A randomized clinical trial of repeated doses of psilocybin for the treatment of obsessive–compulsive disorder

Obsessive–compulsive disorder (OCD) is a chronic, disabling condition affecting roughly 2%-3% of people across their lifetimes, characterised by intrusive thoughts and repetitive behaviours that reduce quality of life and carry societal costs. Current standard treatments (psychotherapy and pharmacotherapy) have limitations including delayed or incomplete response and adherence challenges, motivating exploration of alternative approaches. Psilocybin, a serotonergic psychedelic metabolised to psilocin that acts at multiple 5-HT receptors (notably 5-HT2A), has been associated in prior preclinical, neuroimaging, case series and small clinical studies with increased cognitive flexibility, altered network connectivity relevant to the Cortico-Striato-Thalamo-Cortical (CSTC) circuit implicated in OCD, and preliminary symptom reductions, supporting its evaluation as a candidate therapy for treatment‑resistant OCD. A. and colleagues designed the present study to assess initial safety, tolerability and short‑term efficacy of repeated, weekly doses of psilocybin in people with moderate-to-severe OCD. Building on prior single‑dose and retrospective reports, the trial tested a randomized, double‑blind Phase I comparison of two psilocybin doses versus an active placebo (lorazepam), followed by an open single‑blind phase in which all participants received high‑dose psilocybin. The study aimed to characterise adverse events and suicidality, examine acute and week‑after symptom changes measured with the Yale–Brown Obsessive Compulsive Scale (YBOCS), explore dose–response effects across multiple sessions, and gather preliminary signals to inform larger trials.

The trial was a Phase I study consisting of two sequential phases. Phase I was a randomized, double‑blind trial with three arms: four weekly oral administrations of placebo (lorazepam 1 mg), low‑dose psilocybin (100 µg/kg) or high‑dose psilocybin (300 µg/kg). Phase II was single‑blind (participants blind) in which all participants received four additional weekly high‑dose psilocybin administrations (300 µg/kg). High‑dose sessions had a minimum absolute dose of 15 mg for participants under 50 kg and a maximum of 30 mg for those over 100 kg. The three study groups are termed P + H (placebo in Phase I, high dose in Phase II), L + H (low then high), and H + H (high then high), yielding cumulative exposures ranging from four to eight high‑dose equivalents (the low dose was later treated as one‑third of a high dose in dose–response analyses). Participants were recruited from community referrals and registries between Spring 2019 and Spring 2022, with a 17‑month COVID pause. Of 578 initial contacts, 18 completed baseline assessment; after one pre‑Session 1 withdrawal, 15 entered Phase I (5 per condition). One additional withdrawal after Phase I and one who left before completing Phase II left the main analyses, resulting in 14 completers of Phase II. Inclusion criteria included age 18–65, DSM‑5 OCD confirmed by SCID‑5‑RV, YBOCS ≥16, failure of at least one guideline‑concordant OCD treatment, and ability for independent living. Participants stopped prohibited medications (antidepressants, lithium, antipsychotics, glutamatergic drugs) at least 2 weeks prior to the first session; six participants required gradual tapering. Key exclusions included personal or family history of psychosis/mania, unstable medical conditions, recent substance use disorder, pregnancy, and contraindications to lorazepam or MRI. Randomisation was stratified by YBOCS severity (moderate 16–23 vs high ≥24) with fixed block size 3 and equal allocation; allocation was computer‑generated and concealed from investigators and personnel with participant contact. Sessions occurred weekly and included preparatory visits, an administration day (≈10 hours, extended to 12 hours for sessions 4 and 8), and follow‑up. Administration procedures used eyeshades, standardised music, limited interaction, and two trained facilitators present. Vital signs and YBOCS were measured at baseline and at specified post‑dose time points; daily YBOCS interviews were performed between sessions. No psychotherapy beyond preparatory/debriefing support was provided during sessions. Functional neuroimaging and EEG were obtained after Sessions 4 and 8 but are reported elsewhere. Primary safety assessments included a modified SAFTEE‑GI with items focused on psychedelic‑relevant adverse events, the Columbia‑Suicide Severity Rating Scale (C‑SSRS) for suicidality, and the SCID‑5‑RV Psychotic Screening Module for psychotic symptoms. The primary clinical efficacy measure was the clinician‑administered YBOCS. Inter‑rater reliability on a subset of YBOCS interviews was high (ICC = 0.987). The analysis plan used mixed linear models with Condition (Placebo, Low, High) as a between‑subjects factor and Time as a within‑subjects factor to test condition-by-time interactions and within‑condition changes. Response was defined as ≥35% YBOCS reduction, remission as YBOCS ≤12, and partial response as ≥25% reduction. The study targeted n = 15 to provide 80% power to detect a within‑subject pre‑to‑post effect but was not powered for between‑group comparisons. All participants were included in analyses; one participant had last observation carried forward for end‑of‑treatment categorisations. Ethical oversight included IRB approval, IND oversight, and a data safety monitoring board.

