Blinding Integrity in Psychedelic Randomized Clinical Trials A Systematic Review
This systematic review (s=112) examined blinding in psychedelic randomised clinical trials for psychiatric disorders and found that only about a third assessed blinding, while functional unblinding was common, especially in psilocybin, LSD, ayahuasca and MDMA studies. The review found no control strategy that consistently maintained ideal blinding, raising concerns that expectancy effects may bias reported outcomes.
Authors
- Orsini, D. K.
- Wong, S.
- Di Luch, S.
Published
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.
Research Summary of 'Blinding Integrity in Psychedelic Randomized Clinical Trials A Systematic Review'
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Study Details
- Study Typemeta
- Journal
- Compounds
- APA Citation
Orsini, D. K., Wong, S., Di Luch, S., Chan, B., Vasudeva, S., Lovell, G. F. M., Le, G. H., Jones, B. D. M., Chisamore, N., Mollica, A., Johnson, D. E., Kaczmarek, E. S., Goel, A., Burke, M. J., Mansur, R., McIntyre, R. S., Husain, M. I., & Rosenblat, J. D. (2026). Blinding Integrity in Psychedelic Randomized Clinical Trials A Systematic Review. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2026.0255
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