Single-dose (10 mg) psilocybin reduces symptoms in adults with obsessive-compulsive disorder: A pharmacological challenge study

OCD is a common, early-onset disorder characterised by intrusive obsessions and repetitive compulsions that causes substantial impairment and carries a high global disability burden. Existing pharmacological treatments are limited: tricyclic clomipramine and several selective serotonin reuptake inhibitors (SSRIs) have demonstrable efficacy, and cognitive behavioural therapy with exposure and response prevention is effective, but 30–40% of patients do not respond to these options. Early-stage research and case reports suggest psilocybin, a serotonergic agonist acting at 5-HT2A and other receptors and with downstream glutamatergic effects, may reduce OCD symptoms, yet evidence is sparse and optimal dosing for OCD is uncertain. Pellegrini and colleagues designed a pharmacological challenge study to compare a single mild (10 mg) oral dose of psilocybin with a very low (1 mg) active-control dose, each paired with standardised non-interventional psychological support. The trial aimed to evaluate clinical outcomes—primarily change in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores—and to examine tolerability, with the 10 mg dose chosen to balance putative biological effect against minimising intense psychedelic experiences and improving the feasibility of blinding.

The investigators conducted a fixed-order pharmacological challenge at a dedicated psychopharmacology clinic between October 2022 and July 2024 using COMP360, a pharmaceutical-grade psilocybin formulation. The protocol received Research Ethics Committee approval and was pre-registered. Eligible participants had a primary DSM-IV diagnosis of OCD of at least moderate severity (Y-BOCS ≥16), symptom duration ≥12 months, and were screened out for current or past psychotic disorder, bipolar disorder or mania, first-degree relatives with psychosis, significant suicide attempt history, current major depression (MADRS >24), borderline personality disorder, or medications likely to interact with psilocybin (e.g. lithium, SNRIs). Prior psychedelic use was permitted and recorded. Screening involved an initial remote assessment (including MINI) followed by a comprehensive in-person visit with physical checks, ECG, urine drug screen, blood tests, and confirmation of psychiatric history. Two preparatory sessions were delivered before each dosing day to establish rapport and readiness. Each participant received two single oral doses in fixed order: first 1 mg, then 10 mg, separated by at least four weeks. Dosing occurred in a day-care setting (~9–10 hours on dosing days) with two therapists providing non-interventional, 'inner-directed' support; participants could use music and eyeshades. Four integration sessions were scheduled after each dose (1 day, 1 week, 2 weeks, 4 weeks), and participants were assessed at multiple timepoints across a ~12-week study timetable. The primary clinical outcome was the observer-rated Y-BOCS total score, including obsession and compulsion subscales. Secondary clinical outcomes included MADRS, Beck Depression Inventory (BDI), PHQ-9, and the Sheehan Disability Scale (SDS). A single assessor, blinded to dose and dose order, performed remote observer-rated assessments one day before each dose and at 1, 2 and 4 weeks post-dose. Adverse events were recorded using MedDRA-compliant forms. Cognitive testing (including the ID-ED set shift), EEG and BDNF measurements were collected but are to be reported separately. Participant expectancy was measured with an adapted Credibility/Expectancy instrument; participants and therapists were asked to guess dose after sessions to evaluate blinding. All staff except the blinded assessor were unblinded. For statistics, linear mixed-effects models were specified a priori with participant as a random intercept. Models assessed Time, Dose and their interaction, adjusting for the appropriate pre-dose baseline. An intention-to-treat approach with last observation carried forward (LOCF) was used to handle dropouts. Post-hoc pairwise contrasts were computed with emmeans and Cohen's d effect sizes were reported. Separate models tested whether baseline expectancy moderated clinical change.

