Blinding, Ethics, and Safety Safeguards in Psychedelic Clinical Research

CONFERENCE REPORTER

Functional unblinding is a major methodological issue with psychedelic clinical trials, said Gus Alva, MD. US Food and Drug Administration (FDA) guidance stipulated that an investigational agent should work and separate from placebo, but the integrity of blinding was equally important.¹ Alva noted many patients did not understand or accept that construct of double-blind studies and asked why they should enroll in a trial without knowing whether they would receive active drug, but that uncertainty was the essential premise of a clinical trial. "In the case of a psychedelic, you still kind of know if you had a hallucinogenic experience or not," Alva said, noting that participants often recognized an abrupt, dramatic change in their perception of life.

Unblinding therefore remained a substantial problem. Proposed solutions included active comparators at lower doses of the psychedelic and centrally blinded raters, and FDA policy this year offered suggestions intended to guide the conduct of the various psychedelic trials under way.¹ Alva said these measures also addressed full transparency and ethics. "When individuals are under the influence of something, they are susceptible to being taken advantage of," Alva commented.

The Lykos Therapeutics filing of MDMA for posttraumatic stress disorder illustrated these concerns. The published results appeared strong, yet the committee that voted on the filing gave an overwhelmingly negative recommendation and suggested that another trial be conducted, a decision Alva said was likely based on functional unblinding.² Alva also cited a Canadian study site as a clear example of why firm boundaries needed to be set in place when psychedelic trials were conducted. Current trials often film encounters to preserve the safety of the individuals involved, and Alva said this reflected the updated approach to psychedelic research. Such safeguards were necessary because participants could be vulnerable during dosing.

Dr Alva is a board-certified psychiatrist and the Mood Disorders Section Editor for Psychiatric Times.

References

1. Psychedelic drugs: considerations for clinical investigations. US Food and Drug Administration. July 2026. Accessed October 7, 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/psychedelic-drugs-considerations-clinical-investigations

2. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033.