Opportunity Information: Apply for PAR 27 053
The Exploratory Clinical Neuroscience Research on Substance Use Disorders (R61/R33 Clinical Trial Optional) funding opportunity (PAR-27-053) is an NIH discretionary grant designed to push forward early-stage, high-impact clinical neuroscience studies that can clarify how substance use disorders (SUD) work in the brain. The core emphasis is on exploratory and developmental clinical research that digs into neurobiological mechanisms, especially the fundamental brain circuitry and behavioral processes that shape substance use, craving, reinforcement, decision-making, habit formation, stress responsivity, and related functions. The intent is not simply to test an intervention for efficacy, but to strengthen mechanistic understanding of SUD in humans in ways that can later inform better prevention and treatment strategies.
A defining feature of this opportunity is the phased R61/R33 structure, known as the Phased Innovation Award. In practice, this mechanism is meant for projects that need a staged approach: an initial, milestone-driven exploratory phase (R61) followed by a second phase (R33) that expands or confirms the work once early feasibility or proof-of-concept targets are met. This is a good fit for clinical neuroscience questions where investigators may need to establish feasibility, validate a paradigm, confirm target engagement, or demonstrate that a proposed measure meaningfully captures a brain-behavior mechanism before scaling up. Projects that do not truly need a two-phase structure are steered toward other NIH mechanisms, such as the parent R01 clinical trial-required announcement (for example, PA-25-305 or a later reissue), signaling that the R61/R33 is reserved for proposals where clear go/no-go milestones and phased progression are scientifically justified.
The opportunity is labeled “Clinical Trial Optional,” which generally indicates that applicants may propose either clinical trials or non-trial clinical research, depending on the question and design. This flexibility supports a broad range of mechanistic clinical neuroscience work, including experimental medicine approaches, human laboratory paradigms, neuroimaging or neurophysiology studies, and other clinical designs that aim to explain how SUD-related neurobiology and behavior interact. Regardless of whether a formal clinical trial is included, the work is expected to be grounded in clinical relevance and focused on mechanisms rather than solely descriptive outcomes.
Eligibility is broad and includes many common applicant types across the public, nonprofit, academic, and private sectors. 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; nonprofit organizations (both 501(c)(3) and non-501(c)(3), excluding higher education institutions when listed separately); for-profit organizations (other than small businesses); small businesses; public housing authorities/Indian housing authorities; and Native American tribal governments (federally recognized) as well as other tribal organizations. This wide eligibility range reflects NIH’s interest in drawing strong mechanistic clinical neuroscience proposals from diverse research environments, including community-linked settings when appropriate.
International participation is allowed, but with important boundaries that affect how collaborations can be structured. Non-U.S. entities (foreign organizations) may apply directly, and non-U.S. components of U.S. organizations are also eligible. Foreign components, as defined in the NIH Grants Policy Statement, are allowed as well. At the same time, NIH policy described in the opportunity states that NIH will no longer issue awards to domestic or foreign entities that involve foreign subawards or subcontracts unless the application is submitted under a NOFO specifically designated for funded international collaborations. As a result, applications to this NOFO that include foreign subawards/subcontracts are considered noncompliant and will not be reviewed for funding. This restriction does not prohibit all international involvement: it still allows unfunded international collaborations, foreign components in the appropriate NIH sense, payment for foreign consultants, and procurement of specialized equipment or supplies from foreign vendors, as long as the arrangement does not constitute a foreign subaward/subcontract.
From an administrative standpoint, the opportunity is offered by the National Institutes of Health under the health funding activity category and is listed under CFDA number 93.279. The funding instrument is a grant using the R61/R33 activity code. The posted original closing date is June 16, 2028, and the opportunity record shows a creation date of August 31, 2026. Award ceiling and expected number of awards are not specified in the provided listing, which often means applicants should consult the full NOFO text for budget limits, typical award sizes, project period guidance, and any institute- or program-specific considerations.
Overall, this NOFO is best understood as a pathway for investigators who have a compelling clinical neuroscience idea about SUD mechanisms, but who need a structured, milestone-based ramp from exploratory work into a more robust second phase. The program is positioned to support innovative mechanistic studies that can tighten the link between brain circuitry, behavior, and clinically relevant substance use outcomes, while also enforcing current NIH rules around international subawards/subcontracts so applicants can plan compliant collaborations from the outset.Apply for PAR 27 053
- The National Institutes of Health in the health sector is offering a public funding opportunity titled "Exploratory Clinical Neuroscience Research on Substance Use Disorders (R61/R33 Clinical Trial Optional)" and is now available to receive applicants.
- Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.279.
- This funding opportunity was created on 2026-08-31.
- Applicants must submit their applications by 2028-06-16.
- 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.
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FAQs: Exploratory Clinical Neuroscience Research on Substance Use Disorders (R61/R33 Clinical Trial Optional) - PAR-27-053
What is PAR-27-053?
PAR-27-053 is an NIH discretionary grant opportunity titled "Exploratory Clinical Neuroscience Research on Substance Use Disorders (R61/R33 Clinical Trial Optional)." It supports early-stage, high-impact clinical neuroscience research focused on understanding how substance use disorders (SUD) work in the human brain.
What is the main purpose of this funding opportunity?