Nineteen adults with OCD were enrolled and 18 completed all assessments; one withdrew for non-study-related family reasons after the 1 mg dose. The sample mean age was 38.01 years; 68.4% (n = 13) were male, 58% (n = 11) were taking SSRIs, and 73.7% (n = 14) were psychedelic naïve. Baseline symptom severity was moderately severe (mean Y-BOCS 24.5, SD 3.8) with mean MADRS 12.3 (SD 6.1). On the primary outcome, an ITT linear mixed-effects model (with LOCF) showed a significant overall effect of Time across the study (ANOVA F = 13.23, p < 0.0001). Pairwise comparisons versus the initial baseline (1 day pre-1 mg) indicated Y-BOCS scores at 1, 2 and 4 weeks after the 10 mg dose were significantly lower (all p < 0.0001). The largest reduction occurred at 1 week post-10 mg (β = -3.63), with a large standardised effect (Cohen's d = 1.12). When explicitly comparing doses while adjusting for the respective pre-dose baselines, models showed significant main effects of Dose (F = 23.11, p < 0.0001) and Time (F = 6.33, p < 0.0001), but the Dose × Time interaction was not significant (F = 1.59, p = 0.20). Pairwise dose contrasts identified a statistically significant benefit of 10 mg over 1 mg at 1 week post-dose (β = -4.49, Cohen's d = 0.82, p = 0.002). At 2 weeks the between-dose difference trended toward significance (β = -3.34, d = 0.45, p = 0.06), and by 4 weeks differences were non-significant (β = -2.28, d = 0.19, p = 0.45). Subscale analyses suggested the 1-week advantage for 10 mg was driven primarily by reductions in compulsions (β = -2.44, d = 0.74, p = 0.003) rather than obsessions (β = -1.78, d = 0.50, p = 0.06). Depressive symptoms measured by MADRS showed no significant effects of Time, Dose, or their interaction (all p > 0.05). Self-report measures gave a more mixed picture: BDI showed a significant main effect of Time but no Dose effect; PHQ-9 time effect approached significance; SDS showed a significant Time effect and a Time × Dose interaction, though pairwise dose contrasts at individual timepoints were non-significant. Cognitive and neuroplasticity data were deferred to separate reports. Exploratory subgroup analyses found no significant moderation by SSRI use; participants not taking SSRIs had a numerically larger mean reduction at 1 week (-23.6% vs -17.0%) but this did not reach significance. Gender analyses suggested males had a greater sustained effect at 4 weeks (β = -6.22, p = 0.009), an observation the authors label exploratory given small cell sizes. Expectancy measures did not show significant Visit × Expectancy interactions for Y-BOCS or MADRS. Blinding evaluation was incomplete: the blinded rater later reported being unable to identify active versus control doses, but participant guesses were informative—after 1 mg only 29% guessed correctly (moderate confidence), whereas after 10 mg 92% guessed the higher dose with high confidence, indicating imperfect participant blinding. Adverse events were few and generally mild; no serious adverse events occurred. One participant had an anxiety attack a few hours after the 1 mg dose; no distressing perceptual phenomena were reported.

Pellegrini and colleagues interpret the findings as evidence that a single 10 mg oral dose of psilocybin, given with non-directive psychological support, produced a rapid but transient reduction in OCD symptoms, most notably compulsive behaviours, with the peak effect at one week and attenuation thereafter. The authors note the result aligns with prior small studies that observed symptom improvement across varying doses and argue the 10 mg dose may balance efficacy, tolerability and improved potential for rater blinding compared with higher 'full-dose' regimens. Mechanistic hypotheses discussed include psilocybin's serotonergic agonism (particularly at 5-HT2A), downstream glutamatergic and neuroplastic effects, and transient modulation of cortical regions implicated in OCD such as the anterior cingulate and medial prefrontal cortices; these changes might promote network flexibility and improved cognitive control over compulsive behaviours. The absence of a meaningful change in depressive symptoms suggests the anti‑OCD effect was not mediated via mood improvement in this sample. The investigators acknowledge several key limitations: a small sample size, a fixed (non-randomised) dose order with all participants receiving 1 mg before 10 mg, imperfect participant blinding, and the possibility of carry-over or expectancy-related influences despite analyses showing no significant expectancy effect. They stress that the Dose × Time interaction was not significant, meaning the overall trajectory of change did not differ between doses even though a time-specific between-dose contrast at 1 week was significant; this tempers causal inference. Selection bias toward individuals willing to try psychedelics, and the fact that only a single moderate dose was tested (so relative efficacy versus higher doses remains unknown), are additional caveats. For future work the authors recommend adequately powered, randomised, placebo-controlled trials, exploration of multiple or repeated dosing regimens and dose-ranging studies, and investigation of combined approaches (for example integrating psilocybin with CBT/ERP). They also suggest further mechanistic studies using the cognitive, EEG and biomarker data collected in this trial to clarify how psilocybin may influence compulsive behaviour.

In this small, fixed-order pharmacological challenge, a single 10 mg oral psilocybin dose was well tolerated and produced a rapid, moderately large reduction in OCD symptoms—driven mainly by reduced compulsions—relative to an ultra-low 1 mg active-control dose at one week post-dosing. The benefit diminished by week 2. The authors conclude that these preliminary findings justify a larger, randomised controlled trial to establish efficacy, optimise dosing and examine longer-term outcomes and mechanistic pathways.