Development of Interventions to Prevent and Treat Substance Use Disorders and Overdose (UG3/UH3 - Clinical Trial Optional)

The U.S. Department of Health and Human Services, through the National Institutes of Health and its National Institute on Drug Abuse (NIDA), has issued a Notice of Funding Opportunity (NOFO) titled “Development of Interventions to Prevent and Treat Substance Use Disorders and Overdose (UG3/UH3 – Clinical Trial Optional).” This program is designed to support the discovery and development of interventions for substance use disorders (SUDs) and overdose. The phased award cooperative agreement mechanism (UG3/UH3) allows investigators to conduct early exploratory studies with clear milestones in the UG3 phase and, upon meeting those milestones, advance to the UH3 phase for more comprehensive clinical development. The overarching goal is to produce interventions that can rapidly progress toward FDA approval, regulatory clearance, or broad clinical implementation. The need for such research is critical. More than 40 million individuals in the United States are estimated to have SUDs, and in 2023, drug overdoses were the leading cause of accidental death, with approximately 105,000 deaths. Deaths involving synthetic opioids, psychostimulants, and cocaine contributed significantly, often in combination, underscoring the urgency of developing safe and effective treatments. The NOFO supports pharmacotherapies, device-based treatments, digital therapeutics, and behavioral interventions. Research areas of interest include preventing initiation and progression of SUDs, enhancing adherence to treatment, reducing relapse and overdose risk, and addressing co-morbid conditions such as HIV/AIDS. Pharmacotherapy-focused projects may involve the evaluation of new chemical entities, repurposing of marketed medications, biologics, or natural products. Projects may cover preclinical IND-enabling studies, early-phase clinical trials, and late-phase development aligned with FDA requirements. Device-based interventions such as transcranial magnetic stimulation, vagal stimulation, or other neuromodulatory technologies are strongly encouraged, provided applicants address regulatory pathways and include appropriate control comparators. Digital therapeutics proposals should focus on software-based interventions designed to treat or manage SUDs, with investigators encouraged to consult the FDA on device classification and trial design requirements. Behavioral intervention research must align with the NIH Stage Model for behavioral treatments, limited to Stages I through III, and ensure fidelity of delivery and rigorous evaluation methods. Applications that solely focus on target identification, animal models, mechanistic studies of addiction biology, alcohol as the only substance of use, or late-stage behavioral interventions (Stages IV–VI) are not considered responsive and will not be reviewed. The cooperative agreement mechanism ensures substantial involvement of NIH staff in scientific and programmatic management, including milestone monitoring and data integrity oversight. Applications must include a clear decision tree, quantifiable milestones, and go/no-go criteria to advance from the UG3 to the UH3 phase. Eligible applicants include higher education institutions, nonprofit organizations, for-profit organizations including small businesses, tribal governments and organizations, local and state governments, U.S. federal agencies, public housing authorities, independent school districts, faith-based and community organizations, and regional organizations. Foreign organizations and non-U.S. components of U.S. institutions may apply, but NIH will not issue awards involving foreign subawards or subcontracts. Applicants must complete registrations with SAM.gov, Grants.gov, and eRA Commons before applying. No cost sharing is required. Applications open on September 20, 2025, with the first deadline on October 20, 2025. Additional deadlines recur in February, June, and October each year through June 20, 2028, with an expiration date of August 22, 2028. Scientific merit reviews, advisory council reviews, and anticipated award start dates follow each deadline. The earliest awards are expected in July 2026. Applications must be submitted electronically through NIH ASSIST, Grants.gov Workspace, or institutional system-to-system solutions. Submissions are due by 5:00 PM local time of the applicant organization. Evaluation will be based on three scored review factors: importance of the research (significance and innovation), rigor and feasibility (approach), and expertise and resources (investigators and environment). Additional review criteria include protections for human subjects, use of vertebrate animals, biohazards, budget appropriateness, and compliance with NIH data sharing policies. Peer review will be followed by a second-level review by NIDA’s advisory council, with funding decisions based on scientific merit, program priorities, and availability of funds. For programmatic inquiries, contacts at NIDA include Drew Townsend (preclinical pharmacotherapy), Evan S. Herrmann (clinical pharmacotherapy), Will Aklin (therapeutic devices), Karen Seymour (digital therapeutics), and Carmela Reichel (behavioral therapies). General inquiries may be directed to Iván D. Montoya. Administrative and financial management inquiries should be directed to the Chief Grants Management Officer at NIDA via nidagmbemail@nida.nih.gov. Support for electronic submission issues is available through the eRA Service Desk and Grants.gov support lines.