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Rural Community-Centered Drug Misuse Prevention and Harm Reduction Research: Addressing Implementation, Dissemination, and Equity Challenges across the Continuum of Care (R61/R33 Clinical Trial Only)




November 8, 2023



January 26, 2024




Award Floor:


Match Required?





Entity Types:

State governments, County governments, City or township governments, Special district governments, Independent school districts, Public & State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities, Native American tribal organizations, Nonprofits (with 501(c)(3) status), Nonprofits (without 501(c)(3) status)

Other Eligible Applicants include the following: Alaska Native and Native Hawaiian Serving Institutions; Asian American Native American Pacific Islander Serving Institutions (AANAPISISs); Eligible Agencies of the Federal Government; Faith-based or Community-based Organizations; Hispanic-serving Institutions; Historically Black Colleges and Universities (HBCUs); Indian/Native American Tribal Governments (Other than Federally Recognized); Non-domestic (non-U.S.) Entities (Foreign Organizations); Regional Organizations; Tribally Controlled Colleges and Universities (TCCUs) ; U.S. Territory or Possession; Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply. Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement, are allowed.




Source Type:


The goal of the initiative is to test prevention and harm reduction strategies, extending the continuum of care within the U.S. rural communities impacted by the opioid/psychostimulant misuse epidemic to reduce risks for individuals with unmet prevention and harm reduction needs. Background

The current U.S. opioid epidemic has evolved into an opioid/stimulant epidemic, with mental illness co-morbidities more evident than in the past. Stimulant use has introduced new complexities to the epidemic in terms of behavioral consequences (e.g., psychosis, disorganized behavior), available treatments, and the need for new harm reduction strategies. Addressing the opioid epidemic is even more difficult in rural areas. Challenges specific to rural settings include the scarcity of behavioral health services due to low density of populations [e.g., fewer credentialed behavioral health practitioners, particularly prescribers for medications for opioid use disorder (MOUD)]. In rural areas, there is a greater reliance on publicly-funded services, and non-profit sectors may be limited. Limited access to reliable public broadband services, private vehicles or public transportation inhibit participation in services that are locally available and make common ways to extend reach (e.g., telehealth) difficult. Stigma regarding substance use (generally) and treatment and harm reduction modalities often is more evident than in metropolitan settings. Some systemic drivers of opioid use such as homelessness exist in rural and urban settings but may be more hidden in rural areas. This opioid/stimulant epidemic has entered a period of chronicity which requires a continuum of care that spans from prevention to treatment and recovery. This is reflected in current federal drug control strategies, including those for methamphetamine, which recommend prevention, particularly among youth and young adults, and further development of harm reduction strategies.

In 2017, the National Institute on Drug Abuse (NIDA) launched the Rural Opioid Initiative (, supporting research projects focused on local implementation and demonstration of services to meet the immediate needs for harm reduction infrastructure and referral to Hepatitis C virus (HCV) and/or MOUD care. This notice of funding opportunity (NOFO) will augment this earlier initiative, supporting the development and testing of prevention and/or expanded harm reduction strategies, facilitating the development of an evidence-based continuum of care in response to this continuing rural opioid/stimulant epidemic.


This NOFO will support research projects that develop and test drug misuse prevention and/or harm reduction strategies, extending the continuum of care within U.S. rural communities impacted by the opioid/stimulant epidemic. The overall goal is to reduce drug use and associated risks and harms for individuals with unmet prevention and/or harm reduction needs. Research activities will be conducted in two phases (i.e., developmental R61 phase and implementation and effectiveness trial R33 phase). Each phase of the project must involve community partners and potential end users of the research findings. Projects should leverage the social capital and formal organizations that have arisen in rural communities during this epidemic (e.g., task forces). These projects should yield effective strategies to meet prevention and/or harm-reduction needs in diverse rural communities in the U.S.