The main purpose is to advance exploratory and developmental clinical research that clarifies neurobiological mechanisms of SUD in humans. The emphasis is on mechanistic understanding (how and why SUD-related brain and behavior processes occur), with the intent that these insights can later inform better prevention and treatment strategies.
What kinds of research questions are a good fit for this NOFO?
This NOFO is geared toward clinical neuroscience questions that probe fundamental brain circuitry and behavioral processes involved in SUD. Examples of emphasized mechanisms include substance use, craving, reinforcement, decision-making, habit formation, stress responsivity, and related brain-behavior functions.
Is this opportunity intended to fund intervention efficacy trials?
No. The stated intent is not simply to test an intervention for efficacy. Instead, the focus is on strengthening mechanistic understanding of SUD in humans (for example, establishing or validating a paradigm or measure that captures a brain-behavior mechanism), which can later support the development of more effective prevention and treatment approaches.
What does the R61/R33 "Phased Innovation Award" structure mean?
The R61/R33 structure is a two-phase, milestone-driven approach. The first phase (R61) is an exploratory stage designed to meet predefined feasibility or proof-of-concept milestones. If those milestones are achieved, the project can progress to the second phase (R33), which expands or confirms the work.
Why would an applicant choose an R61/R33 instead of a single-phase mechanism?
This mechanism is intended for projects that truly need a staged ramp-up, such as when investigators must establish feasibility, validate a paradigm, confirm target engagement, or demonstrate that a proposed measure meaningfully captures a brain-behavior mechanism before scaling up.
What if a project does not need a two-phase structure?
Projects that do not truly require a two-phase, milestone-based approach are steered toward other NIH mechanisms. The information provided specifically references the parent R01 clinical trial-required announcement (for example, PA-25-305 or a later reissue) as an alternative pathway.
What does "Clinical Trial Optional" mean in this NOFO?
"Clinical Trial Optional" means applicants may propose either clinical trials or non-trial clinical research, depending on the scientific question and study design. The opportunity is designed to accommodate both approaches when they are appropriate for mechanistic clinical neuroscience aims.
What types of study designs are described as relevant to this opportunity?
The description highlights mechanistic clinical neuroscience work such as experimental medicine approaches, human laboratory paradigms, neuroimaging studies, neurophysiology studies, and other clinical designs aimed at explaining interactions between SUD-related neurobiology and behavior.
Does the research need to be clinically relevant even if it is not a clinical trial?
Yes. Regardless of whether a formal clinical trial is included, the work is expected to be grounded in clinical relevance and focused on mechanisms rather than purely descriptive outcomes.
Who is eligible to apply?
Eligibility is broad and includes many organization types across the public, nonprofit, academic, and private sectors. Eligible applicants listed 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; nonprofit organizations (501(c)(3) and non-501(c)(3), excluding higher education institutions when listed separately); for-profit organizations (other than small businesses); small businesses; public housing authorities/Indian housing authorities; and federally recognized Native American tribal governments as well as other tribal organizations.
Are international (non-U.S.) organizations allowed to apply?
Yes. Non-U.S. entities (foreign organizations) may apply directly. In addition, non-U.S. components of U.S. organizations are eligible, and foreign components (as defined in the NIH Grants Policy Statement) are allowed.
Are foreign subawards or foreign subcontracts allowed under this opportunity?
No. The information provided states that NIH will no longer issue awards to domestic or foreign entities that involve foreign subawards or subcontracts unless the application is submitted under a NOFO specifically designated for funded international collaborations. Applications to this NOFO that include foreign subawards/subcontracts are considered noncompliant and will not be reviewed for funding.
Does the restriction on foreign subawards/subcontracts prohibit all international involvement?
No. International involvement may still be possible through routes that do not constitute foreign subawards/subcontracts. The description specifically notes that unfunded international collaborations, foreign components (in the NIH sense), payment for foreign consultants, and procurement of specialized equipment or supplies from foreign vendors may still be allowable, provided they are structured in a way that does not create a foreign subaward/subcontract.
What is the funding instrument and activity code?
The funding instrument is a grant, using the NIH R61/R33 activity code (the phased innovation award structure described in the opportunity).
What is the CFDA number associated with this opportunity?
The listing identifies CFDA number 93.279.
What are the key dates listed for this opportunity?
The opportunity record shows a creation date of August 31, 2026, and the posted original closing date is June 16, 2028.
Is there an award ceiling or an expected number of awards stated in the listing?
No. The provided listing does not specify an award ceiling or the expected number of awards. This often means applicants would need to consult the full NOFO text for budget limits, typical award sizes, project period guidance, and any institute- or program-specific considerations.
How should applicants think about milestones for the R61 phase?
The R61 phase is described as milestone-driven, with go/no-go targets tied to feasibility or proof-of-concept. The opportunity highlights milestones such as establishing feasibility, validating a paradigm, confirming target engagement, or demonstrating that a measure meaningfully captures a brain-behavior mechanism before moving to the R33 phase.
What is the overall "best fit" project profile for this NOFO?
The NOFO is positioned as a pathway for investigators with compelling mechanistic clinical neuroscience ideas about SUD who need a structured, milestone-based ramp from exploratory work into a more robust second phase, and who can plan collaborations in a way that complies with NIH restrictions on foreign subawards/subcontracts.
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