The National Institutes of Health (NIH) has announced the reissuance of the Funding Opportunity Announcement (FOA) titled *Drug Discovery for Nervous System Disorders (R21 Clinical Trials Not Allowed)*, aimed at supporting exploratory research for developing novel therapeutic agents to treat nervous system disorders. This initiative is jointly supported by the National Institute of Mental Health (NIMH), National Institute on Aging (NIA), National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the National Institute on Drug Abuse (NIDA). The FOA encourages research focused on the identification, design, and preclinical testing of small molecules and biologics, such as gene therapies or microbial therapies, with therapeutic potential. The goal is to stimulate discovery and development of new treatments for mental health disorders, substance use disorders (SUD), alcohol use disorders (AUD), and age-related neurological diseases.

This FOA particularly targets projects that explore novel approaches for drug discovery, including new methodologies for drug identification, lead optimization, and initial testing of pharmacokinetics. Emphasis is placed on using innovative techniques, such as machine learning for drug design, to optimize candidates that address fundamental nervous system processes related to disease. Potential areas of research include targeting neuronal dysfunction, neuroinflammation, neurotransmitter activity, and neurotrophic factors. The FOA also supports biotechnology products such as gene-based and cell therapies, focusing on preclinical stages of drug development, but excludes clinical trials.

Applicants can request up to $275,000 in direct costs over two years, with a maximum of $200,000 in any single year. Eligible organizations include higher education institutions, nonprofits, government agencies, and small businesses. Both U.S. and foreign institutions may apply, and collaborations between different types of organizations are encouraged. The project period is limited to two years, making this opportunity ideal for high-risk, high-reward research projects.

To be responsive to this FOA, research proposals must focus on therapeutic discovery, rather than on understanding disease mechanisms or conducting clinical trials. Applications that focus on target identification or clinical development beyond preclinical safety testing will be considered non-responsive. Proposals are expected to be innovative, and while preliminary data is not required for R21 applications, applicants are encouraged to provide a strong conceptual framework and justify the feasibility of their approaches. Additionally, NIH promotes data sharing and expects successful applicants to make their assay data and chemical structures publicly available.

Key deadlines follow standard NIH submission dates, with the earliest submission date being January 16, 2022, and the final expiration date being January 8, 2025. Applications must be submitted electronically via Grants.gov, and applicants should ensure they are registered with all required NIH and federal systems, such as eRA Commons and SAM, before submitting. NIH staff strongly encourage potential applicants to discuss their proposals with the appropriate scientific contacts within NIMH, NIA, NIAAA, or NIDA.

Applicants will be evaluated on several criteria, including the significance of the project, innovation, the approach taken, and the research environment. NIH peer review panels will assess how well the project addresses the critical barriers in the field of therapeutic discovery and the likelihood that the research will lead to new, impactful treatments for nervous system disorders.