Participant flow and baseline characteristics: Of 18 who completed baseline assessment, one was withdrawn before Session 1 for dropping below inclusion cut‑offs and two withdrew early during Phase I, leaving 15 participants who completed Phase I (5 per arm). Fourteen participants completed Phase II (one participant discontinued after four sessions in L + H). Participants had long‑standing OCD (mean duration 18.8 years, SD = 10.0) and severe baseline symptoms (mean YBOCS = 28.6, SD = 5.2; range 19–39). Safety and tolerability: Across the trial there were 20 placebo sessions, 20 low‑dose sessions and 75 high‑dose sessions. Overall adverse event frequency was low and largely similar across session types. Three symptoms differed by session type in chi‑square tests: nausea was most common during low‑dose sessions, while itching and rash were most common during the active placebo (lorazepam) sessions. Depression was numerically higher during psilocybin sessions but did not differ significantly. No serious adverse events were reported. The SCID psychosis screening detected no incident psychotic symptoms at session day, one‑week post‑session, or during 6‑month follow‑up. Suicidality measured by the C‑SSRS showed baseline lifetime passive ideation in 7/15 participants and more limited prior ideation/behaviour; on session days there were no significant differences between session types in change in any of the five ideation levels (passive to active with plan/intent). Participants receiving high‑dose psilocybin in Phase II showed no suicidality during those sessions. Routine laboratory tests (CBC, CMP) showed no significant changes between baseline and after Sessions 4 and 8. Efficacy — symptom change: Next‑day (day‑after) analyses over the first four randomized weeks used mixed linear models including baseline and the day after each weekly session. YBOCS scores decreased significantly over time (F(4,21.85) = 6.50, p < 0.001). There was a significant main effect of Condition collapsed across time (F(2,50.61) = 5.48, p = 0.007), but no condition‑by‑time interaction (F(8,21.82) = 1.16, ns). The condition effect reflected that averaged across the four weeks both psilocybin groups had lower mean YBOCS (high mean ≈ 17.8; low mean ≈ 20.6) than placebo. Next‑week (one week after each session) analyses across the first four weeks again showed significant reductions over time (F(5,20.21) = 2.56, p < 0.001). Conditions did not differ significantly collapsed across time (F(2,59.76) = 2.48, p = 0.092), and no condition‑by‑time interaction was present (F(10,20.21) = 0.36, ns). Planned simple slope analyses found no significant within‑condition reduction, but pooled psilocybin (low + high, N = 10) versus placebo (N = 5) showed a significant week‑after reduction across the four weeks (F(1,12.95) = 4.98, p = 0.044). Across the full eight‑week treatment (Phase I + Phase II) including baseline and week‑after assessments, scores decreased over time (F(9,25.59) = 6.13, p < 0.001), with no significant condition‑collapsed difference (F(2,95.03) = 2.54, p = 0.084) and no condition‑by‑time interaction (F(18,25.81) = 0.32, ns). Response and remission: Collapsing across the three sequence conditions to examine outcomes after all participants had received at least four high‑dose equivalents, and using last observation carried forward for the one early discontinuation, 73% of participants (LOCF, N = 15) met response criteria (≥35% YBOCS reduction) at one week after the final (8th) session and 40% met remission criteria (YBOCS ≤12). Among completers (N = 14), 71.4% were responders and 42.9% remitted. Six‑month follow‑up data suggested that many participants sustained benefit prospectively, though exact rates are provided in figures/tables reported in the paper. Dose–response and correlational findings: A post‑hoc cumulative dose analysis treated low dose as one‑third of a high dose and correlated cumulative exposure with percent YBOCS reduction. There was a significant positive correlation between cumulative psilocybin exposure and symptom reduction across treatment (r = 0.59, p < 0.01). The correlation between cumulative dose at end of treatment and percent reduction at 6 months among the 14 completers approached significance (r = 0.45, p = 0.051, one‑tailed). Visual inspection indicated that 4 of 5 participants in the H + H (highest cumulative dose) condition had 6‑month YBOCS scores equal to or lower than their post‑treatment scores, compared with fewer participants in the other groups. Exploratory predictors: Post‑hoc chi‑square analyses indicated that recent discontinuation of serotonin reuptake inhibitors (SRIs) prior to study entry was associated with non‑response: those who had been on SRIs before the trial were more likely to be non‑responders (X2 = 8.18, p = 0.004 for responder status; X2 = 5.63, p = 0.018 for partial response). The three non‑responders all had recently discontinued SRIs; they also lacked prior psychedelic experience and one had a diagnosis of borderline personality disorder. The extracted text does not provide detailed subgroup sample sizes beyond these observations.

