Subjective features of the psilocybin experience that may account for its self-administration by humans: a double-blind comparison of psilocybin and dextromethorphan

Carbonaro and colleagues frame the study around an apparent paradox: psilocybin is used non-medically at substantially higher rates than dextromethorphan (DXM) despite lacking many classical markers of abuse liability such as robust euphoria, reliable self-administration in animal models, or dopaminergic mechanisms typical of addictive drugs. Earlier research and epidemiological data show relatively modest, stable lifetime use of psilocybin in the USA (~8.2% for those 12+) compared with very low lifetime DXM use (~0.05%), and anthropological reports suggest many psilocybin users take it infrequently in ceremonial or insight-oriented contexts rather than for repeated recreational use. The authors note that both drugs can produce psychedelic-type subjective effects, yet their non-medical use profiles differ markedly, motivating a closer comparison of qualitative experiential domains that might underpin motivation to reuse psilocybin. The present report uses data from a rigorously blinded, within-subject comparison of three doses of oral psilocybin, a high dose of DXM, and placebo in experienced hallucinogen users. The primary aim was to identify subjective effect domains that could plausibly predict subsequent self-administration or non-medical use by comparing psilocybin and DXM at doses that produced comparable overall drug-strength ratings. By examining a broad set of self-report measures collected during and after sessions, the investigators sought to characterise qualitative differences—beyond peak drug strength—that might explain why psilocybin is more likely to be used again non-medically than DXM. A secondary contextual aim was to inform which types of retrospective versus in-session ratings best relate to desire to repeat an experience.

This was a double-blind, complete crossover study in which 20 healthy adults with histories of classic and dissociative hallucinogen use completed five experimental sessions. Participants (mean age 29 years, range 22–43; 11 females; 19 White, 1 Asian American) received oral doses in randomised order: psilocybin 10, 20, and 30 mg/70 kg, dextromethorphan hydrobromide 400 mg/70 kg (expressed as base), and placebo. Sessions were spaced at least 48 hours apart (typically about a week) and took place in a living room‑like setting; participants spent most of the session lying with eyeshades and headphones playing a curated programme of classical and world music, and were encouraged to focus on internal experience. Two identically appearing capsules were administered with ~100 ml of water each session. Monitors were blinded to drug condition, except that one of ten monitors knew the set of drugs in the study but not individual session order. A comprehensive battery of subjective measures was collected at multiple time points. Within-session ratings of overall drug effect and liking were obtained before dosing and repeatedly up to ~500 minutes after administration. About 7 hours after administration (end of session) participants completed standardised scales: the 5D-ASC (Altered States of Consciousness), the States of Consciousness Questionnaire (SOCQ, including the Mystical subscale derived from MEQ30 items), the Hallucinogen Rating Scale (HRS), and an End of Session Subjective Effects Questionnaire assessing meaning, spiritual significance, insight, challenge, liking, joy, and peace. One week after the final session participants completed a 202-item Retrospective Comparative Effects Across Sessions Questionnaire (rating each session relative to their strongest possible experience) after reviewing written session reports; a similar comparative questionnaire and rank-ordering of session preference/meaning/insight/spiritual significance were completed at one month. Statistical analyses used IBM SPSS. Time-course comparisons employed planned t tests versus placebo at each time point. Peak and post-session ratings were analysed with repeated measures ANOVAs and Fisher's LSD post hoc tests; scores were scaled to 0–100 and peak defined as each participant's maximum post-dose value. Rank-order data at one month were analysed with Friedman's ANOVA and Wilcoxon signed-rank tests. For binary repeated measures (wanting to repeat within a month), Cochran's Q tested differences across conditions and McNemar tests were used for planned comparisons among placebo, 30 mg/70 kg psilocybin, and DXM. Statistical significance was set at p ≤ 0.05. The extracted text notes small amounts of missing data for some ratings and indicates these were recorded.

