Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition

Classic and atypical hallucinogens form a pharmacologically heterogeneous group that alter perception, thought, and emotion. Psilocybin, metabolised to psilocin, acts primarily at serotonin (5-HT) receptors (notably 5-HT2A) and has a well-characterised history of clinical study. Dextromethorphan (DXM), by contrast, is an NMDA receptor antagonist with multiple additional actions and, at high doses, can produce dissociative hallucinogenic effects similar in some respects to ketamine. Previous work has suggested overlaps in subjective effects across these mechanistic classes and raised the possibility of shared glutamatergic and serotonergic interactions, but direct within-subject comparisons of psilocybin and DXM had not been reported. Carbonaro and colleagues therefore conducted a double-blind, within-subject comparison to characterise and contrast subjective, behavioural and physiological effects of single oral doses of psilocybin (10, 20, 30 mg/70 kg), DXM (400 mg/70 kg), and placebo in hallucinogen-experienced volunteers. The study explicitly minimised expectancy effects and focused on measures of altered subjective experience, alongside standard physiological and performance assessments, to determine similarities and differences between these two mechanistically distinct hallucinogens.

Twenty healthy, hallucinogen-experienced volunteers (11 females; mean age 28.5 years) completed a within-subject, randomized, balanced crossover study. Inclusion required prior use of both classic hallucinogens (mean reported uses 60.9) and dissociative anesthetic hallucinogens (mean 19.0). Exclusion criteria included current significant medical conditions, pregnancy or nursing, substance dependence (excluding nicotine and caffeine), and personal or first-degree family histories of schizophrenia, bipolar disorder, delusional or related psychotic disorders. The institutional review board approved the protocol and participants provided written informed consent. Participants completed five approximately 7-hour experimental sessions separated by at least 48 hours, receiving in randomized order placebo, psilocybin 10, 20, and 30 mg/70 kg, and DXM 400 mg/70 kg. Capsules were identical in appearance and two were administered with water each session. To minimise expectancy, participants and most staff were told that they might receive placebo or any of 38 different psychoactive drugs; one of ten session monitors was aware of the drug repertoire but remained blind to sequence. Sessions took place in a living room-like setting; participants generally reclined with eyeshades and headphones playing a curated programme of classical and world music, and were encouraged to focus on their inner experience. Physiological measures (systolic and diastolic blood pressure, heart rate, pupil diameter) and behavioural tasks (Circular Lights hand–eye coordination, Balance with eyes closed) were assessed repeatedly up to 360 min post-administration; subjective measures were recorded up to ~480 min. End-of-session questionnaires at about 7 h included the 5D-ASC, MEQ30 (Mystical Experience Questionnaire), Mysticism Scale, Psychological Insight Questionnaire (37 items), Challenging Experience Questionnaire, Hallucinogen Rating Scale (HRS), and a Pharmacological Class Questionnaire. Vomiting was recorded; CYP2D6 phenotyping was performed about one month later with a low DXM dose to identify poor metabolizers. Data analysis used repeated measures ANOVAs, Fisher’s LSD post hoc tests, Cochran’s Q for dichotomous outcomes, and planned t tests for time-course comparisons; significance was set at p ≤ 0.05. Peak effects were defined as the maximum (or minimum for performance tasks) observed after administration.

