Cooperative Agreement to Support a Human Abuse Potential Study of Botanical Kratom (U01 Clinical Trial Required) | RFA FD 24 025

Opportunity Information: Apply for RFA FD 24 025

The Food and Drug Administration (FDA) is offering a cooperative agreement to fund a required clinical trial that will run a formal Human Abuse Potential (HAP) study of botanical kratom (Mitragyna speciosa). The opportunity is framed around the fact that kratom use is already widespread in the United States (an estimated 1.7 million people aged 12 and older reported use in 2021) while rigorous, controlled clinical evaluations of its abuse potential have not yet been completed. Because kratom alkaloids show affinity and activity at mu opioid receptors, FDA views it as important to generate high-quality human data on the drug-like subjective effects and abuse-related outcomes associated with taking botanical kratom. The overall goal is to produce evidence that can better inform researchers, clinicians, consumers, and public health decision-making about kratom safety and risk.

The core purpose of the award is to support a well-controlled HAP study designed to characterize both the abuse potential and the subjective effects of botanical kratom in humans. A key context point in the announcement is that FDA is already conducting a pilot dose-finding and safety study of botanical kratom. That pilot is expected to supply practical inputs needed to execute the larger HAP study, including recommended kratom doses, identification of a suitable botanical supply provider, and components that support an Investigational New Drug (IND) application such as safety information and chemistry, manufacturing, and controls (CMC) data. Applicants are expected to be capable of meeting IND submission requirements, meaning they need the infrastructure and expertise to operate in a regulated clinical research environment, manage controlled investigational product issues, and produce documentation at a level acceptable for FDA oversight.

In terms of study expectations, FDA directs applicants to follow the design principles in the guidance titled "Assessment of Abuse Potential of Drugs." The study is expected to be conducted in a human pharmacology laboratory and may be structured as inpatient or outpatient, but either way the application should spell out on-site safety measures and clear criteria for discharging participants after dosing sessions. The target population is nondependent participants who nevertheless have a history of recreational drug use, specifically including opioids and botanical kratom. This is typical for HAP work because it aims to recruit people who can detect and report psychoactive effects reliably without enrolling individuals who are currently physically dependent. The announcement also signals that a naloxone challenge may be used prior to qualification to rule out physical dependence, which is a practical safeguard in studies involving opioid-like activity.

Applicants are expected to propose a standard multi-phase HAP structure, generally including a screening phase, a qualification phase, a treatment phase, and a follow-up visit. During the qualification phase, participants receive placebo and a positive control drug dose and are evaluated using a bipolar "drug liking" visual analog scale (VAS) from 0 to 100. FDA specifies performance criteria for this phase: the placebo response should fall in a middle band (roughly 40 to 60 points), while the positive control should fall outside that placebo range and differ from placebo by at least 15 points. These qualification rules are meant to ensure the study can actually discriminate drug effects from placebo effects before proceeding to the more resource-intensive treatment phase.

The treatment phase is expected to use a within-subject, randomized, double-blind design with both placebo and active controls. The design should include multiple doses to support dose-response interpretation: typically two to three doses of a positive control and three doses of botanical kratom, allowing investigators to construct a dose-response curve for kratom and compare it against a known reference. Dose selection is expected to be coordinated with FDA and informed by the agency pilot dose-ranging work. The expected route of administration is oral, using encapsulated botanical kratom, and the protocol should include appropriate washout periods between sessions to minimize carryover effects and protect participant safety.

For endpoints, the primary outcome measure is the maximum effect (Emax) on VAS "drug liking." The solicitation also expects other subjective and behavioral intent measures such as ratings of "high," "sedation," and willingness to take the product again. FDA notes that additional reinforcement-oriented measures may be proposed, such as behavioral economics tasks and/or willingness-to-pay assessments, but these should be discussed with FDA to ensure they fit the regulatory intent of the HAP evaluation. Timing of assessments should be aligned with expected pharmacodynamic peaks (for example, around Tmax), and the study should incorporate safety and physiological monitoring, with pupillometry provided as an example of an objective opioid-relevant physiological measure.

From an application quality standpoint, FDA explicitly expects a statistical analysis plan that includes a power analysis justifying the sample size. This matters because HAP studies rely on within-subject comparisons and need enough participants to detect meaningful differences in drug liking and other subjective endpoints across doses and controls. A strong application would therefore make clear how the design, qualification criteria, endpoint timing, and analytic methods work together to support interpretable conclusions about abuse potential and subjective effect profiles.

The deliverable at the end of the project is a detailed final study report that documents the methods, results, conclusions, and interpretation of the HAP findings for botanical kratom. In practical terms, FDA is funding the generation of a regulatory-grade evidence package describing how much participants like kratom relative to placebo and a positive control, whether effects scale with dose, what other subjective effects are prominent, and what safety or physiological signals appear under controlled conditions.

Administratively, this is an FDA discretionary funding opportunity using a cooperative agreement mechanism (U01), which typically implies substantial FDA involvement during the project (for example, coordination on dose selection, design decisions, and other key elements). The funding opportunity number is RFA-FD-24-025 under CFDA 93.103, in the broad activity area of agriculture, consumer protection, and food and nutrition. The award ceiling is $2,000,000, with one expected award. Eligibility is broad and includes many government entities, public and private institutions of higher education, tribal governments and organizations, nonprofits (with or without 501(c)(3) status), and for-profit organizations (including small businesses). The original application closing date listed for the opportunity is March 21, 2024.

• The Food and Drug Administration in the agriculture, consumer protection, food and nutrition sector is offering a public funding opportunity titled "Cooperative Agreement to Support a Human Abuse Potential Study of Botanical Kratom (U01 Clinical Trial Required)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.103.
• This funding opportunity was created on 2024-01-16.
• Applicants must submit their applications by 2024-03-21. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Each selected applicant is eligible to receive up to $2,000,000.00 in funding.
• The number of recipients for this funding is limited to 1 candidate(s).
• 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, Unrestricted.

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