Blinding integrity in psychedelic research: Evidence from a comparative randomized controlled trial of psilocybin, MDMA, and methylphenidate in healthy volunteers.

L Belinger; Nathalie M. Rieser; Etna Engeli; L Becciolini; M Clamote; M Pribis; F Saissi; G A Florineth; N L Hehl; Marcus Herdener; Katrin H. Preller

doi:10.1016/j.euroneuro.2026.112879

Blinding integrity in psychedelic research: Evidence from a comparative randomized controlled trial of psilocybin, MDMA, and methylphenidate in healthy volunteers.

L Belinger, Nathalie M. Rieser, Etna Engeli, L Becciolini, M Clamote, M Pribis, F Saissi, G A Florineth, N L Hehl, Marcus Herdener, Katrin H. Preller

European Neuropsychopharmacology May 28, 2026 DOI: 10.1016/j.euroneuro.2026.112879 (opens in new tab)

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Study at a glance

AI-extracted from the abstract

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 Psychedelic research
Key findings	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.

Comparable studies

Other randomized controlled trials on MDMA, most cited first.

Study	Year	Design	Participants
MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Patients with severe PTSD, including those with comorbidities such as dissociation,...	2021	Randomized controlled trial	n = 90
The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Patients with chronic post-traumatic stress disorder refractory to both psychotherapy...	2010	Randomized controlled trial	n = 20
3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Military veterans and first responders aged 18 or older with chronic PTSD lasting 6...	2018	Randomized, double-blind, dose-response, phase 2 clinical trial	n = 26
A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD) Patients with treatment-resistant PTSD	2012	Randomized controlled trial	n = 12
MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Adults with moderate to severe post-traumatic stress disorder	2023	Randomized controlled trial	n = 104

Citations in the library

Cited by 1

Molecules, meaning, and physiology: disentangling the active ingredients of psychedelic therapeutics Frontiers in Neuroscience August 3, 2026

Cites 42

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