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National Institute of Mental Health (NIMH)

Purpose

Purpose

The National Institute of Mental Health (NIMH) seeks public comment on strategies to build a coordinated evidence base that can guide clinical practice and implementation for rapid-acting psychotropic interventional drugs (RAPIDs) for mental illnesses and related brain disorders. The purpose of this Request for Information (RFI) is to gather information that may inform strategies to advance real-world evidence and pragmatic clinical research for RAPIDs, which may or may not require psychotherapy provided at the same time or clinical care support. For the purposes of this RFI, RAPIDs refer broadly to pharmacologic interventions for mental health conditions, with varying levels of evidence, that may produce clinically meaningful symptom reduction within hours or days and that may require structured clinical delivery, monitoring, or follow-up. Because individual RAPIDs differ substantially in level of scientific support, regulatory status, safety profile, and barriers to implementation, respondents are encouraged to specify the compound(s) and clinical indication(s) to which their comments apply. 

This request is for information and planning purposes only and should not be construed as a solicitation, a funding opportunity announcement, or an obligation on the part of the Federal Government. NIH does not intend to make awards based on responses to this RFI or otherwise pay for the preparation of any information submitted or for the Government's use of such information. 

Responses should not include personally identifiable information and should be compliant with Health Insurance Portability and Accountability Act (HIPAA) regulations. This is not a request for applications and is solely designed to solicit stakeholder feedback.

Background

RAPIDs, such as psilocybin, esketamine, and 3,4-methylenedioxymethamphetamine (MDMA), are being studied and, in some cases, used in clinical settings for serious mental illnesses and related mental health conditions, including treatment-resistant or treatment-refractory conditions, suicidal ideation and behaviors, and conditions for which existing Food and Drug Administration's (FDA) approved treatments may not produce adequate or lasting clinical benefit. The research challenge is not limited to whether these interventions can work under tightly controlled conditions. A central question is how, if emerging RAPID treatments are FDA-approved, they should be delivered safely, effectively, and sustainably in real-world care to optimize the full benefit for individuals living with serious mental illnesses.

Further, Executive Order 14401, "Accelerating Medical Treatments for Serious Mental Illness," issued on April 18, 2026, emphasized the need to accelerate innovative research models, broaden clinical trial participation, support data sharing, and generate real-world evidence for emerging rapid-acting treatments for serious mental illnesses. These priorities highlight the importance of rigorous approaches that can support timely learning while preserving appropriate scientific, clinical, privacy, and safety standards.

Traditional randomized controlled trials to establish efficacy and safety remain an essential first step. However, for agents with FDA approval, many practical questions require complementary approaches, including pragmatic clinical trials, hybrid effectiveness-implementation studies, and analyses of real-world clinical outcome data. A coordinated, systematic approach is necessary to address broad questions about generalizability, care settings, safety monitoring, and long-term clinical outcomes. Approaches may include all-active-treatment comparative designs in which every participant receives an evidence-based or FDA-approved intervention, with assignment informed by patient preference, site capability, or randomization among available options.

Evidence gaps are particularly important for adult and older adult populations and for settings that serve veterans, Medicaid beneficiaries, rural communities, and individuals receiving care in safety-net or settings with limited resources. Federal health care delivery systems such as the Veterans Health Administration, and the Indian Health Service may offer particular advantages as coordinated real-world evidence settings to examine the utilization of agents whose safety and efficacy have already been established. Feasibility will differ across these systems and by compound and study design. In the Department of Defense, for example, medical readiness and retention standards, duty limitations, and drug testing requirements may constrain participation, particularly in pragmatic or adaptive designs and for compounds without FDA approval. NIMH is interested in understanding how real-world studies can address a broad range of mental health and substance use disorder indications, as well as common psychiatric and medical comorbidities.

Without coordinated research infrastructure and harmonized measures, real-world data generated across various clinical, community, and payer settings may remain fragmented and difficult to interpret. Existing real-world data could be highly informative if harmonized and analyzed with appropriate legal, privacy, and scientific safeguards. Using common data elements, data systems that can work together, and pragmatic study designs will be critical to generating evidence that can guide decisions for clinical care and implementation.