Specific Topics of Research Interest

Projects need to identify ways to implement evidence-based practices that overcome the existing challenges noted above (e.g., low density of people and services, as well as the factors that limit access to existing services). Multi-component and multi-level (e.g., client/patient, providers, systems-level interventions) strategies are encouraged. Project aims should address how the locally-tailored strategies will lead to outcomes appropriate to implementing prevention (e.g., reducing individual or community drug use, prevent escalation including transition to injection) and/or harm reduction (e.g., reducing overdose, preventing HCV acquisition). Projects are required to propose sustainable, scalable, and equitable approaches for accelerating the movement of evidence-based and promising prevention and/or harm reduction strategies into routine use within rural communities. Increasing the likelihood of sustainability may be achieved by capitalizing on state and local initiatives (e.g., task force activities, opioid settlement funds) and/or make use of local stakeholder infrastructures (e.g., Communities That Care coalitions).

Projects supported through this NOFO will use the R61/R33 mechanism. Each phase of the project must involve meaningful engagement of community partners and potential end users of the research findings. These partners may include representatives of state or local health departments or other agencies responsible for funding substance use prevention, providers of harm reduction programs, drug treatment or other services relevant to the settings of the grant, as well as persons with lived experience with substance use and individuals associated with the justice system, education systems, emergency medical services, clinical settings, or medical providers. Existing task forces, community coalitions, community partnerships, etc. related to substance use should be incorporated, if present, to minimize overlap and duplication. The R61 phase is expected to be developmental and formative in nature and should focus on future sustainability and scalability of an intervention, based on meaningful inclusion of rural perspectives and priorities learned from community partners and potential end users of the research findings. During the R33 phase, research teams will test the implementation and effectiveness of the selected prevention and/or harm reduction strategies in the context of selected service or system settings. Selected strategies should address cross-cutting issues that are relevant to local communities such as stigma reduction and promotion of health equity. Research teams should build on existing research knowledge regarding implementation facilitators and barriers with local data collection, as needed. Aims related to implementation and effectiveness are required to be provided.

For this NOFO, substance use prevention refers to selective or indicated prevention strategies. The intention is to reduce risks for substance misuse, delay experimentation, or delay escalation to injection drug use or substance use disorder. Prevention services may be delivered in a range of settings, including schools, behavioral health centers, federally qualified health centers or rural health centers, social service settings such as child/family service agencies, juvenile and adult justice systems (including special problem courts) and other community venues. The objective is to introduce sustainable prevention programs where they do not exist and increase the depth, reach, and use of evidence-based principles.

Harm reduction generally refers to reducing the harms attributable to active drug use and, in traditional public health terms, may be seen as tertiary prevention. The most common harm reduction services include the provision of unused, sterile injection equipment in syringe service programs (SSPs). Services offered by SSPs also may include screening and referral for consequences of injection such as viral hepatitis, HIV, other infectious disease prevention such as condoms or pre-exposure prophylaxis and attention to basic needs such as hygiene or food. SSPs may be freestanding or incorporated into health departments, AIDS service organizations, free clinics or other settings and their other services may or may not be fully integrated with harm reduction. The objective here is to establish harm reduction services where they do not exist or to expand the scope of services with the expectation that local uptake of preventive services (e.g., HCV screening, syringe distribution) will increase and harmful effects of drug use will be reduced (e.g., fewer injection site infections, fewer cases of intentional or unintentional overdose, fewer new cases of viral hepatitis).

Responsive application s will document unmet prevention and/or harm reduction needs in the selected communities and address equity across various aspects of the research (e.g., the diversity of collaborator group members, the identification and recruitment of study participants, selection, and implementation of intervention strategies, etc.). Applications must demonstrate how they target communities at greatest risk of adverse events related to opioid use, and document appropriate indicators such as opioid overdose deaths, case reports of acute Hepatitis C infection, drug seizures, 911 calls for overdose, etc.

This NOFO seeks a range of research studies including, but not limited to, the following:

