FDA issues first psychedelic drug trial guidance

The US Food and Drug Administration (FDA) offered a framework for clinical investigations and drug development programs evaluating psychedelic drugs to treat medical conditions, such as substance use and psychiatric disorders.

The draft guidance, released on 23 June 2023, spells out the nonclinical, clinical and safety considerations for running trials for so-called classic psychedelics, which include 5-HT2 agonists such as psilocybin and lysergic acid diethylamide (LSD), as well as methylenedioxymethamphetamine (MDMA).

“By publishing this draft guidance, the FDA hopes to outline the challenges inherent in designing psychedelic drug development programs and provide information on how to address these challenges. The goal is to help researchers design studies that will yield interpretable results that will be capable of supporting future drug applications,” Tiffany Farchione, director of the Division of Psychiatry in the FDA’s Center for Drug Evaluation and Research, said in a statement.

The guidance applies to clinical trials conducted under an investigational new drug application (IND), including academic studies that are not aimed at supporting marketing applications.

Clinical considerations

The agency may consider the public health effects of the drug – including risks for substance use disorder, accidental exposure and overdose – as part of the overall benefit-risk calculation, according to the guidance.
FDA will apply the same evidentiary standard for evaluating the effectiveness of psychedelic drugs as for all other drugs but noted that there are some unique considerations for psychedelics, specifically challenges in designing “adequate and well-controlled” clinical studies.

For instance, the use of a traditional placebo may not be effective because trial subjects receiving an active drug may have “intense perceptual disturbances,” resulting in functional unblinding. Patients receiving an inactive control, on the other hand, could experience a “nocebo effect,” or worsening of symptoms because they are aware they did not receive treatment. The use of subperceptual doses of the psychedelic drug or other psychoactive drugs that mimic the psychedelic experience may be considered, according to the guidance document.

FDA also raised concerns about coupling psychedelic drug administration with psychological support or psychotherapy, noting that it complicates the assessment of effectiveness and creates challenges for future product labeling.

“Sponsors should plan to justify the inclusion of a psychotherapy component and describe any trial design elements intended to reduce potential bias or to quantify the contribution of psychotherapy to the overall treatment effect,” the agency wrote. “A factorial design may be useful for characterizing the separate contributions of drug and psychotherapy to any observed treatment response.”

Safety issues

The draft guidance outlines the type of safety monitoring that should be in place during the treatment session, including observation by two monitors – a lead monitor who is health care provider with graduate-level professional training and clinical experience in psychotherapy and who is licensed to practice independently, and one assistant monitor with a bachelor’s degree and at least one year of clinical experience in a licensed mental health care setting.

The FDA also advised that trials of drugs with functional activity at the 5-HT2B receptor that are intended to be chronically administered will likely need baseline and follow-up echocardiograms to assess valve structure and function and pulmonary artery pressures. Patients with preexisting valvulopathy or pulmonary hypertension should generally be excluded until the cardiac risk has been characterized, according to the guidance.

Nonclinical, clinical pharmacology and abuse potential

The draft guidance also outlines the types of chemistry, manufacturing, and controls (CMC) information that should be submitted to the agency and when a psychedelic drug may be considered a botanical. Additionally, FDA notes that the number and types of nonclinical studies needed to support a marketing application will depend on the treatment paradigm, including whether the use is single-dose or requires intermittent dosing.

Sponsors will also need to characterize the pharmacokinetics and/or pharmacodynamic of psychedelic drugs both in vitro and in vivo. Specifically, sponsors should evaluate:

The effect of a high-fat meal on the pharmacokinetics of an oral psychedelic drug early in drug development
The potential drug-drug and drug-disease interactions to inform inclusion/exclusion criteria and potential future labeling
The dose-response relationship

New drug application submissions for psychedelic drug products should include both data from an abuse potential assessment and a proposal for drug scheduling under the Controlled Substances Act. For investigational psychedelic drugs that are Schedule I controlled substances, researchers must comply with applicable regulations from the US Drug Enforcement Administration (DEA) as well as FDA regulations.

Comments on the draft guidance can be submitted to regulations.gov and labeled as Docket No. FDA-2023-D-1987. The public comment period closes on 25 August 2023.

Psychedelic drugs draft guidance

FDA issues first psychedelic drug trial guidance

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