Blinding Integrity in Psychedelic Randomized Clinical Trials

In randomized clinical trials of psychedelic drugs for psychiatric disorders, the drugs' strong subjective effects often reveal which treatment participants or raters think they received, a phenomenon called functional unblinding. A systematic review of 112 trials found that only 29.5% assessed whether blinding was maintained, yet 57.1% cited blinding as a limitation. Blinding failure exceeded 90% in psilocybin, LSD, and ayahuasca studies and 85% in MDMA trials with inert placebos. Ketamine trials rarely assessed blinding but fared better when midazolam was used as an active comparator. No control strategy consistently preserved ideal blinding, raising concerns about the validity of efficacy estimates.

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Abstract

Importance: Psychedelic drugs possess acute psychoactive effects that can compromise blinding integrity in randomized clinical trials (RCTs). Functional unblinding, when participants or raters correctly identify treatment allocation based on subjective effects, may bias outcomes through expectancy effects, challenging the validity of efficacy estimates and regulatory acceptance. Objective: To systematically quantify the prevalence of blinding integrity assessment and the extent of functional unblinding in psychedelic RCTs for psychiatric disorders. Evidence Review: A systematic review was conducted in accordance with PRISMA guidelines across OVID, MEDLINE, Embase, and APA PsycINFO (January 1, 2020, to December 11, 2025), supplemented by manual searches of 3 prior reviews for studies prior to January 2020. Eligible studies included all RCTs investigating psychedelics as psychiatric interventions. Data extracted included blinding integrity assessment methods and results for participants and raters. Findings: Of 112 RCTs (11 psilocybin, 17 lysergic acid diethylamide [LSD], 78 ketamine, 11 3,4-methylenedioxymethamphetamine [MDMA], 2 ayahuasca, 2 N,N-dimethyltryptamine [DMT], and 1 noribogaine), only 29.5% (n = 33) evaluated blinding integrity, yet 57.1% (n = 64) cited blinding as a limitation. Functional unblinding was substantial: psilocybin, LSD, and ayahuasca studies frequently reported blinding failure values of more than 90% among participants and raters, inert placebo-controlled MDMA trials exceeded 85%, and ketamine trials rarely assessed blinding (17.9%) but showed improved preservation with midazolam vs saline controls. No control strategy consistently achieved ideal blinding. Conclusions and Relevance: This first evaluation of blinding integrity in psychedelic RCTs indicates functional unblinding is pervasive among participants and raters raising concerns about the validity of efficacy findings. Few trials assess blinding or expectancy, highlighting the need for standardized, validated measures and innovative designs to separate true pharmacological effects from expectancy-driven responses.