Time-course and peak effects: Both psilocybin and DXM produced orderly, time-related subjective effects with maximal impact around 2–4 hours and waning by 6 hours. Peak overall drug-effect ratings during sessions were comparable for DXM and the two highest psilocybin doses, and psilocybin showed clear dose-related increases across measures. However, retrospective liking assessed at end of session and at one week differed: 20 and 30 mg/70 kg psilocybin produced significantly higher ratings of liking than DXM, despite similar peak in-session liking. Subjective domains proposed to predict reinforcing effects: The investigators grouped questionnaire items into nine descriptive domains hypothesised to relate to likelihood of reuse: classic abuse-liability effects (liking/euphoria), visual effects, positive mood, insight, positive social effects, increased awareness of beauty (visual/music), awe/amazement, meaningfulness, and mystical experience. At the end‑of‑session assessment (seven hours post-dose), psilocybin exceeded placebo on 36 of 37 measures; DXM exceeded placebo on 25 of 37. Comparing psilocybin to DXM, there were no measures on which DXM was higher. Psilocybin was significantly higher than DXM on 9, 26, and 32 of the 37 measures at the 10, 20, and 30 mg/70 kg doses, respectively. For measures showing significant differences, the 30 mg/70 kg psilocybin dose was on average over 200% greater than DXM (range 131–474%). One-week retrospective ratings showed a similar pattern: psilocybin exceeded placebo on 26 of 27 assessed measures and generally exhibited dose-related increases; DXM exceeded placebo on 14 of 27. Psilocybin was higher than DXM on 8, 18, and 26 of the 27 measures at 10, 20, and 30 mg/70 kg respectively, with the high psilocybin dose again averaging over 200% greater than DXM for measures with significant differences (range 139–335%). Desire to repeat and one‑month rankings: An item asking how soon participants would like to repeat the experience showed the following percentages indicating a desire to repeat within a month or less: placebo 50%, psilocybin 10 mg 80%, 20 mg 80%, 30 mg 75%, and DXM 25%. Planned comparisons found the highest psilocybin dose significantly higher than DXM. At one month, rank-order analyses for preference to repeat, psychological insight, personal meaning, and spiritual significance indicated that all active drug conditions exceeded placebo, with 20 and 30 mg/70 kg psilocybin rated significantly higher than DXM. Nausea, physical distress, and psychological challenge: Ratings of nausea and physical distress at one week were greater for all active conditions versus placebo, with psilocybin showing dose-related increases but DXM producing the greatest somatic symptoms. Means (±SEM) for nausea on a 0–100 scale were: placebo 0.95 (0.68), psilocybin 10 mg 19.45 (5.28), 20 mg 27.15 (5.51), 30 mg 37.05 (5.35), and DXM 53.50 (7.14). Physical distress means were placebo 1.10 (0.62), 10 mg 20.75 (5.18), 20 mg 29.05 (6.13), 30 mg 35.40 (5.74), and DXM 54.00 (6.06). Measures of psychological challenge were higher than placebo for all active conditions; DXM did not differ statistically from any psilocybin dose on those challenge metrics. The extracted text also notes that about 45% of participants rated the 30 mg/70 kg psilocybin session among the top 10 most meaningful or insightful experiences of their lives, rates significantly above placebo and DXM.

Carbonaro and colleagues interpret the findings as indicating that qualitative aspects of the psilocybin experience—across nine proposed domains—differentiate it from DXM even when overall in-session drug strength is similar. The study team emphasises that retrospective measures of liking and evaluations of meaning, insight, awe, and mystical-type experiences were greater for psilocybin (particularly at 20–30 mg/70 kg) than for DXM, and these differences corresponded with greater self-reported disposition to repeat the psilocybin sessions. Such patterns are consistent with epidemiological differences in non-medical use between psilocybin and DXM. The authors note important caveats. The nine domains were selected on an a priori, intuitive basis rather than derived empirically, so their independence and completeness are uncertain; some domains (for example, meaningfulness and mystical experience) are likely to overlap. The analysis did not focus on experiential features expected to reduce future use, although previously published results from the same study indicated that psychologically challenging experiences were similar or greater after psilocybin than DXM, while DXM tended to produce more aversive somatic symptoms such as nausea and vomiting. The investigators also caution that the present findings concern typical psychoactive doses of psilocybin and cannot be generalised to microdosing regimens, which involve lower doses, more frequent administration, and different intents. In terms of implications, the study suggests that laboratory assessments of abuse potential that rely solely on peak in-session liking may miss important predictors of future use; retrospective liking and broader qualitative appraisals of meaning, awe, insight, and social or aesthetic effects may better capture motivational aspects relevant to repeating use. The authors recommend future research to empirically determine the structure and independence of the proposed domains and to identify any additional experiential dimensions relevant to predicting non-medical use of classic psychedelic drugs. No separate conclusion section is provided in the extracted text.