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Grant Analysis

Purpose & Target

The grant's core objective is to support basic research aimed at understanding and mitigating the harmful and lethal effects of acute exposure to Ultra-Potent Synthetic (UPS) opioids and their combinations, as well as their persistent or delayed health impacts.
Target recipients are diverse U.S.-based organizations engaged in scientific research.
This is a SECTOR-SPECIFIC grant, focused on medical and public health research related to chemical countermeasures and toxicology.
Geographic scope is limited to U.S. organizations; foreign entities are not eligible to apply, although foreign components of U.S. organizations may be allowed.
Key filtering criteria include a focus on specific DHS Chemicals of Concern (CoC) within the opioid category, and the exclusion of clinical trials, pain management, or substance use disorder treatment research.
This is a recurring grant opportunity, being a reissue, and part of the broader Chemical Countermeasures Research Program (CCRP) within NIH.

Financial Structure

Grant Type: Financial assistance (R01 Research Project Grant).
Total Funding: NIH intends to support up to four awards, corresponding to a total of $2,000,000 in FY 2026.
Maximum Funding per Award: Application budgets are limited to $300,000 direct costs per year.
Project Period: The maximum project period is five years.
Currency: USD.
Cost Sharing: Cost sharing is not required.
Pre-Award Costs: Allowable as described in the NIH Grants Policy Statement Section 7.9.1.
Eligible Costs: Direct costs that reflect the actual needs of the proposed project.

Eligibility Requirements

Organization Type

Higher Education Institutions: Public/State Controlled, Private
Nonprofits: With or without 501(c)(3) IRS Status (other than Institutions of Higher Education)
For-Profit Organizations: Small Businesses, Other than Small Businesses
Local Governments: State, County, City/Township, Special District, Indian/Native American Tribal Governments (Federally Recognized and Other)
Federal Government: Eligible Agencies, U.S. Territory or Possession
Other: Independent School Districts, Public Housing Authorities/Indian Housing Authorities, Native American Tribal Organizations (other than Federally recognized tribal governments), Faith-based or Community-based Organizations, Regional Organizations

Geographic Location

Eligible applicants must be U.S. organizations.
Non-domestic (non-U.S.) entities are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components (as defined by NIH Grants Policy Statement) are allowed within an application submitted by an eligible U.S. organization.

Registrations

System for Award Management (SAM) with an active and current registration (requires annual renewal).
Unique Entity Identifier (UEI) – obtained through SAM.gov registration.
eRA Commons account for the organization and for all Program Directors/Principal Investigators (PD/PIs).
Grants.gov registration.
Registration processes can take 6+ weeks; must be completed before application submission.

Project Exclusions

Applications proposing clinical trials are not allowed.
Applications using opioids or agents not on the DHS list of Chemicals of Concern (CoC) will not be reviewed.
Applications focused on pain management, substance use disorders (SUD), or behavioral research to improve medication-based treatment programs are not responsive.
Efficacy studies (e.g., creation or validation of pre-identified Medical Countermeasures) without examining the causal mechanisms underlying overdose effects and toxicity, or delayed/extended pathophysiology, are not responsive.
Mitigation strategies where antidotes are administered prophylactically or co-administered with UPS opioids, or outcomes using chronic/sub-chronic dosing/exposure regimens that do not emulate acute UPS exposure, are not responsive.
Applications focusing solely on the discovery and testing of orthosteric/direct µ-opioid receptor antagonists are not responsive.

Application Limits

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
Duplicate or highly overlapping applications will not be accepted if under review at the same time.

Application Process

Application Submission Timeline

Open Date (Earliest Submission Date): October 18, 2025
Letter of Intent Due Date: 30 days prior to the application due date (not binding, but encouraged).
Application Due Dates:
November 18, 2025
November 18, 2026
November 18, 2027 (Latest)
All applications are due by 5:00 PM local time of the applicant organization.
Applicants are encouraged to apply early to allow time for corrections.
If a due date falls on a weekend or Federal holiday, the deadline is automatically extended to the next business day.

Submission Method

Applications must be submitted electronically via NIH ASSIST, an institutional system-to-system (S2S) solution, or Grants.gov Workspace.
Paper applications are not accepted.
Applicants must have active registrations for SAM, UEI, eRA Commons, and Grants.gov prior to submission.

Required Documentation and Materials

Follow all instructions in the Research (R) Instructions in the 'How to Apply - Application Guide', with any program-specific instructions from this NOFO taking precedence.
Standard forms include SF424(R&R) Cover, Project/Performance Site Locations, Other Project Information, Senior/Key Person Profile.
Budget: R&R or Modular Budget, R&R Subaward Budget.
PHS 398 Cover Page Supplement, Research Plan, Human Subjects and Clinical Trials Information, Assignment Request Form.
Resource Sharing Plan must be included.
A Data Management and Sharing Plan is required for all research generating scientific data, regardless of requested direct costs.
Appendix: Only limited materials are allowed (e.g., blank questionnaires/surveys). Publications or other materials are not allowed in the Appendix.

Post-Award Requirements & Reporting

Annual Research Performance Progress Reports (RPPR) are required for multiple-year awards.
Financial statements must be submitted as required.
A final RPPR, invention statement, and expenditure data are required for award closeout.
Recipients must comply with all provisions in effect during the award period, other Department regulations, and applicable statutory provisions.
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approval is required for protocols involving human subjects.
Recipients must provide NIH copies of documents related to all major changes in ongoing protocols.
Awards are subject to NIH Grants Policy Statement terms and conditions.