All active drug conditions produced measurable subjective, physiological and behavioural effects; 20 participants completed the study. Time-course: effects were typically detectable by 2 hours, peaked between 2 and 4 hours, and declined by 6 hours; DXM and the higher psilocybin doses showed broadly similar time-courses, although DXM produced larger and longer-lasting impairment on balance. Physiology and performance: DXM and all psilocybin doses increased systolic blood pressure, heart rate, and pupil diameter but did not significantly increase diastolic blood pressure. Both compounds reduced performance on Circular Lights and Balance tasks; DXM produced significantly larger decreases on the Balance task than psilocybin. Nausea and emesis: vomiting occurred in 0% after placebo, 0% after 10 and 20 mg/70 kg psilocybin, 10% (2 of 20) after 30 mg/70 kg psilocybin, and 55% (11 of 20) after 400 mg/70 kg DXM. DXM produced significantly higher monitor- and participant-rated nausea and queasiness than psilocybin. Overall intensity and classification: peak participant ratings of overall drug effect strength did not differ between DXM and the high psilocybin doses, indicating comparable perceived intensities. On the Pharmacological Class Questionnaire, most participants identified psilocybin sessions as classic hallucinogen (85–90% across doses), with analog similarity ratings of 75%, 83% and 90% for 10, 20 and 30 mg/70 kg respectively. DXM was chosen as a dissociative anesthetic by 60% of participants, with a 65% analog similarity to the dissociative class and 28% similarity to classic hallucinogens. Subjective phenomenology: both drugs increased a wide array of hallucinogen-sensitive measures, but differences emerged. Visual effects: of 18 visual-effect measures analysed, high-dose psilocybin exceeded DXM on 12 (75%), reflecting more movement, brighter, more distinctive and complex imagery (including textured and kaleidoscopic images), and stronger eyes-open visual effects. Mystical and insight-related experiences: psilocybin produced dose-related increases on most questionnaires; the proportion meeting pre-specified criteria for a “complete” mystical experience on the MEQ30 was 0%, 0%, 20%, 40%, and 0% for placebo, 10, 20 and 30 mg/70 kg psilocybin and DXM respectively, with 30 mg/70 kg psilocybin significantly greater than placebo, low-dose psilocybin and DXM. The 37-item Psychological Insight Questionnaire scores were significantly higher after each psilocybin dose than after DXM. Music absorption: psilocybin elicited greater absorption/ emotional engagement with music than DXM on the assessed items. Disembodiment and other differences: DXM produced significantly greater increases on the Disembodiment subscale of the 5D-ASC (feelings of being out of the body, not having a body, floating). DXM also yielded greater light-headedness and somatic symptoms than psilocybin. CYP2D6 phenotyping identified one poor metabolizer; inspection suggested no obvious deviation in that participant’s data. Reported differences generally remained after sensitivity checks such as excluding ratings from the single partially unblinded monitor.

Carbonaro and colleagues interpret the findings as showing that, under double-blind, within-subject conditions that minimised expectancy, psilocybin and DXM produce comparable overall intensities and similar time-courses of acute drug effects. Nevertheless, qualitative differences were evident: at dose levels producing similar overall intensity, psilocybin elicited relatively greater visual complexity, mystical-type experiences, psychological insight and musical absorption, whereas DXM produced greater disembodiment, light-headedness, nausea and a higher incidence of emesis. The authors situate these results within earlier literature that has contrasted classic serotonergic hallucinogens and NMDA antagonist dissociatives. The greater visual vividness and patterning after psilocybin aligns with findings comparing tryptamine or lysergamide drugs with ketamine, while enhanced disembodiment after DXM is consistent with reports for dissociatives. They also note that the orderly dose–response for psilocybin and the similarity to prior psilocybin studies support the robustness of the methodology, and that the hallucinogen-experienced sample here showed less session-time anxiety or unresponsiveness than hallucinogen-naive participants in other studies—an effect that might reflect tolerance or selection bias. Key uncertainties and limitations acknowledged by the authors include potential memory-impairing effects of DXM that may have reduced the ability of in-session items to capture some mystical-type phenomena, and the possibility that vomiting could have reduced absorption in some cases—although vomiting typically occurred after 90 minutes, making substantial pre‑absorption purging unlikely. They also emphasise the influence of context and the comparator set on participants’ classification of drug effects, highlighting that subjective taxonomy may vary with study design. Finally, the investigators note the need for further psychometric validation of instruments such as the Psychological Insight Questionnaire and for more comprehensive measures of music-related experiences in future comparative studies.