Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers

Classic serotonergic hallucinogens (for example psilocybin) and NMDA receptor–mediated dissociatives (for example ketamine and dextromethorphan, DXM) are being revisited as rapid-acting treatments for mood and other psychiatric disorders. Previous work suggests that, despite distinct molecular targets, these two drug classes may share downstream effects on cortical network activity and glutamate-driven neuroplasticity, and that aspects of the acute subjective experience—such as mystical-type phenomena for classic psychedelics or dissociation for NMDA antagonists—could be relevant to clinical benefit. However, canonical constructs (for example ‘‘mystical experience’’ or ‘‘dissociation’’) do not capture all instances of therapeutic response, and there is a need to characterise drug-occasioned experiences in broader, meaning-oriented ways that may better predict enduring psychological effects. Mathai and colleagues report new analyses from a double-blind, within-subjects crossover trial in which healthy, hallucinogen-experienced volunteers received placebo, a high dose of DXM, and three doses of psilocybin under psychologically supportive conditions. The present paper focuses on data collected at the end of each session (~7 h postdose) and at 1 week, asking: how do participants rate the session as personally meaningful, spiritually significant, psychologically challenging, and psychologically insightful across drug conditions and time; how do persisting psychological effects attributed to the drug compare between conditions at 1 week; and how are end-of-session ratings related to persisting effects?

Twenty healthy adult volunteers (11 female, 9 male; mean age 28.5 years) with substantial prior use of classic psychedelics and dissociatives completed the study. Participants were medically and psychiatrically healthy; most were Caucasian and all had at least a high school education. The trial used a within-subjects, double-blind crossover design with five sessions per participant: inactive placebo, DXM HBr (400 mg/70 kg), and psilocybin at 10, 20, and 30 mg/70 kg. Session order was counterbalanced using a 5-order Williams design and sessions were separated by an average of 10 days. To reduce expectancy effects, participants were told they could receive placebo or doses of 38 different psychoactive drugs and that at least one session would involve a serotonergic or a dissociative hallucinogen; staff were identically blinded except for one monitor who knew drug class but not sequence. Sessions occurred in a living-room-like setting with eyeshades, headphones and a standardised music playlist, and two monitors provided psychological support. Preparatory visits (about 8 h total) and post-session check-ins (1–2 days after dosing) were used to establish rapport and monitor safety. Key subjective measures were collected at session end (~7 h) and at 1 week. End-of-session measures included the Pharmacological Class Questionnaire (participants guessed drug class, drug and dose), four single-item subjective effects ratings (SERs) of personal meaningfulness, spiritual significance, psychological insight and psychological challenge rated 1–8, a physical distress scale (0–5), and a disembodiment subscale from the 5D-ASC assessing bodily dissociative experiences (expressed as percent of maximum). At 1 week the same four SERs were re-rated and the Persisting Effects Questionnaire (PEQ), a 145-item instrument, assessed positive and negative changes across six domains (attitudes toward life, attitudes toward self, mood, relationships, behaviour and spirituality), scored as percentages of maximum possible. Analyses used mixed-effects models (compound symmetry covariance, REML) to compare drug conditions and time, with Geisser–Greenhouse corrections and Tukey post hoc tests where appropriate; effect sizes were reported as Cohen’s dz. The authors treated missing data as missing at random (MAR) for two participants and proceeded with the mixed model approach which can accommodate MAR. Relationships between SERs and PEQ outcomes were tested with Pearson correlations (end-of-session ratings met normality tests), and an exploratory multiple linear regression tested whether physical distress or disembodiment during DXM sessions predicted positive or negative mood change at 1 week. Qualitative thematic analysis was also performed on open-ended end-of-session descriptions for the DXM 400 mg/70 kg and psilocybin 30 mg/70 kg conditions: the researchers developed a 16-codebook organised into five themes, double-coded responses with interrater reliability assessed by pooled Cohen’s kappa, and refined themes by consensus.

