FDA Outlines Considerations for Conducting Clinical Investigations Using Psychedelic Drugs

In June 2023, the Food and Drug Administration (“FDA”) released Draft Guidance outlining its current view of the psychedelic research landscape. The Draft Guidance is aimed at researchers conducting clinical trials using psychedelic drugs. While the FDA does not define psychedelics, it indicated that the shorthand term “psychedelic” includes “classic psychedelics,” which are typically understood to be 5-HT2 agonists (e.g., psilocybin and lysergic acid diethylamide (“LSD”)) as well as entactogens or empathogens (e.g., methylenedioxymethamphetamine (“MDMA”)).

Below is a summary of some of the key takeaways from the Draft Guidance. Once finalized, the Draft Guidance will represent the FDA’s current thinking on the development of psychedelic drugs.

Clinical Pharmacology

The Draft Guidance directs sponsors to conduct both in vitro and in vivo studies to characterize the pharmacology of the drug. While this is standard practice for pharmaceutical research, there are some psychedelic-specific concerns the FDA recommends addressing:

1. Many psychedelic drugs bind to the 5-HT_2Breceptor, whose activation has been associated with an increased risk of cardiac valve stiffening. This risk is not well-understood and until it is, the FDA has three recommendations:
   1. Excluding participants with preexisting valvulopathy or pulmonary hypertension.
   2. Giving participants echocardiograms before, during and after research to investigate the drug’s impact on valve structure, blood pressure and QT interval length.
   3. Investigating potential heart valve toxicity for drugs that bind to the 5-HT_2Breceptor in both rodent and non-rodent models.
2. Known drug interactions to consider:
   1. Chronic use of selective serotonin reuptake inhibitors (“SSRIs”) or monoamine oxidase inhibitors (“MAOIs”) may attenuate the effects of psychedelics.
   2. Chronic use of SSRIs or MAOIs, or chronic use of tricyclic antidepressants or lithium, may potentiate the effects of psychedelics.
3. The effect of a high-fat meal on the pharmacokinetics of orally administered psychedelic drugs.
4. Toxicity studies should represent the intended dosing of the drug. For example, if it is intended to be consumed intermittently (e.g., ketamine for major depressive disorder), the toxicity studies should investigate this dosing schedule at the preclinical level.
5. Abuse potential studies, if not already done, are generally necessary for successful drug applications.

Clinical

The following recommendations apply generally to clinical trials that will be conducted under an investigational new drug (“IND”) application, including trials that are not intended to support marketing applications (e.g., research or academic studies). The FDA encourages sponsors to request a meeting with the agency to obtain feedback on a specific drug development program. Additionally, if research is being conducted with a scheduled psychedelic such as psilocybin, clinicians will need to follow Drug Enforcement Administration guidelines. Researchers must also ensure compliance with state and local laws as sometimes states or municipalities will restrict the use of a drug that is not scheduled federally.

• Traditional double-blind studies with a placebo control may be less effective. Individuals who receive the active substance will likely be well aware of it due to the perception-altering effects of these drugs. In contrast, those who receive the placebo may have no effect, but due to the intensity of psychedelics will likely realize they received the placebo, functionally unblinding them. This leads to a potential nocebo effect, where participants may feel their symptoms are worse knowing they received the inert drug. The FDA suggests that an inactive control may allow for better contextualization of any safety findings. Sponsors can also consider the use of subperceptual doses of a psychedelic drug or other psychoactive drugs that mimic some aspects of the psychedelic experience.
• Due to the strong nature of the drugs, the FDA has several safety monitoring recommendations that should be followed as the FDA may place studies under an IND application under clinical hold if they are unreasonably risky to the participants. For example, the FDA recommends observation by two monitors for the duration of the treatment session, with the lead monitor being a health care provider with graduate-level professional training and clinical experience in psychotherapy and licensed to practice independently.
• For clinical trials investigating the potential benefit of psychedelics on chronic diseases, such as post-traumatic stress disorder or major depressive disorder, the FDA recommends that sponsors evaluate the effect of the treatment at 12 weeks and thereafter continue to follow subjects in an open-label, one-year extension period to monitor for symptom recurrence, or potentially, the need for repeat dosing.

Psychotherapy

Incorporating psychotherapy is common in research investigating the medical benefits of psychedelic drugs. However, the Draft Guidance on this topic is sparse and is likely to be updated prior to being finalized. Currently, the FDA has determined that the contribution of psychotherapy to psychedelic treatment has not been well-characterized and that drug sponsors should consider how to justify the incorporation of psychotherapy into their clinical trials and subsequent treatment programs. The FDA also included the following two recommendations regarding psychotherapy:

• The intake/outtake psychotherapist(s) be separate from the one(s) collecting data from participants during the experiment to minimize biases.
• The FDA recommends considering how psychotherapy will be incorporated into treatment at a practical level and how this will need to be expressed for purposes of drug dosing, packaging, and marketing.

Practical Takeaways

The Draft Guidance represents a pivotal step toward legitimizing the potential role of psychedelic drugs in modern medicine. It reflects an evolving understanding of the unique challenges and opportunities presented by psychedelics, paving the way for further research into their potential benefits. As the FDA continues to refine its stance on the development of psychedelic drugs, collaboration among researchers, regulators and the medical community will likely be key to harnessing the full potential of these substances while ensuring patient safety and well-being.

If you have any questions or would like help regarding questions on the conduct of clinical investigations, please contact:

• Carolina Wirth at (202) 780-2989 or cwirth@hallrender.com;
• Raminta Kizyte at (303) 557-2112 or rkizyte@hallrender.com; or
• Your primary Hall Render contact.

Special thanks to Shayan Abtahi, summer associate, for their assistance in the preparation of this article.

Hall Render blog posts and articles are intended for informational purposes only. For ethical reasons, Hall Render attorneys cannot—outside of an attorney-client relationship—answer specific questions that would be legal advice.