Projects that test ways to incorporate peers into intervention implementation (e.g., outreach, service delivery).
Efforts to expand the range of available prevention and/or harm reduction services through modalities such as Project ECHO and/or telehealth enabled by clinics, providers, or mobile services.
Tests of strategies to build local capacity to deliver or expand the reach of prevention and/or harm reduction services through training and consultation among:
Healthcare providers (e.g., pediatricians, family practice physicians, internists, nurse practitioners), paraprofessionals (e.g., community health workers, recovery coaches),
First responders (e.g., emergency medical services, emergency departments, firefighters, law enforcement) to effectively respond to overdoses (e.g., stigma reduction, crisis intervention training, prevention of needlestick and sharps injuries) and/or engage in “warm hand-offs” to services.
Integration of prevention and/or harm reduction services into comprehensive systems of substance use or behavioral health (e.g., hub and spoke models of substance use service delivery; behavioral health networks; harm reduction networks).
Integration of prevention and/or harm reduction into novel settings including:
Primary care, including rural community health centers, emergency departments, and specialty settings that also deliver primary care services such as Planned Parenthood or AIDS service organizations,
Job Corps, vocational or rehabilitation training or other transitions to competitive employment serving high risk populations,
Programs for individuals experiencing physical disabilities,
Programs that provide outreach to individuals who are unhoused or receiving housing services.
Studies of strategies to deliver prevention services to parents, children, youth and/or families involved in social service settings including:
Settings that serve people experienced intimate partner violence,
Clinical settings serving parents being treated for substance use disorder,
Diversion programs and other settings related to the justice system.
Community-engaged partnerships with rural organizations and residents who identify as historically marginalized are required. Selected strategies should address areas of broad concern such as stigma as experienced by people who use drugs and stigma as perceived from or enacted by service providers or other key members of the community (e.g., first responders).

Drug treatment is not primary focus of this NOFO; however, applicants will need to document existing treatment and recovery resources that serve their project’s area, including inpatient and outpatient services and available forms of MOUD. Applications should indicate how referrals to treatment resources will be made, as needed, as well as how they will determine eligibility for referral. All referrals to treatment should include a “warm handoff” rather than simply providing referral information. Projects also should address mental health crisis intervention and include protocols for managing suicidality, psychotic behavior, and other acute psychiatric conditions, as well as intentional or unintentional overdose.

Milestones & Transition to the R33 Phase

Research supported through this NOFO will be conducted in two phases using the R61/R33 Exploratory/Developmental Phased Award mechanism. Support will be provided for up to 5 years, which includes initial support of up to 2 years for the R61 phase, followed by up to 3 years of support for the R33 phase. Transition to the R33 phase is contingent upon successfully meeting proposed R61 milestones. See Section IV. 2. Content and Form of Application Submission, SF424(R*R) Other Project Information for instructions for milestones.

Applicants must include milestones that are expected to be achieved by the end of the R61 phase. Milestones should be specific, quantifiable, and scientifically justified to showcase readiness for the R33 phase; they should not be simply a restatement of the specific aims for the R61 phase. Applicants must include a discussion of the suitability of the proposed milestones for assessing success in the R61 phase and the implications of successful completion of these milestones for the proposed R33 phase of the project. These should include efforts to create structures that enable collaborations with community stakeholders and other potential users of data from the project to guide rural specific recommendations and any pilot/feasibility testing of intervention or implementation components needed to progress to the R33 phase, as well as plans to increase intervention sustainability and rural credibility during and beyond the project period.

For transition to the R33 phase, awardees must submit the transition package no less than two months before the completion of the R61 phase. The transition plan should include the R61 progress report describing, in detail, the progress towards the R61 milestones and a description of how research proposed for the R33 phase will be supported by the completion of the R61 phase milestones. These materials will be evaluated by NIH program staff to determine whether the milestones were achieved. R33 funding decisions will be based on the original R61/R33 peer review recommendations, successful completion of transition milestones, any proposed changes to the R33 research based on R61 findings, program priorities, and availability of funds.

Funding of the R61 phase and completion of milestones does not guarantee funding of the R33 phase of the project. Phase two (R33) will provide possible funding for up to 3 years to conduct a clinical trial examining implementation and effectiveness of prevention and/or harm reduction interventions in rural communities. Potential applicants are strongly encouraged to consult with NIDA Program staff early in the application development process to discuss alignment of their study ideas with research priorities.

Applications not responsive to this NOFO:

Applications that do not focus on U.S. rural communities.
Studies that only focus on substance use treatment and do not focus on prevention and/or harm reduction.
Projects without community partnerships.
Projects without proposed plans for intervention sustainability.
Applications that do not include a milestone plan for the R61 phase.
Plan for Enhancing Diverse Perspectives (PEDP)

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21- 310, submitted as Other Project Information as an attachment (see Section IV).
Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.

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