Masking efficacy: participants identified the correct drug class on 60–90% of guesses for active conditions, the specific drug on 35–65% of guesses, and correctly identified all parameters (including psilocybin dose range) on 15–35% of guesses, indicating partial but imperfect blinding. End-of-session subjective ratings and 1-week follow-up: all active drug conditions (DXM and all psilocybin doses) produced higher ratings than placebo on the four SERs (personal meaning, spiritual significance, psychological insight, psychological challenge) both at session end and at 1 week. Ratings were generally stable over time, though spiritual significance decreased significantly at 1 week for psilocybin 30 mg/70 kg and trended downward for other active drugs; psychological insight tended to increase at 1 week for active drugs. At session end, psilocybin 30 mg/70 kg yielded higher ratings of personal meaning and psychological insight compared with DXM and psilocybin 10 mg/70 kg, but these differences were not significant at 1 week. Placebo SERs increased modestly by 1 week. Qualitative characterisation: thematic analysis of open-ended responses for high-dose DXM and psilocybin 30 mg/70 kg used a final codebook of 16 codes across five themes (descriptions/modifiers, somatic experiences, mental/psychological experiences, insight, transpersonal experiences). Interrater reliability on a sample was strong (pooled Cohen’s kappa = 0.801). Persisting effects (PEQ) at 1 week: all active drug conditions showed positive persisting effects versus placebo across assessed domains. Psilocybin, particularly at 20 and 30 mg/70 kg, tended to produce positive changes across more domains than DXM; the two highest psilocybin doses produced positive change in all six domains. Direct domain-by-domain statistical differences between active drugs were generally not significant. Relationships between end-of-session ratings and persisting effects: for DXM, rating the experience as personally meaningful was the strongest predictor of positive changes in attitudes toward life, self, mood, relationships and spirituality at 1 week. However, DXM session ratings of psychological insight unexpectedly predicted negative change in attitudes toward life. Physical distress during DXM sessions predicted negative change in mood at 1 week: the multiple regression for negative mood change was significant [F(2,16) = 5.12, p = 0.02, R2 = 0.39], with physical distress coefficient b = 0.01 (p = 0.02), while disembodiment was not a significant predictor (p = 0.07); Pearson correlation between physical distress and negative change in mood was r(19) = 0.50 (p = 0.03). For psilocybin 20 mg/70 kg, end-of-session ratings of personal meaning, spiritual significance and insight were broadly predictive of positive changes across domains at 1 week. No such predictive relationships were observed for psilocybin 30 mg/70 kg in the statistical tests conducted, a finding the authors attribute to a possible ceiling effect in the session measures.

Mathai and colleagues interpret these findings to indicate that, when administered within psychologically supportive conditions typical of psychedelic research, a high experimental dose of DXM and psilocybin produce session experiences rated as meaningful and predictive of enduring positive psychological effects at least up to 1 week. The authors note that this is, to their knowledge, the first direct human comparison of enduring psychological effects between a dissociative and a classic psychedelic under matched conditions, and that the data are consistent with prior work showing that psilocybin occasioned stronger mystical-type and insight experiences while DXM produced greater somatic discomfort and disembodiment. The discussion emphasises two practical points drawn from the data. First, dissociatives such as DXM may have therapeutic potential when used in contexts that cultivate psychologically valuable experiences and provide supportive preparation and integration; this contrasts with current regulatory approaches that seek to minimise psychoactive effects of some approved dissociative-containing medications. Second, physical tolerability is important: DXM’s greater association with nausea and other physical distress predicted negative mood change at 1 week, suggesting that minimising such distress should be a priority in clinical applications. The authors also acknowledge several limitations. Carryover is a concern in crossover designs because psychological effects of psilocybin and perhaps high-dose DXM can persist beyond 1 week; the counterbalanced order mitigates but does not eliminate this risk. Generalisability to clinical populations is uncertain, since healthy, hallucinogen-experienced volunteers may differ from treatment-seeking patients in capacity to derive or integrate benefit. The study may have been underpowered to detect head-to-head differences, and the experimental context was optimised over decades for psilocybin rather than for dissociatives, which may influence comparative outcomes. The authors further note that high-dose DXM may impair episodic memory more than psilocybin, potentially affecting insight-related processes. Overall, the investigators conclude that both dissociatives and classic psychedelics can occasion psychologically meaningful experiences associated with short-term enduring benefits when delivered with supportive care, and they recommend further research to optimise dosing, delivery, tolerability and therapeutic frameworks for dissociative-assisted interventions. The authors caution that these findings are preliminary, limited by sample and design, and that further clinical investigation is needed.