Mechanisms of Tolerance (R21/R33 - Clinical Trial Required) | PAR 19 311

Opportunity Information: Apply for PAR 19 311

Mechanisms of Tolerance (R21/R33 - Clinical Trial Required) is a National Institutes of Health funding opportunity (PAR-19-311) from NIAAA that targets a specific gap in alcohol research: why some people become less sensitive to alcohol over time (tolerance), how that tolerance is biologically and behaviorally regulated, and how those changes can set the stage for alcohol use disorder (AUD). The FOA is centered on human-relevant mechanisms and requires a clinical trial component, meaning applicants are expected to include prospective human research that meets the NIH definition of a clinical trial rather than limiting the work to purely observational or basic laboratory studies.

The scientific emphasis is on uncovering and formalizing the mechanisms that control alcohol sensitivity and tolerance across different levels of analysis. On the mechanistic side, the FOA encourages teams to generate testable hypotheses about cellular, molecular, and neural circuit or network processes that shape alcohol responses, including how repeated exposure alters the body and brain in ways that change subjective intoxication, impairment, and drinking behavior. On the modeling side, it pushes applicants to build quantitative or computational models that can predict how tolerance emerges and how that trajectory relates to escalation of drinking and progression toward AUD. The key idea is not only to describe tolerance, but to explain it mechanistically and forecast its development in a measurable way.

The grant uses a phased innovation structure (R21/R33) designed to support high-risk, high-impact work that needs an early stage to prove feasibility before scaling. The R21 phase functions as the exploratory and groundwork period. During this phase, applicants may conduct secondary analyses of existing datasets or run small pilot studies to refine measures, validate experimental approaches, establish recruitment and retention strategies, and generate preliminary evidence that supports the central hypothesis and modeling approach. Importantly, the R21 is expected to culminate in clear, objective milestones that demonstrate the project is ready to expand rather than remaining exploratory.

If the R21 milestones are met, the project may transition into the R33 phase, where the hypothesis testing and model development are expanded and more fully powered. The R33 is meant to be the substantive research phase in which the team executes the larger clinical trial work, rigorously tests the proposed mechanisms, and advances predictive models with stronger empirical support. The transition is not automatic; NIAAA program staff evaluate whether the predefined R21 milestones have been achieved and determine readiness for the R33 stage. This milestone-driven handoff is a core feature of the FOA and effectively requires applicants to plan the early phase with concrete deliverables that de-risk the later phase.

This opportunity is specifically framed around tolerance mechanisms relevant to AUD development in humans. Applicants whose primary focus is on animal studies of tolerance mechanisms are pointed toward a different FOA (PAR-18-659). Applicants whose emphasis is the genetic basis of tolerance are directed to another related FOA (PA-18-660). In other words, PAR-19-311 is positioned for clinical-trial-oriented research that links mechanisms and prediction in ways that can directly inform understanding of human AUD risk and progression.

Eligibility is broad and includes many organizational types, reflecting an intent to attract diverse research teams and settings. Eligible applicants include federal, state, county, city, township, and special district governments; public and private institutions of higher education; independent school districts; public housing authorities; federally recognized tribal governments and other tribal organizations; nonprofits with or without 501(c)(3) status; for-profit organizations (other than small businesses) and small businesses; and additional categories. The FOA explicitly highlights a wide range of other eligible applicant types, including Alaska Native and Native Hawaiian Serving Institutions, AANAPISIs, Hispanic-serving institutions, HBCUs, Tribally Controlled Colleges and Universities, faith-based and community-based organizations, regional organizations, non-U.S. entities (foreign organizations), and U.S. territories or possessions. This breadth supports multi-site clinical work and partnerships that can recruit diverse populations and incorporate community or healthcare-system contexts relevant to alcohol risk and outcomes.

Administratively, this is a discretionary NIH grant in the health research area (CFDA 93.273). The opportunity was created on 2019-07-10, and the original closing date listed is 2022-01-07. The listing does not specify an award ceiling or the expected number of awards in the provided source details, so prospective applicants would typically confirm current budget guidance, application due dates, and any reissued or updated versions of the FOA in NIH systems before preparing a submission.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Mechanisms of Tolerance (R21/R33 - Clinical Trial Required)" 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 2019-07-10.
• Applicants must submit their applications by 2022-01-07. (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 19 311

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