A. and colleagues interpret their findings as preliminary evidence that repeated weekly low‑ and high‑dose psilocybin administrations are generally safe and well tolerated in this small sample of individuals with moderate‑to‑severe OCD. No serious adverse events, incident psychotic symptoms, clinically meaningful changes in laboratory parameters, or increases in suicidality attributable to dosing sessions were observed. The authors highlight that, across sessions, adverse event frequency was low and largely similar across session types, with only a few symptoms differing by session type. On efficacy, the researchers report significant reductions in YBOCS scores over time, with psilocybin conditions showing larger decreases than placebo when collapsed across the randomized Phase I weeks and when pooled in some analyses. They note meaningful reductions both the day after dosing and at 1‑week post‑dose, and that by the end of the eight‑week course a majority of participants met responder criteria and a substantial proportion remitted. The authors emphasise a dose‑exposure relationship: cumulative psilocybin exposure correlated with greater symptom reduction during treatment and showed a trend toward predicting more durable improvement at 6 months. The authors discuss exploratory findings that recent discontinuation of SRIs before study entry was associated with poorer outcomes, suggesting potential pharmacodynamic interactions or receptor changes that might blunt psilocybin's therapeutic effects. They note that all three non‑responders had recently ceased SRIs, lacked prior psychedelic experience, and one had comorbid borderline personality disorder, but caution that the sample is too small to draw firm conclusions and that these observations warrant further investigation. Key limitations acknowledged by the authors include the small sample size (n = 15 analysed; 14 completers), limited power to detect between‑group effects, potential selection bias towards highly motivated participants with resources to attend frequent sessions, restricted demographic representativeness, and inability to robustly test moderators (OCD subtype, duration, comorbidity). They also point to the burdensome assessment schedule and lack of formal blinding fidelity measurement; while a low‑dose arm and active placebo were used to bolster blinding, the distinct subjective effects of psychedelics remain a challenge. The authors recommend that future trials address washout timing for concomitant SRIs (or consider stratified designs), streamline assessments and standardise preparatory and integration protocols, prospectively measure expectancy and blinding, and explore personalised dosing or adjunctive interventions to enhance response variability. Larger, multi‑site trials are proposed to replicate safety signals, confirm efficacy, and optimise dosing frequency and spacing to balance therapeutic effect with durability of response. The authors conclude that their data provide a preliminary but meaningful contribution to the evidence base on psilocybin for OCD, supplying the field with safety, tolerability and early efficacy signals for repeated weekly dosing that justify further investigation in adequately powered trials.

The authors conclude that multiple weekly doses of psilocybin were safe, well tolerated and associated with clinically meaningful reductions in OCD symptoms in this small Phase I sample, with higher cumulative exposure linked to greater symptom reduction. They state that these findings support further investigation in larger trials to confirm efficacy, clarify mechanisms, and optimise dosing and integration strategies for potential clinical use in OCD.