NIMH is also interested in how measurement innovation, including approaches that assess clinical impact in or near real time, could complement ongoing federal efforts to improve behavioral health outcome measurements. Relevant measures may include symptoms, functioning, durability of effect, adverse events (e.g., hospitalization), patient experience, healthcare service utilization, and total cost of care.

NIMH is interested in strategies that can produce useful near-term evidence while also supporting longer-term, scalable clinical research infrastructure. For example, an initial demonstration period could establish core infrastructure for a coordinated demonstration network of participating clinical sites and care settings, including shared protocols, site partnerships, common data elements, safety monitoring processes, privacy-protective data flows, near-real-time measurement approaches, and pilot pragmatic studies. Such a network could support structured sharing of harmonized data, operational lessons, safety findings, and implementation experience across settings to accelerate learning and inform later scale-up. A subsequent scale-up period could support larger multi-site studies across additional populations, indications, delivery models, and care settings.

Information Requested

NIMH seeks input on near-term, scalable research approaches capable of producing the timely, practical evidence needed to move promising interventions into responsible clinical practice. Specifically, NIMH is interested in the infrastructure, methods, partnerships, and data strategies including pragmatic clinical trials and real-world data necessary to generate interpretable evidence. This evidence is vital to inform clinical, health system, and payer decisions in a variety of clinical settings. NIMH seeks input from a broad array of interested parties, including but not limited to the following: 

• People with personal experience;
• Patient and caregiver advocacy organizations; and professional societies;
• Researchers and academic institutions;
• Community mental health organizations, health systems, clinicians, and other providers;
• Current providers of RAPIDs operating in jurisdictions where such services are legally available; rural and safety-net care organizations; and Veterans Affairs (VA) affiliated clinical and research settings;
• State mental health authorities; state Medicaid agencies; commercial and public payers; and organizations that maintain existing data from state programs, provider systems, health systems, registries, or payer sources;
• Therapy developers; pharmaceutical, biotechnology, data, and digital health companies; philanthropic organizations; and other federal, public, or private organizations with relevant expertise.

NIMH invites comments on any or all of the following topics relevant to the optimal administration of RAPIDs for serious mental illness and related brain disorders across clinical care settings. 

Respondents are encouraged to address any of the following topics in which they have relevant experience or expertise; responses do not need to address all topics. Respondents are encouraged to provide specific examples, evidence gaps, priority research questions, recommended methods, feasible data sources, implementation considerations, and barriers to adoption or scalability.

1. Priority real-world effectiveness questions and patient-centered outcomes relevant to the administration of RAPIDs for serious mental illnesses and related brain disorders

NIMH seeks input on the most important real-world effectiveness questions that could be addressed by a coordinated network to inform clinical care, practice guidelines, health system adoption, payer decision-making, and patient-centered choices. 

• Priority clinical, functional, quality-of-life, and patient-centered real-world outcomes for RAPIDs administered for serious mental illnesses and related brain disorders, including symptom remission durability, reductions in concomitant daily psychotropic medications (polypharmacy), employment and workplace productivity, interpersonal and family functioning, and reductions in acute healthcare utilization (e.g., emergency department visits and psychiatric hospitalizations)
• Comparisons and benchmarks useful for evaluating RAPIDs in real-world care, including usual care, existing pharmacologic approaches, procedural care models, stepped-care or sequential approaches, and other real-world alternatives.
• Real-world evidence and outcomes most meaningful for distinct conditions, including recovery-oriented outcomes for RAPIDs interventions in substance use disorders, such as reductions in use frequency, craving management and prolonged retention in treatment.
• Real-world outcomes most meaningful for adults, older adults, veterans, Medicaid beneficiaries, rural populations, and patients served in safety-net settings including impact on caregivers and capacity for independent living.