Evaluation Criteria

Overall Impact

Reviewers assess the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved.

Importance of the Research

Significance: Evaluation of the proposed research's importance in context of current scientific challenges. Does it address a knowledge gap, solve a critical problem, or create a valuable conceptual/technical advance? Assessment of the rationale and scientific background (including preliminary data).
Innovation: Extent to which novel concepts, methods, or technologies are applied, or existing ones are used in novel ways, to enhance the project's overall impact. Note: Technical/conceptual innovation can influence importance, but a project without novel approaches can still be critically important.

Rigor and Feasibility

Rigor: Evaluation of the potential to produce unbiased, reproducible, robust data. Assessed based on experimental design rigor, appropriate controls, sufficient/justified sample size, and quality of analysis/interpretation/reporting plans. Plans to address relevant biological variables (e.g., sex, age) will be evaluated.
For human subjects/vertebrate animals: rigor of intervention/study manipulation, justification of outcome variables, generalizability, and appropriateness/diversity of the sample.
Feasibility: Evaluation of the proposed approach's soundness and achievability. For studies with less certainty, the potential for major advances should balance the uncertainty. For human subjects: adequacy and feasibility of recruitment/retention plan, likelihood of achieving enrollment based on demographics.

Expertise and Resources

Investigator(s): Evaluation of the investigator's demonstrated background, training, and expertise relevant to the proposed work. For Multiple Principal Investigator (MPI) applications, the quality of the leadership plan for coordination/collaboration is assessed.
Environment: Evaluation of the appropriateness of institutional resources to ensure successful execution of the proposed work.

Additional Review Considerations (no separate scores)

Protections for Human Subjects: Justification for involvement, adequacy of protection against risks, potential benefits, importance of knowledge gained, and data/safety monitoring (if applicable). For exempt research, justification for exemption, human subjects involvement/characteristics, and material sources are reviewed.
Vertebrate Animals: Description of procedures, justification for animal use vs. alternatives, appropriateness of species, interventions to minimize discomfort/pain, and justification for euthanasia method if not consistent with AVMA guidelines.
Biohazards: Evaluation of proposed protection measures for specific hazardous materials or procedures.
Authentication of Key Biological and/or Chemical Resources: Brief plans for identifying and ensuring the validity of these resources.
Budget and Period of Support: Assessment of whether the budget and requested project period are fully justified and reasonable in relation to the proposed research.

Compliance & Special Requirements

Regulatory Compliance

Awards are subject to 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
Recipients must comply with all applicable nondiscrimination laws, as agreed upon during SAM.gov registration.
Submission of an Assurance of Compliance (HHS-690) is required.
Compliance with all federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 (Public Policy Requirements, Objectives and Other Appropriation Mandates), is mandatory.
Recipients are responsible for ensuring activities comply with all applicable federal regulations.

Data Management & Security

For research generating scientific data, recipients must adhere to the 2023 NIH Policy for Data Management and Sharing and implement the approved Data Management and Sharing Plan.
If the award involves ongoing access to HHS information/operational technology systems, or handling Personal Identifiable Information (PII)/Personal Health Information (PHI) from HHS, recipients must develop cybersecurity plans modeled after the NIST Cybersecurity Framework.

Health IT Standards

If funding involves implementing, acquiring, or upgrading health IT, recipients must use health IT that meets standards in 45 CFR part 170, Subpart B.
If for eligible clinicians/hospitals, health IT certified under the ONC Health IT Certification Program must be used.

Mandatory Disclosure

Recipients or subrecipients must disclose any violations of federal criminal law involving fraud, bribery, or gratuity that could affect the federal award, as per 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Research-Specific Requirements

Applications must focus on mechanisms (molecular, cellular, genetic, circuitry, structural) and biological pathways (gene expression, signal transduction, neural, developmental) related to UPS opioid exposure.
Research must address either the deleterious effects and lethal consequences of acute exposure to UPS opioids (e.g., fentanyl, carfentanil, nitazenes) and/or their combinations (e.g., fentanyl and xylazine), or non-lethal, delayed, or persistent pathophysiological effects after acute exposure.
Applications must include at least one opioid identified as a DHS Chemical of Concern (CoC). Other chemicals may be used as tools, but main research must focus on DHS CoC.
Studies cannot focus solely on the discovery and testing of orthosteric/direct µ-opioid receptor antagonists.
Applicants must clearly differentiate direct toxic effects from long-term effects, and mechanisms secondary to acute effects from direct pharmaco-toxicological effects.
Testing and validating mechanistic hypotheses using appropriate translational post-exposure models (e.g., respiratory depression) with multiple time points (acute/immediate and delayed/persistent effects) is encouraged.
The use of multiple assays/models/systems (e.g., in vitro, ex vivo, in vivo) is encouraged to enhance rigor and reproducibility.
Applicants are strongly encouraged to contact the Scientific/Research Contact(s) prior to submission for questions regarding the NOFO, including the DHS CoC.

Exclusions from Scope

No research on pain management, substance use disorders (SUD), or behavioral research for medication-based treatment programs.
No efficacy studies without examining causal mechanisms.
No mitigation strategies involving prophylactic/co-administered antidotes or chronic/sub-chronic dosing regimens that do not emulate acute UPS exposure.

Grant Details