CNSPulse
W57

BLINDING INTEGRITY IN PSYCHEDELIC RANDOMIZED CONTROLLED TRIALS: A SYSTEMATIC REVIEW

Diana Orsini — Sabrina Wong1, Sara Di Luch1, Brendan Chan1, Shreya Vasudeva1, Gabrielle Lovell1, Gia Han Le1, Brett Jones1, Noah Chisamore1, Adriano Mollica1, Danica Johnson1, Ishrat Husain1, Matthew Burke1, Roger McIntyre1, Joshua Rosenblat1 1University of Toronto

2026 ASCP Annual Meeting

Importance: Psychedelic drugs possess acute psychoactive effects that can compromise blinding integrity in randomized controlled 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 2020–July 2025), supplemented by manual searches of three 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 105 RCTs (psilocybin n=10, lysergic acid diethylamide (LSD) n=7, ketamine n=73, 3,4-Methylenedioxymethamphetamine (MDMA) n=10, ayahuasca n=2, N,NDimethyltryptamine (DMT) n=2, noribogaine n=1), only 29.5% (n=31) evaluated blinding integrity, yet 58.1% (n=61) cited blinding as a limitation. Functional unblinding was substantial: psilocybin, LSD, and ayahuasca studies frequently reported blinding failure values of > 90% among participants and raters; inert placebo controlled MDMA trials exceeded 85%; ketamine trials rarely assessed blinding (17.8%) but showed improved preservation with midazolam versus 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.