Single-dose psilocybin for treatment-resistant obsessive-compulsive disorder: A case report

Treatment-resistant major depressive disorder is difficult to treat and carries greater symptom burden, chronicity, disability, suicidality, and costs than treatment-responsive depression. Previous research has shown progressively lower remission rates with successive antidepressant courses, and failure of two adequate courses commonly defines treatment resistance. Preliminary studies have suggested potential antidepressant effects of psilocybin, a tryptamine alkaloid in psilocybe mushrooms, including in patients with life‑threatening cancer and in small pilot studies of major depressive disorder and treatment‑resistant depression. Goodwin and colleagues set out to identify an acceptable and efficacious single dose of a proprietary, synthetic formulation of psilocybin (COMP360) and to assess its safety when given with psychological support to outpatients experiencing a treatment‑resistant major depressive episode. The aim was to evaluate dose–response (25 mg, 10 mg, and 1 mg control) with a primary efficacy assessment at 3 weeks and follow-up to 12 weeks.

This was a Phase II, double‑blind, dose‑finding, parallel‑group randomized clinical trial conducted at 22 sites across 10 countries between March 2019 and September 2021. The sponsor, COMPASS Pathfinder, provided the synthetic psilocybin formulation and engaged contract research organisations to supervise conduct and perform assessments; remote blinded raters administered the primary outcome measure. The trial protocol followed ICH Good Clinical Practice and had independent ethics approval at each site. Eligible adults (≥18 years) met DSM‑5 criteria for a single or recurrent episode of major depressive disorder without psychotic features and had a current episode that had failed two to four adequate antidepressant trials, as documented by the MGH Antidepressant Treatment Response Questionnaire. Participants completed a 3–6 week run‑in during which prohibited central nervous system medications were tapered, and they received at least three preparatory sessions with therapists. Two therapists (lead and assisting) were present for the drug administration session; therapists received standardised training and were masked to dose assignment and did not collect efficacy assessments. Participants were randomised centrally in a 1:1:1 ratio, stratified by country and prior psilocybin experience, to receive a single oral dose of 25 mg, 10 mg, or 1 mg psilocybin (control). The administration session lasted 6–8 hours in a nonclinical, calming room; participants wore eyeshades, listened to a curated music playlist, and returned home after effects dissipated. Two integration sessions were provided (day 2 and week 1). Participants were asked to remain off antidepressant medication for the first 3 weeks post‑dosing but could start treatment if clinically necessary. The primary efficacy end point was change from baseline (day −1) to week 3 in the Montgomery‑Åsberg Depression Rating Scale (MADRS) total score, assessed by blinded, experienced raters by telephone at prespecified time points through week 12. Key secondary end points were response (≥50% decrease in MADRS at week 3), remission (MADRS ≤10 at week 3), and sustained response (week 3 response maintained through week 12). Safety assessments included adverse events coded with MedDRA, suicidality monitoring with the Columbia Suicide Severity Rating Scale, vital signs, laboratory tests, urine drug screens, and 12‑lead ECGs. The statistical plan powered the trial for a 6‑point difference in MADRS change with 90% power assuming an SD of 11; 216 participants were planned. Efficacy analyses used a modified intention‑to‑treat set (all randomised participants who received treatment and had at least one postbaseline efficacy assessment). A ‘‘hypothetical strategy’’ imputational approach was applied to MADRS scores after initiation of new antidepressant treatment, treating these as progressively worse (missing‑not‑at‑random); other missing data were handled as missing‑at‑random. The primary analysis used a mixed model for repeated measures (MMRM) comparing each active dose with the 1‑mg control, and a hierarchical testing procedure was prespecified to control type I error across the primary and three key secondary end points. Response and remission were analysed with generalized linear mixed models and sustained response with logistic regression. Safety analyses were descriptive and included all treated participants.