2. Pragmatic clinical trial designs and real-world study methods relevant to the administration of RAPIDs for serious mental illnesses and related brain disorders

NIMH seeks input on research designs that can generate rigorous, generalizable, and timely evidence on the effectiveness and safety of RAPIDs deployed in clinical care settings. 

• Study approaches best suited to studying RAPIDs in real-world care, such as pragmatic clinical trials, hybrid effectiveness-implementation studies, platform and sequential designs, registry-based studies, embedded studies, and observational studies.
• Methods for strengthening causal inference and reducing bias when using electronic health record (EHR), claims, registry, provider-system, state-program, and other real-world data to evaluate RAPIDs.
• Approaches for balancing internal validity, generalizability, feasibility, patient preference, site burden, and speed in studies of RAPIDs.
• Study designs, milestones, and interim findings that could provide useful information about the effectiveness and safety of RAPIDs when long-term efficacy trials are infeasible, without compromising scientific rigor.
• Approaches for determining when evidence from blinded randomized controlled trials is sufficient to support pragmatic or real-world studies of a given RAPID, and methods for assessing and mitigating functional unblinding and expectancy effects (e.g., active comparators and assessment of blinding integrity).

3. Safety monitoring and adverse event assessment relevant to the administration of RAPIDs for serious mental illnesses

NIMH seeks input on safety evidence needed for responsible medical use of rapid-acting psychotropic interventions across care settings and patient populations. 

• Safety outcomes to capture, including acute, delayed, psychiatric, medical, cognitive, functional, and patient-reported safety outcomes.
• Special considerations for monitoring procedures, escalation pathways, emergency protocols, and adverse-event reporting systems for RAPIDs in real-world settings.
• Evidence needed to inform clinical practice standards for RAPIDs, including medical or psychiatric monitoring and use of settings that provide more intensive care. 
• Special considerations for capturing and reviewing RAPIDs safety data in or near real time while minimizing burden on patients and clinical sites.

4. Delivery models, care settings, and operational requirements for optimal administration of RAPIDs for mental illnesses and related brain disorders.

 NIMH seeks input on studies to determine if these interventions, particularly those requiring specialized administration or extended clinical monitoring (such as psychedelics), can be delivered safely and effectively in different settings and service configurations, including individual and group-based approaches. 

• Evidence needed to compare RAPIDs delivery models across outpatient, inpatient, intensive outpatient, emergency, Veterans Affairs, community mental health, academic medical center, specialty clinic, and integrated health-system settings.
• Care elements to evaluate for RAPIDs, including screening, monitoring duration, post-administration observation, follow-up, and telehealth-enabled care.
• Operational measures to assess RAPIDs feasibility, site readiness, workflow impact, and scalability.

5. Patient selection, risk stratification, and priority populations for evidence-based administration of RAPIDs for mental illnesses and related brain disorders across clinical care settings

NIMH seeks input on evidence needed to identify who is most likely to benefit, who may be at elevated risk from adverse effects from RAPIDs, and how to support appropriate access and availability across care settings. 

• Clinical characteristics such as; treatment history; history of recreational or other non-medical use of RAPIDs or related substances; concomitant medications, particularly other psychotropic medications; comorbid medical or psychiatric conditions such as substance use disorder; family history and genetic or pharmacogenomic markers associated with therapeutic response or adverse event vulnerability, geographic, economic, clinical, care-delivery, and care-history factors to measure in studies of RAPIDs.
• Predictors of RAPIDs benefit, nonresponse, relapse, discontinuation, adverse outcomes, and need for higher monitoring intensity.
• Approaches for accounting for common psychiatric and medical comorbidities that may affect RAPIDs safety, effectiveness, delivery model, or follow-up needs.

6. Adjunctive psychological support, integration services, and continuity of care delivery of RAPIDs for mental illnesses and relevant brain disorders across clinical care settings

NIMH seeks input on the role, timing, intensity, and duration of psychological support and related services before, during, and after administration. 

