Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

Treatment-resistant depression is described as a difficult-to-treat condition with progressively lower remission rates after successive antidepressant trials, as shown in the STAR*D series (first through fourth courses: 36.8%, 30.6%, 13.7%, and 13.0%, respectively). Failure of two adequate antidepressant trials is commonly used to define treatment-resistant depression, and affected patients have greater illness severity, chronicity, disability, health comorbidity, hospitalisation, suicide risk, and economic burden than those with treatment-responsive depression. Psilocybin, a tryptamine alkaloid found in psilocybe mushrooms, has shown antidepressant potential in preliminary studies in cancer-related depression and in small pilot studies of major depressive disorder, including some work in treatment-resistant populations and trials comparing psilocybin with escitalopram. Goodwin and colleagues designed the present study to identify an acceptable efficacious dose and to assess the safety of a proprietary, synthetic formulation of psilocybin (COMP360) given as a single dose together with psychological support in adults with a treatment-resistant major depressive episode. The trial aimed to test two active dose levels (25 mg and 10 mg) against a very low-dose control (1 mg) with a primary efficacy assessment at 3 weeks and follow-up to 12 weeks.

This was a Phase II, double-blind, randomized, parallel-group, dose-finding trial conducted at 22 sites across 10 countries (Europe and North America) from March 2019 through September 2021. The sponsor, COMPASS Pathfinder, provided the proprietary synthetic psilocybin (COMP360) and funded the trial; contract research organisations handled trial conduct, remote MADRS rating, and statistical analysis, and the sponsor participated in interpretation and post hoc analyses. The trial followed ICH Good Clinical Practice and institutional ethics approvals; participants provided written informed consent. Eligible outpatients were adults (≥18 years) meeting DSM-5 criteria for single or recurrent major depressive episodes without psychotic features and meeting criteria for treatment-resistant depression (failure of two to four adequate prior treatments, defined using the MGH ATRQ). Recruitment was by referral and advertisement. During a 3–6 week run-in, prohibited centrally acting medications were tapered and discontinued at least 2 weeks before baseline, and participants had at least three preparatory therapy sessions. Randomisation (1:1:1 to 25 mg, 10 mg, or 1 mg psilocybin) was central and stratified by country and prior psilocybin experience. Therapists (lead and assisting) were trained through an online and in-person curriculum and remained blinded to dose assignments. On day 1 participants received a single administration session (6–8 hours) in a nonclinical room, with music and eyeshades and two therapists present; a trial psychiatrist was available. Integration sessions occurred on day 2 and at week 1. Participants were asked to remain off antidepressant treatment for the first 3 weeks but could restart 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; 0–60, higher scores worse), assessed by trained remote raters by telephone at scheduled visits through week 12. Key secondary end points were response (≥50% reduction in MADRS at week 3), remission (MADRS ≤10 at week 3), and sustained response (response at week 3 maintained through week 12). Safety assessments included adverse events (MedDRA coding), suicidality (Columbia Suicide Severity Rating Scale), vital signs, laboratory tests including urine drug screen, and ECGs. The planned sample (216; 72 per group) provided 90% power to detect a 6-point difference in mean change in MADRS between active and control, assuming SD 11.0. Efficacy analyses used a modified intention-to-treat set (all randomised who received treatment and had ≥1 postbaseline efficacy assessment). The primary analysis employed a mixed model for repeated measures (MMRM) comparing each active dose with 1 mg, adjusting for treatment, visit, pooled site, treatment-by-visit interaction, and baseline MADRS, with Rubin's rules to combine multiple-imputation results. A "hypothetical strategy" estimand was used to impute post-initiation MADRS scores for participants who started a new antidepressant (progressively worsening imputation), while a "composite strategy" classified participants who initiated new depression treatment or withdrew for lack of efficacy or adverse events as nonresponders on subsequent visits. Response and remission analyses used generalized linear mixed models; sustained response used logistic regression. A hierarchical testing procedure controlled type I error by testing the 25-mg group first then the 10-mg group across the primary and three key secondary end points.

Of 428 screened participants, 233 were randomised and received psilocybin (safety set) and had at least one postbaseline efficacy assessment (modified intention-to-treat): 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% (25 mg), 12% (10 mg), and 13% (1 mg). Baseline characteristics were similar across groups: mean age 39.8 years, 52% female, 92% White, mean lifetime depressive episodes 6.9, and 86% reported current episode duration >1 year. Two thirds were on antidepressant treatment at screening. Mean baseline MADRS scores were 31.9 (25 mg), 33.0 (10 mg), and 32.7 (1 mg). Prior psilocybin exposure was reported by 6%. The least-squares mean change from baseline to week 3 in MADRS was −12.0 points in the 25-mg group, −7.9 in the 10-mg group, and −5.4 in the 1-mg group. The between-group difference for 25 mg versus 1 mg was −6.6 (95% CI −10.2 to −2.9; P<0.001). The 10-mg versus 1-mg difference was −2.5 (95% CI −6.2 to 1.2; P=0.18). Because the 10-mg comparison was not significant, the prespecified hierarchical testing procedure terminated further formal significance testing of secondary end points. Observed response rates at week 3 were 37% (25 mg), 19% (10 mg), and 18% (1 mg); the odds ratio for response for 25 mg versus 1 mg was 2.9 (95% CI 1.2 to 6.6). Remission at week 3 occurred in 29% (25 mg), 9% (10 mg), and 8% (1 mg); the odds ratio for remission for 25 mg versus 1 mg was 4.8 (95% CI 1.8 to 12.8). Sustained response through week 12 was observed in 20% (25 mg), 5% (10 mg), and 10% (1 mg); confidence intervals for odds ratios included 1. Post hoc and per‑protocol analyses yielded results consistent with the primary analysis. Adverse events were 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 adverse events in the 25-mg group were headache (24%) and nausea (22%); dizziness and fatigue occurred in 6% each. Severe day‑1 adverse events were reported by 4% (25 mg), 8% (10 mg), and 1% (1 mg). From day 2 to week 3, severe adverse events occurred in 9% (25 mg), 7% (10 mg), and 1% (1 mg). Serious adverse events from day 2 to week 3 included suicidal ideation (two participants) and intentional self-injury (two participants) in the 25-mg group; in the 10-mg group there were suicidal ideation (two participants), intentional self-injury (one), and one hospitalisation for severe depression; no serious adverse events were reported in the 1-mg group in that interval. From week 3 to week 12, serious adverse events in the 25-mg group included suicidal behaviour in three participants and other events; the 10-mg and 1-mg groups had a small number of serious events including intentional self-injury. At baseline passive or active suicidal ideation without intent was reported by 27% (25 mg), 36% (10 mg), and 24% (1 mg). Worsening of suicidal state from baseline to week 3 occurred in 14% (25 mg), 17% (10 mg), and 9% (1 mg). Three participants in the 25-mg group reported suicidal behaviour after week 3; all had prior histories of suicidal behaviour or self-injury and did not show treatment response at week 3. No clinically significant changes in vital signs, laboratory tests, or ECGs were observed.

Goodwin and colleagues conclude that a single 25-mg dose of proprietary synthetic psilocybin given with psychological support produced a significantly greater reduction in MADRS scores at 3 weeks than a 1-mg control in participants with treatment-resistant major depressive episodes, whereas the 10-mg dose did not differ significantly from 1 mg. The investigators note that secondary end points (response and remission at week 3) were generally consistent with the primary finding, but hierarchical testing stopped after the nonsignificant 10-mg comparison and therefore the secondary results cannot be declared statistically significant under the prespecified testing strategy. Sustained response at 12 weeks did not show a statistically reliable benefit for the 25-mg dose compared with 1 mg. The authors frame the trial as addressing limitations of earlier pilot studies by using a parallel-group design, remote blinded raters for the primary outcome, multi-site recruitment, and follow-up to 12 weeks. They also emphasise that the manualised preparation, support, and integration protocol was time-limited and intended to facilitate safety rather than to serve as a stand-alone psychotherapy. Safety concerns receive particular attention: psilocybin at the doses tested was associated with common transient adverse events (headache, nausea, dizziness, fatigue) and with occurrences of suicidal ideation, self-injury, and suicidal behaviour in a subset of participants, particularly given the high baseline prevalence of suicidality in the sample. The investigators therefore recommend clinical vigilance regarding suicidality in future trials. Limitations acknowledged by the study team include the absence of an active comparator, limited ethnic diversity of participants, exclusion of persons judged to be at clinically significant suicide risk, and challenges to blinding because of the overt subjective effects of the higher doses. They also note that findings apply to the specific proprietary formulation used and that larger, longer trials including head-to-head comparisons with existing treatments are required to determine efficacy and safety more definitively. The authors stress the need for further research rather than asserting definitive clinical effectiveness.