Blinding integrity in psychedelic research: Evidence from a comparative randomized controlled trial of psilocybin, MDMA, and methylphenidate in healthy volunteers.
L Belinger, N M Rieser, E J E Engeli, L Becciolini, M Clamote, M Pribis, F Saissi, G A Florineth, N L Hehl, M Herdener, K H Preller
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology May 28, 2026 DOI: 10.1016/j.euroneuro.2026.112879 via PubMed
Summary
AI-generated from the abstractIn a double-blind randomized trial with 120 healthy volunteers who received psilocybin, MDMA, or methylphenidate (active placebo), overall blinding was insufficient. Psilocybin had the highest rates of functional unblinding, MDMA moderate levels, and methylphenidate the lowest. As an active placebo, methylphenidate provided more effective blinding for MDMA than for psilocybin. Incorporating certainty levels of substance guesses revealed a more differentiated pattern with lower functional unblinding rates. Decision factors and subjective substance experiences were associated with phenomenological effects. Prior substance experiences did not influence accuracy of forced-choice guesses. These findings offer empirical guidance for designing and reporting blinding procedures in psychedelic trials.
Study at a glance
| Characteristics | Randomized controlled trial Double-blind Peer reviewed |
|---|---|
| Sample size | 120 |
| Population | Healthy volunteers |
| Interventions | Psilocybin MDMA Methylphenidate |
| Topics | MDMA Psilocybin |
| Keywords | Blinding assessment Blinding integrity Methylphenidate |
| Key finding | Overall blinding was insufficient, with psilocybin showing the highest rates of functional unblinding, MDMA moderate levels, and methylphenidate the lowest. |
Abstract
Maintaining effective blinding is a major methodological challenge in psychedelic research. This study provides a comprehensive evaluation of blinding integrity in 120 healthy volunteers who received either psilocybin, MDMA, or methylphenidate (active placebo) in a double-blind, randomized controlled trial. Using a multi-level assessment incorporating forced-choice substance guesses, certainty ratings, decision factors, and subjective substance effects, the analyses characterize blinding integrity and its relation to the substance experience. Results indicate that overall blinding was insufficient, with psilocybin showing the highest rates of functional unblinding, MDMA moderate levels, and methylphenidate the lowest. As an active placebo, methylphenidate provided more effective blinding for MDMA than for psilocybin. Incorporating certainty levels of substance guesses revealed a more differentiated pattern, with lower functional unblinding rates. Decision factors and subjective substance experiences were associated with phenomenological substance effects. Prior substance experiences did not influence accuracy of forced-choice substance guesses. These findings provide empirical guidance for the design and reporting of blinding procedures in psychedelic trials and underscore the value of systematic, multi-level assessment of blinding integrity.