Of 428 individuals screened, 233 were randomised, received study drug, and had at least one postbaseline efficacy assessment (modified intention‑to‑treat and safety sets). Group sizes were 79 in the 25‑mg group, 75 in the 10‑mg group, and 79 in the 1‑mg group. By week 12, withdrawal rates were 6% in the 25‑mg group, 12% in the 10‑mg group, and 13% in the 1‑mg group. Baseline characteristics were similar across groups: mean age 39.8 years, 52% female, 92% White, mean number of lifetime depressive episodes 6.9, and 86% with current episode duration >1 year. Baseline MADRS scores averaged 31.9 (25 mg), 33.0 (10 mg), and 32.7 (1 mg). Prior psilocybin exposure was reported by 6% of participants. The primary efficacy result at week 3 showed a least‑squares mean change in MADRS of −12.0 points in the 25‑mg group, −7.9 points in the 10‑mg group, and −5.4 points in the 1‑mg group. The between‑group difference for 25 mg versus 1 mg was −6.6 points (95% CI −10.2 to −2.9; P<0.001). The 10 mg versus 1 mg comparison was −2.5 points (95% CI −6.2 to 1.2; P=0.18), which was not statistically significant; because of the prespecified hierarchical testing procedure this nonsignificant comparison terminated formal significance testing for the subsequent secondary end points. Observed response rates at week 3 were 37% (25 mg), 19% (10 mg), and 18% (1 mg), with an odds ratio for response of 2.9 (95% CI 1.2 to 6.6) for 25 mg versus 1 mg. Remission rates at week 3 were 29% (25 mg), 9% (10 mg), and 8% (1 mg), with an odds ratio for remission of 4.8 (95% CI 1.8 to 12.8) for 25 mg versus 1 mg. Sustained response at week 12 occurred in 20% (25 mg), 5% (10 mg), and 10% (1 mg); the odds ratio for sustained response for 25 mg versus 1 mg was 2.2 (95% CI 0.9 to 5.4), with the confidence interval including 1. Adverse events were common: reported in 84% of participants in the 25‑mg group, 75% in the 10‑mg group, and 72% in the 1‑mg group. On day 1 the most frequent events in the 25‑mg group were headache (24%), nausea (22%), dizziness and fatigue (6% each). Severe adverse events on day 1 were uncommon. From day 2 to week 3, severe adverse events were reported in 9% (25 mg), 7% (10 mg), and 1% (1 mg). Serious adverse events included suicidal ideation and intentional self‑injury in the 25‑mg and 10‑mg groups; no serious adverse events were reported in the 1‑mg group during that interval. Between week 3 and week 12, three participants in the 25‑mg group reported suicidal behaviour; all three had prior histories of suicidal behaviour or nonsuicidal self‑injury and lacked a treatment response at week 3. Worsening of suicidal state from baseline to week 3 occurred in 14% (25 mg), 17% (10 mg), and 9% (1 mg). No clinically significant changes in vital signs, laboratory tests, or ECGs were observed. Initiation of new antidepressant treatment before week 3 occurred in 5% (25 mg), 12% (10 mg), and 18% (1 mg); additional participants started treatment after week 3.

Goodwin and colleagues interpret the findings as demonstrating the feasibility of single‑session psilocybin monotherapy, with psychological support, for up to 12 weeks in patients with treatment‑resistant major depression. A single 25‑mg dose produced a statistically significant greater reduction in MADRS total score at 3 weeks than a 1‑mg control, whereas the 10‑mg dose did not differ significantly from control. The authors note that response and remission at week 3 were generally directionally consistent with the primary outcome but that the prespecified hierarchical testing stopped after the nonsignificant 10‑mg comparison, so secondary end points cannot be considered definitively statistically significant. Safety considerations are emphasised: headache, nausea, dizziness, and fatigue were common, and there were numerically greater occurrences of suicidal ideation and self‑injurious behaviour in the 25‑mg and 10‑mg groups compared with the 1‑mg group. The investigators highlight the need for clinical vigilance regarding suicidality in future psilocybin trials. They also describe design strengths intended to address limitations of earlier work, including a multicentre, parallel‑group design, remote blinded raters, a manualised but time‑limited preparation and integration protocol, and a trial population largely naïve to psilocybin. The authors propose that dose‑dependent pharmacokinetics and receptor occupancy may account for the greater effect at 25 mg versus 10 mg. Limitations acknowledged include absence of an active comparator, limited ethnic diversity of participants, exclusion of individuals judged to be at significant suicide risk, and challenges to blinding posed by the pronounced subjective effects of higher doses; the trial did not assess participants' ability to guess dose allocation. They also note that whether other psilocybin preparations would yield similar results is unknown. The extracted text ends before the final sentences of the Discussion, and the paper's concluding remarks are thus not fully available in the provided text.