Mechanisms of Alcohol Tolerance (R21/R33 Clinical Trial Not Allowed) | PAR 18 659

Opportunity Information: Apply for PAR 18 659

The NIH funding opportunity titled "Mechanisms of Alcohol Tolerance (R21/R33 Clinical Trial Not Allowed)" (Funding Opportunity Number PAR 18 659; CFDA 93.273) supports research aimed at improving the scientific understanding of how alcohol tolerance develops and how that process contributes to the transition from alcohol use to alcohol dependence. The announcement is framed around two connected goals: first, to generate new, testable hypotheses about the biological, behavioral, and other key factors that shape sensitivity and tolerance to alcohol; and second, to move the field toward a shared, integrative framework that explains the underlying mechanisms of tolerance and links them to the progression of alcohol-related problems and dependence. A central theme is that tolerance is not just a simple decrease in response to alcohol, but a complex set of adaptations that can vary across individuals and contexts, and that understanding those adaptations may clarify why some people escalate drinking and develop more severe alcohol use disorders.

The FOA uses a Phased Innovation grant structure (R21/R33), which is designed to help projects progress from early-stage exploration to more definitive hypothesis testing. In practical terms, the R21 phase supports preparatory work that reduces uncertainty and strengthens the eventual larger study. This can include secondary analyses of existing datasets, development of new analytic approaches, exploratory modeling, or pilot studies meant to establish feasibility and refine hypotheses. If the R21 phase produces strong justification and clear next steps, the project can transition into the R33 phase, where investigators are expected to scale up and more rigorously test the hypotheses generated earlier. The phased design encourages applicants to treat the first phase as a purposeful springboard into a more robust, mechanism-focused research effort in the second phase, rather than two disconnected studies.

The "Clinical Trial Not Allowed" designation signals that the funded work should not be structured as a clinical trial, meaning it should not prospectively assign human participants to interventions to evaluate health-related outcomes in a clinical trial framework. The intent is to support mechanistic and hypothesis-driven research that can involve analysis of existing data or non-trial human and non-human research approaches, but without the hallmark features of an intervention study designed as a clinical trial. Applicants would be expected to design their aims accordingly, focusing on mechanisms, pathways, and explanatory models of tolerance rather than intervention efficacy testing.

A wide range of organizations are eligible to apply, reflecting the program's interest in broad participation and diverse research settings. Eligible applicants include state, county, and local governments; special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; federally recognized Native American tribal governments; tribal organizations that are not federally recognized; public housing and Indian housing authorities; nonprofits with and without 501(c)(3) status (outside of higher education institutions); for-profit organizations (other than small businesses); small businesses; and other entities. The FOA also explicitly highlights additional eligible applicants such as Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), Tribally Controlled Colleges and Universities (TCCUs), faith-based or community-based organizations, eligible federal agencies, regional organizations, non-U.S. (foreign) organizations, and U.S. territories or possessions. This breadth suggests NIH is open to proposals that bring in varied expertise, populations, and research environments, including work conducted outside the United States when scientifically justified.

Administratively, the opportunity is a discretionary grant program administered by the National Institutes of Health, created on February 14, 2018, with an original closing date listed as May 7, 2021. While the source excerpt does not provide an award ceiling or the expected number of awards, the overall structure and the use of the R21/R33 mechanism indicate a program built to support a pipeline from exploratory work to expanded research within a single, staged award. In summary, the FOA is essentially a call for mechanistic, hypothesis-generating and hypothesis-testing research that can explain why tolerance emerges, what pathways drive it, how it differs across individuals, and how it feeds into the broader trajectory toward alcohol dependence, using a phased approach that starts with pilots or secondary analyses and then advances to more comprehensive testing.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Mechanisms of Alcohol Tolerance (R21/R33 Clinical Trial Not Allowed)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.273.
• This funding opportunity was created on 2018-02-14.
• Applicants must submit their applications by 2021-05-07. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

Apply for PAR 18 659

[Watch] Creating a grant proposal using the step-by-step wizard inside the applicant portal: