Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences

Classic serotonergic psychedelics (serotonin 2A receptor agonists) such as psilocybin and dissociative hallucinogens (NMDA receptor antagonists) such as dextromethorphan (DXM) differ in primary pharmacology but may produce overlapping subjective effects. Earlier blinded work had found that a high oral dose of DXM (400 mg/70 kg) produced subjective profiles similar to those of classic hallucinogens on a range of self-report measures, yet relatively little work has directly compared the acute neurocognitive effects of classic and dissociative hallucinogens in the same participants. Barrett and colleagues designed a double-blind, placebo-controlled, within-subjects complete-crossover study to compare dose-dependent neurocognitive effects of oral psilocybin (10, 20, and 30 mg/70 kg) with a single high oral dose of DXM (400 mg/70 kg). The investigators tested two primary hypotheses: that DXM would produce greater impairments than psilocybin on psychomotor, memory, and executive-function tasks, and that psilocybin would produce greater effects on a visual-perception task given its known visual network effects.

This report uses cognitive assessment data collected as part of a larger double-blind, placebo-controlled, complete-crossover study. Twenty medically and psychiatrically healthy adult volunteers (11 females; mean age 28.5 years, range 22–43) with substantial prior use of both classic and dissociative hallucinogens were enrolled. Exclusion criteria included current substance dependence (except nicotine and caffeine), significant medical or psychiatric disorders, personal or immediate family history of psychosis or bipolar disorder, and pregnancy or lactation. Study procedures had institutional review board approval and were registered on ClinicalTrials.gov. Each participant completed five blinded drug sessions in a counterbalanced 5-order Williams design: placebo, DXM 400 mg/70 kg, and psilocybin 10, 20, and 30 mg/70 kg. Sessions were spaced to ensure washout between administrations; participants undertook two preparatory visits with practice on the cognitive tasks. Capsules were administered in a comfortable, monitored, living-room-like setting; participants reclined with eyeshades and music between testing intervals. Urine screening for recent cocaine, benzodiazepine, and opioid use was required before sessions. Blinding was maintained by informing participants that a wide range of possible drug conditions might be given. Neurocognitive assessment comprised a battery of validated tasks targeting psychomotor performance, working memory, episodic memory, executive function/associative learning, global cognition, and visual perception. Tasks included the Penn Computerised Neurocognitive Battery (CNB) components (motor praxis, Penn Line Orientation Test), a letter N-back working-memory task, a word-encoding/recall/recognition episodic memory task analysed with dual-process signal-detection and ROC methods, the digit symbol substitution task (DSST) for associative learning and executive function, and the Mini–Mental State Examination (MMSE) for gross cognitive impairment. Some tasks (MMSE, N-back, PLOT) were administered only once per session; others were repeated hourly. Timing of each task relative to peak subjective effects is reported. Statistical analyses used mixed-effects repeated-measures ANOVA or ANCOVA models, with responses nested within participant. For most cognitive outcomes the average motor praxis response time at the corresponding assessment period was included as a covariate to control for general psychomotor slowing. Models were estimated with lme4/lmerTest in R and multiple comparisons were corrected using Tukey’s method. The paper reports missing-data patterns: four volunteers were unable to complete cognitive assessments in the DXM condition due to impairing effects, three were unable to complete assessments in the 30 mg/70 kg psilocybin condition, and several isolated missing baseline or task data points occurred; partial data were retained where possible.

Gross motor tasks and overall strength of drug effect. Both the circular lights (hand–eye coordination) and balance tasks showed clear time- and dose-dependent drug effects. DXM produced greater impairment than the 10 and 20 mg/70 kg psilocybin conditions on the circular lights task and greater impairment than any psilocybin dose on the balance task. Peak monitor-rated strength of observed drug effects differed from placebo for all active conditions, and the 10 mg/70 kg psilocybin condition produced lower peak strength ratings than 20 and 30 mg/70 kg psilocybin and DXM. Psychomotor slowing was evident: there was a main effect of drug condition on motor praxis response time (F[4] = 6.52, p < 0.001), with slower responses during 20 and 30 mg/70 kg psilocybin and 400 mg/70 kg DXM versus placebo; accuracy on that timed task was not affected. Global cognition and executive function. MMSE scores did not differ significantly by drug condition; one participant scored below the conventional cutoff in their DXM session, but all other scores were ≥26. On the DSST there were strong effects of drug condition, time point, and their interaction for number of trials attempted (F[4] = 23.52, p < 0.0001), accuracy (F[4] = 10.56, p < 0.0001), and substitution recall accuracy (F[4] = 11.59, p < 0.0001). Psilocybin produced a dose-dependent decrease in the number of trials attempted at peak effects, consistent with a speed–accuracy trade-off, whereas DXM impaired both the number of trials attempted and the accuracy of attempted trials. Working memory (letter N-back). Analyses revealed main effects of n-back load and drug condition and significant interactions. Discriminability showed main effects of n-back (F[2] = 38.53, p < 0.0001) and drug condition (F[4] = 3.47, p < 0.05) with an interaction (F[8] = 3.51, p < 0.001). Response bias and response time also showed main effects and interactions (response bias drug effect F[4] = 6.75, p < 0.001; response time drug effect F[4] = 8.50, p < 0.0005). Patterned results indicate that psilocybin produced dose-dependent impairments in working-memory discriminability and increased response times under the 2-back (working-memory) condition, whereas DXM produced a liberal response bias in the 0-back condition (interpreted as impaired response inhibition). Episodic memory. Free recall was reduced by both drugs (main effect on recall accuracy F[4] = 11.22, p < 0.0001), with DXM producing larger decreases than psilocybin. Recognition measures from ROC analysis showed drug effects on AUC (F[4] = 6.42, p < 0.0005) and sensitivity A′ (F[4] = 5.94, p < 0.0005). Planned comparisons indicated that DXM reduced both familiarity and recollection indices relative to the 10 mg/70 kg psilocybin condition (familiarity z = -2.08, p < 0.05; recollection z = -2.15, p < 0.05), indicating a selective detrimental effect of DXM on recognition memory processes. Visual perception (PLOT). No significant drug effects were observed on accuracy of line-orientation judgments. However, drug condition affected mean excess clicks for correct trials (F[4] = 4.80, p < 0.005) and median response time for incorrect trials (F[4] = 4.48, p < 0.005). Psilocybin produced dose-dependent increases in response time on error trials, while DXM increased excess clicks for correct trials compared with placebo and the low psilocybin dose, suggesting different patterns of effort or strategy rather than a simple shared deficit. Missing data and control for psychomotor slowing. Several participants could not complete tasks during the most impairing conditions (four in DXM, three in 30 mg psilocybin), and analyses included motor praxis response time as a covariate so that reported cognitive effects reflect domain-specific changes after accounting for general psychomotor slowing.

Barrett and colleagues interpret the results as showing clear, dose-dependent cognitive effects of psilocybin across associative learning, working memory, episodic memory, and some visual-perception measures. Overall, the 400 mg/70 kg DXM dose produced cognitive effects that, for many measures, were in the range of those produced by 20–30 mg/70 kg psilocybin, but important domain-specific differences emerged. Both drugs caused psychomotor slowing, yet neither produced widespread global cognitive impairment or delirium as measured by the MMSE (aside from one individual in the DXM session). The investigators therefore conclude that acute subjective changes under these drugs are not equivalent to clinical delirium. In memory domains, DXM produced a selective impairment of recognition sensitivity, recollection, and familiarity relative to low-dose psilocybin and reduced free recall to a greater extent than psilocybin, consistent with prior reports on dissociative NMDA antagonists. In executive and working-memory domains, psilocybin produced a dose-dependent impairment of working-memory discriminability and slowed responses under working-memory load, while DXM selectively impaired response inhibition and broader executive control as evidenced by a liberal response bias on the 0-back condition and impaired DSST accuracy. Visual-processing findings were nuanced: the study did not find psilocybin effects on basic line-orientation accuracy (a lower-level visual task), aligning with prior work that suggests classic psychedelics preferentially affect higher-level visual processes; nevertheless, psilocybin increased response time on error trials and DXM increased mean excess clicks on correct trials, consistent with different effects on task strategy or effort. The authors acknowledge several limitations. Only a single high dose of DXM was administered, limiting dose–dose comparisons; pharmacokinetic measures were not collected so drug concentrations could not be correlated with performance or metabolism; several tasks were administered only once per session, introducing potential confounds between task timing and subjective effect strength; and the sample comprised experienced hallucinogen users, which may limit generalisability. Missing data from a few participants may have affected balance in the counterbalanced design, and subtle practice effects cannot be entirely excluded despite pre-session training. Finally, the timing of the PLOT late in sessions may have reduced sensitivity to visual-perception effects. In terms of implications, the investigators suggest that the differential cognitive profiles may underlie contrasting subjective outcomes: greater impairment of episodic memory and executive control by DXM could help explain lower reported psychological insight and personal meaningfulness after DXM compared with psilocybin, while greater balance impairment and broader domain effects with DXM might indicate higher safety risk if misused outside controlled settings.

This study provides a dose–response characterisation of psilocybin’s acute cognitive effects and a within-subject comparison with a high dose of DXM. Despite overlapping subjective strength and effects on psychomotor performance, visual perception, and associative learning, psilocybin and DXM produced distinct cognitive signatures: psilocybin more strongly affected working memory, whereas DXM more selectively impaired episodic recognition, response inhibition, executive control, and balance. The authors conclude these differences are relevant for understanding divergent subjective experiences and potential safety considerations when these drugs are used outside controlled environments.