This funding opportunity announcement (FOA), issued by the National Institutes of Health (NIH) and managed by the National Center for Complementary and Integrative Health (NCCIH), invites applications for mid-phase clinical trials of natural products. These trials aim to investigate botanicals, dietary supplements, and probiotics with compelling preliminary evidence supporting their potential for health benefits. The scope of natural products includes standardized nutritional compounds, such as omega-3 fatty acids and polyphenols. Proposals must include sufficient preliminary data showing bioavailability and reproducible target engagement, which refers to a measurable effect on the hypothesized biological mechanism. This FOA will not support efficacy or cancer treatment trials and requires rigorous compliance with FDA regulations if applicable.

The primary goal of this initiative is to optimize the use of natural products in preparation for future large-scale efficacy trials. It aims to determine the best formulations, dosages, and patient characteristics that influence treatment response. Emphasis is placed on conditions such as pain management, sleep disorders, gastrointestinal issues, and mental health conditions, including anxiety and depression. Other priority areas include research into gut microbiome interactions, cannabinoid effects, and naturally occurring psychedelics. The FOA aligns with NCCIH’s mission to improve symptom management and reduce health disparities.

Eligibility is broad and includes institutions of higher education, nonprofits, small businesses, for-profit organizations, and local and state governments. Foreign organizations may participate under certain conditions. Applicants must register with SAM, eRA Commons, and Grants.gov to submit applications. The FOA emphasizes inclusivity and requires a Plan for Enhancing Diverse Perspectives (PEDP) to ensure broad participation and representation in research teams and study populations.

Applications are expected to follow rigorous methodological standards, including randomization, appropriate comparator conditions, and sample sizes adequate for study objectives. The required documentation includes a clinical protocol synopsis, regulatory compliance plans, and justification for the natural product under investigation. Proposals must address ethical considerations, data and safety monitoring, and milestones for study progress. Investigators are also encouraged to engage stakeholders and ensure the availability of natural product supplies.

Applications are due on three cycles per year, with the first due June 23, 2025, and the final deadline on October 20, 2026. Funding is contingent on available appropriations, and budgets are expected to stay below $350,000 per year in direct costs, with the project period recommended at three years. Proposals exceeding these limits require strong justification.

Successful applications will demonstrate significant potential to advance scientific knowledge about natural products and their mechanisms of action. Peer review will focus on significance, approach, expertise, and feasibility. A key determinant for funding will be the capacity to address unmet scientific needs and align with NCCIH’s strategic priorities, such as advancing symptom management and addressing health disparities.