• Types of preparation, structured psychological support, integration services, medication management, care coordination, and follow-up to evaluate for RAPIDs.
• Adjunctive service elements to consider as essential, optional, indication-specific, patient-specific, or setting-specific for RAPIDs.
• Approaches for evaluating whether adjunctive services for RAPIDs improve durability, safety, patient experience, functioning, or later health care use.

7. Durability of response, retreatment, and longitudinal outcomes of RAPIDs for mental illnesses and related brain disorders across clinical care settings

NIMH seeks input on how to measure durability, relapse, maintenance strategies, and repeated exposure in real-world care. 

• Follow-up intervals and outcome measures needed to assess RAPIDs response, remission, relapse, functioning, quality of life, and patient experience.
• Evidence needed to determine retreatment frequency, safe and effective intervals between treatments, limits on the number of treatments, predictors of durable response, and safety implications of repeated exposure.
• Utilization outcomes related to RAPIDs to track over time, including hospitalization, emergency department use, crisis service use, relapse, retreatment, and follow-up care.
• Near-real-time signals to identify early relapse, safety concerns, or the need for additional follow-up after RAPIDs administration.

8. Data sources and measurement infrastructure relevant to RAPIDs. 

NIMH seeks input on data infrastructure and measurement strategies needed to support real-world evidence generation, including measurement approaches that can assess clinical and operational impact in or near real time. 

• Novel data sources and measurement approaches needed to capture the unique profile of RAPIDs, including rapid symptom change, how long the effect lasts, retreatment intervals, and acute monitoring and staffing burdens.
• Approaches for researchers, health systems, state agencies, payers, and other stakeholders to leverage and harmonize data from emerging sources, including state programs and provider systems, with attention to common data elements, ability of data systems to work together, data quality, privacy-protective linkage, and longitudinal follow-up capabilities needed to support real-world evidence generation.

9. Payment and utilization evidence needed for optimal outcomes for patients with mental illnesses

Given the unique delivery models of RAPIDs which may involve sustained episodes of therapeutic intervention, there are important considerations associated with the delivery model, including provider training needs, duration of efficacy, and real-world impact (including employment, quality of life, and family functioning) which may impact the evaluation of efficacy.

• Definitions of an episode of RAPIDs care, including screening, administration, extended clinical monitoring, psychological support, and integration services, and the evidence needed to develop sustainable care models, bundled services, or episode-based care.
• Healthcare utilization measures needed to assess the potential immediate and downstream impacts of RAPIDs, including effects on acute crisis service use, emergency department use, hospitalization, and relapse.

10. Strategies for rapid translation from research to practice for RAPIDs and emerging rapid-acting interventions for serious mental illnesses and related brain disorders

NIMH seeks input on strategies to accelerate responsible translation from research to clinical practice, including approaches that can produce interpretable findings during an initial demonstration period and support later scale-up. 

• Accelerated evidence-generation strategies to move promising RAPIDs from research into responsible clinical practice while preserving rigor, safety, and ability to interpret findings.
• Adaptive, pragmatic, embedded, and platform-style designs for producing near-term evidence to inform clinical, health-system, and payer decisions.
• Approaches to support near-real-time learning, including outcome measurement dashboards, interim analyses, embedded learning health system models, rapid evidence synthesis, site-readiness tools, implementation playbooks, and payer-facing evidence summaries.
• Components of a near-term RAPIDs evidence package to inform next-stage research, health-system implementation, payer, and scale-up decisions, including a safety framework, common data elements, site-readiness metrics, pilot pragmatic results, a real-time outcome measurement strategy, delivery-model comparisons, cost and utilization findings, and implementation tools.

11. Research infrastructure, access, and phased implementation needed for optimal deployment of RAPIDs and emerging rapid-acting interventions for serious mental illnesses

NIMH seeks input on infrastructure and methods needed to generate real-world evidence for rapid-acting psychotropic interventions. NIMH is particularly interested in approaches that could begin with a limited demonstration period and support later national scale-up. 

