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

The study was conducted at the University Hospital of Psychiatry Zurich as a randomised, double-blind, placebo-controlled, parallel-group trial. Data were collected between October 2023 and September 2025. Ethical approval and regulatory authorisation were obtained, and all participants gave written informed consent. Eligible participants were German-speaking, medically and psychologically healthy adults aged 18-40 years with no more than 10 lifetime experiences of psychedelics, MDMA, or methylphenidate. Recruitment took place through online advertisements, mailing lists, flyers, and word of mouth. Of 173 enrolled participants, 120 were included in the final analysis, with 40 participants per group. Participants were randomised in a 1:1:1 ratio to receive psilocybin, MDMA, or methylphenidate, with the pharmacy handling allocation. Psilocybin and MDMA were the experimental substances, while methylphenidate served as an active placebo because it can produce overlapping stimulant and cardiovascular effects without being expected to match the primary psychedelic effects. The doses were 15 mg psilocybin, 100 mg MDMA, and 60 mg methylphenidate. Participants received standardised briefing about the expected effects of all three substances before administration, were supervised for at least eight hours afterwards, and underwent monitoring of acute effects and blood pressure. Blinding integrity was assessed after acute effects subsided. Blinding was evaluated using three main elements: certainty ratings on visual analogue scales for each substance, forced-choice substance guesses, and multiple-choice questions about the factors that informed those guesses. Investigators completed the same certainty and forced-choice assessments. Subjective experience was measured retrospectively using the 5-Dimensional Altered States of Consciousness Questionnaire (5D-ASC), which yields dimension, subscale, and overall intensity scores. The analysis used chi-squared tests or Fisher’s exact tests to examine whether prior substance use was associated with correct guessing. Certainty ratings were compared with one-way ANOVA and Tukey post-hoc tests. Forced-choice data were summarised in 3 × 3 confusion matrices and analysed with Bang’s Blinding Index, including a weighted version that incorporated certainty of correct guesses. Binomial tests and chi-square tests examined whether guesses differed from chance. The relationship between subjective experience and blinding was assessed with ANOVA models, including analyses of overall intensity by received substance and guessed substance, with post-hoc comparisons adjusted using Bonferroni correction.

Participants had a mean age of 27.6 years, 50.8% were female, and the sample was predominantly White/Caucasian and highly educated. Prior substance use was reported by 30.8% for psychedelics, 24.2% for MDMA, and 15.8% for methylphenidate. Prior substance use was generally not associated with correct forced-choice guesses, and the one exception reported for prior psychedelic use and methylphenidate allocation did not remain significant after correction for multiple comparisons. Certainty ratings were highest for the substance actually received. For participants, mean certainty for the correct substance was 82.8% in the psilocybin group, 60.5% in the MDMA group, and 50.6% in the methylphenidate group. Investigators showed a similar pattern, with mean certainty of 84.6% for psilocybin, 58.3% for MDMA, and 58.2% for methylphenidate. Certainty differed significantly by substance group for both participants and investigators. Forced-choice accuracy was 69.2% for participants and 70.8% for investigators overall. Accuracy was highest for psilocybin, at 92.5% for participants and 95.0% for investigators, and lower for MDMA and methylphenidate. The authors report that blinding was not fully successful, with Bang’s Blinding Index indicating strongest functional unblinding for psilocybin, intermediate unblinding for MDMA, and the lowest unblinding for methylphenidate. For participants, the BI values were 0.89 for psilocybin, 0.48 for MDMA, and 0.25 for methylphenidate; weighted values were slightly lower at 0.77, 0.40, and 0.20. For investigators, the corresponding BI values were 0.92, 0.36, and 0.40, with weighted values of 0.81, 0.30, and 0.34. Binomial and chi-square tests indicated that guesses were not independent of actual allocation. Decision factors varied by substance and by guessed allocation. For psilocybin, sensory perceptions were the most common basis for guessing. For MDMA, feelings and mood were most prominent. For methylphenidate, alertness featured more often, but responses were more heterogeneous. The authors interpret this as showing that subjective phenomenology influenced substance identification. Subjective effect intensity differed strongly by substance received. Psilocybin produced higher overall intensity than MDMA, which in turn was higher than methylphenidate. When guessed substance was considered, overall intensity was also higher when psilocybin or MDMA was suspected than when methylphenidate was suspected. There was no significant interaction between received and guessed substance. The authors note that participants allocated to methylphenidate who guessed psilocybin reported especially strong experiences, similar to those in the psilocybin group, which they present as a pattern contributing to misclassification.

Belinger and colleagues interpret the findings as showing that blinding in this trial was limited, but not uniformly so across substances. Psilocybin was associated with the greatest functional unblinding and highest certainty, MDMA showed intermediate values, and methylphenidate performed best as an active placebo overall. The authors argue that forced-choice accuracy alone can overstate the degree of unblinding, because certainty ratings reveal substantial heterogeneity: many correct guesses were made with only moderate or low confidence. They therefore conclude that blinding integrity should be assessed with multiple measures rather than a single guess-based outcome. The authors link blinding failure primarily to the phenomenological strength and distinctiveness of subjective drug effects. Psilocybin produced the most intense subjective experience, and participants’ reported decision factors suggest that sensory alterations, mood changes, and alertness guided their guesses in ways that matched known effects of the substances. They emphasise that MDMA and methylphenidate are more similar in some externally observable effects than in internal subjective experience, which may help explain differences in misclassification patterns between participants and investigators. They also suggest that some participants showed particularly strong placebo-like responses, especially when methylphenidate was mistaken for psilocybin. In relation to earlier research, the authors state that their accuracy rates were lower than in some previous psychedelic studies, which they interpret as indicating somewhat better blinding integrity than has often been reported. They also note that prior substance experience did not appear to meaningfully affect blinding, suggesting that both substance-naïve and previously exposed participants may be included in future work without major blinding penalties. The authors acknowledge several limitations and uncertainties. Blinding was measured only on the day of substance administration, so guesses may have changed later. They did not assess expectancy directly, so they cannot determine how expectancy interacted with compromised blinding or outcome interpretation. The sample was relatively homogeneous, consisting of healthy volunteers, which limits generalisability to clinical populations. They also caution that their conclusions about the suitability of methylphenidate as an active placebo are context-specific and should not be taken to apply equally across substances or trial designs. For future research and trial design, the authors recommend routine inclusion of forced-choice guesses, certainty ratings, decision factors, and expectancy measures to provide a fuller picture of blinding integrity. They suggest that methylphenidate may be a more suitable active control for MDMA than for psilocybin, while noting that no placebo strategy fully solves the blinding problem. They also discuss the possibility of multi-arm or multi-dose designs, more objective outcome measures, and alternative analytic approaches to reduce the impact of functional unblinding.

The authors conclude that multi-level assessment is essential for evaluating blinding in psychedelic trials. They state that methylphenidate appears to function reasonably well as an active placebo for MDMA, but not for psilocybin, and that no currently available control strategy fully preserves blinding when strong subjective drug effects are present. They recommend more comprehensive blinding and expectancy assessment in future psychedelic research.