Inter-Agency Committee on Drug Control (ICDC) meetings, where representatives from NIDA, FDA and DEA participate as the core members. Synthetic cathinones (more commonly known as “bath salts”), synthetic cannabinoids, and fentanyl analogs have been recent priorities for testing.

Goal

The continuation of NIDA’s Abuse Liability Testing Program in 2021 and beyond will allow the Federal Government to generate essential pharmacological data to guide scheduling decisions for newly encountered “street drugs.”

David J. McCann, Ph.D., Division of Therapeutics and Medical Consequences

NIDA Drug Supply Program

Posted February 2021

Background

The NIDA Drug Supply Program (NDSP) is administered by the Division of Therapeutics and Medical Consequences (DTMC). In addition to funding research in drug abuse, addiction, prevention, and treatment, NIDA facilitates such research to accomplish its mission by providing chemicals and research probes that are either unavailable, difficult to obtain, or very expensive to buy to researchers. In addition, this program also provides analytical services and limited pharmacokinetic testing for researchers’ experimental samples.

The NDSP provides various controlled drugs, other chemical substances, and marijuana and nicotine research cigarettes for research purposes to investigators working in the area of drug abuse, drug addiction, and related disciplines at academic institutions and research laboratories both within the U. S. and elsewhere worldwide. The availability of controlled substances is regulated by the United States Drug Enforcement Administration (DEA), Department of Justice under the Controlled Substances Act (CSA), and the U.N. Convention on Psychotropic Substances. Materials in the NDSP are prepared, stored, and distributed in full compliance with all local, federal and international regulations. The controlled drugs produced and distributed within the NDSP include hallucinogens, stimulants, sedatives and hypnotics, narcotics, designer drugs, cannabinoids, marijuana, as well as many other categories of controlled substances. The NDSP also maintains an inventory of other chemical substances such as opioid peptides, radio- and mass-labeled compounds, and drug metabolites. In addition, continuous efforts are made to synthesize new compounds and add them to the inventory in response to the developing needs of the research community. The stability and purity of all such compounds are periodically monitored and maintained.

During the last 40 years, the NDSP has provided approximately 20,000 compound shipments to researchers from an inventory of ca. 2,200 batches of more than 900 individual compounds. A group of more than 2,000 investigators have received materials from the NDSP since its inception.

Goal

The continuation of NIDA’s Drug Supply Program in 2021 and beyond will allow the Federal Government to continue to provide DEA controlled and non-controlled compounds that are unavailable, difficult to obtain, or very expensive to buy to researchers. Additionally, state-of-the-art analytical services will continue to be available to researchers that would otherwise struggle to have access to similar resources.

Richard “Rik” Kline, Ph.D., Division of Therapeutics and Medical Consequences