• Core infrastructure needed for RAPIDs research, including a data coordinating function, federated clinical sites, harmonized protocols, common measures, safety reporting, quality assurance, statistical support, and evidence synthesis.
• Products most useful at the end of an initial RAPIDs demonstration period, including a harmonized measure set, safety framework, pilot pragmatic study findings, real-time measurement strategy, utilization and cost analyses, delivery-model comparisons, implementation tools, and payer-facing evidence summaries.
• Implementation support, access, availability and geographic reach strategies needed to make RAPIDs evidence generation feasible in real-world care settings.
• Phased implementation approaches to support initial RAPIDs demonstration activities, refinement of infrastructure and measures, educational resources for patients/providers, and later expansion across additional sites, populations, indications, delivery models, and care settings.

12. Public-private partnerships and coordination with state partners to enable optimal deployment of RAPIDs and emerging rapid-acting interventions for serious mental illnesses and related brain disorders

NIMH seeks input on public-private partnerships and coordination with state partners that could support rigorous, sustainable real-world evidence generation for RAPIDs. 

• Public-private partnership models to support collaboration among federal partners, state mental health authorities, state Medicaid agencies, state-supported research programs, state-regulated provider systems, academic medical centers, health systems, rural providers, VA-affiliated settings, current providers operating in jurisdictions where such services are legally available, payers, industry partners, digital health and data organizations, philanthropic funders, and other relevant stakeholders.
• Approaches for accounting for variation across state legal, regulatory, clinical, Medicaid, and data-sharing environments.
• Agreements, technical infrastructure, and governance processes needed to support privacy-protective data sharing for RAPIDs across state programs, provider systems, payers, health systems, state data holders, and research partners.
• Governance, funding, data-sharing, and operational models to sustain public-private RAPIDs partnerships beyond an initial demonstration period while maintaining scientific independence and public trust.
• Mechanisms to support industry or philanthropic contributions of products, funding, or other in-kind resources to real-world evidence generation, including donation or free-goods programs, cooperative research and development agreements, and gift acceptance under applicable federal authorities, along with safeguards to preserve scientific independence and public trust.
• Governance structures that allow meaningful industry and stakeholder input on research priorities and operational feasibility while reserving protocol design, data access, analysis, and publication decisions to federal and academic partners, consistent with applicable laws governing federal advisory bodies and conflict-of-interest requirements.

To avoid duplication with the Department of Health and Human Services Health Resources & Services Administration Request for Information, Training and Care Delivery Models for Safe Administration of Potential FDA-Approved Psychedelic Therapies in Ambulatory Clinical Settings, NIMH is not seeking recommendations that establish provider qualifications, licensure, training or supervision requirements; staffing ratios; facility or clinic-certification requirements. Comments addressing these features should focus on how they should be measured or compared in research and how they relate to patient outcomes. 

Nothing in this RFI affects the FDA's statutory authority under the Federal Food, Drug, and Cosmetic Act (21 USC 321 et. seq.) to regulate drugs. Additionally, participation in real-world RAPIDs research does not exempt entities from site-specific DEA schedule I/II registrations, physical security requirements (21 CFR 1301.71 – 1301.80), quotas (21 U.S.C 826), or strict in-person administration protocols. This RFI is for information and planning purposes only."

How to Submit a Response

Responses to one or more topic areas within this RFI should be submitted electronically through [email protected] and must be received by November 9, 2026 at 11:59 p.m. Eastern Time.

Respondents are encouraged to clearly identify the topic area, respondent type or perspective represented, such as patient or caregiver, clinician, clinician specialty, health system, researcher, payer, federal/state agency, industry organization, professional society, advocacy organization, philanthropic organization, data or digital health organization, or other stakeholders.

The Government reserves the right to use the information submitted in response to this RFI at its discretion. Please note that the Government will not pay for the preparation of any information submitted or for use of that information.

When responding to this RFI, do not include proprietary, classified, confidential, or sensitive information in responses. The Government reserves the right to use any non-proprietary technical information submitted in response to this RFI.

Inquiries

Please direct all inquiries to:

National Institute of Mental Health (NIMH) 
Email: [email protected]