Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life

Of 428 individuals screened, 233 participants were randomised and received a single dose of psilocybin (safety and modified intention-to-treat sets): 79 in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. By week 12, withdrawals were 5 (6%) in the 25-mg group, 9 (12%) in the 10-mg group, and 10 (13%) in the 1-mg group. Baseline characteristics were similar across groups: mean age 39.8 years, 52% female, 92% White, 95% with prior depressive episodes (mean 6.9 lifetime episodes), and 86% with current episode duration >1 year. Two thirds were taking antidepressants at screening, and mean baseline MADRS scores were approximately 32 across groups. Prior exposure to psilocybin was reported by 6% of participants. Primary efficacy: the least-squares mean change in MADRS from baseline to week 3 was −12.0 points (25 mg), −7.9 points (10 mg), and −5.4 points (1 mg). The adjusted 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 comparison yielded a difference of −2.5 (95% CI −6.2 to 1.2; P=0.18). Because the 10 mg comparison was not significant, the prespecified hierarchical testing halted, and the trial did not claim statistical significance for subsequent secondary end points. Secondary and other outcomes: the incidence of response at week 3 was 37% in the 25-mg group, 19% in the 10-mg group, and 18% in the 1-mg group (odds ratio 25 mg vs 1 mg 2.9; 95% CI 1.2 to 6.6). Remission at week 3 occurred in 29% of participants in the 25-mg group versus 9% and 8% in the 10-mg and 1-mg groups respectively (odds ratio 25 mg vs 1 mg 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); the odds ratio for 25 mg versus 1 mg was 2.2 (95% CI 0.9 to 5.4), with the confidence interval including 1. Sensitivity, per-protocol, and post hoc analyses adjusting for sex or number of lifetime episodes produced results consistent with the primary analysis. Safety: 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 the day of dosing, the most frequent events in the 25-mg group were headache (24%), nausea (22%), dizziness (6%), and fatigue (6%). Severe adverse events on day 1 were uncommon (4% in 25 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 included suicidal ideation and intentional self-injury in the higher-dose groups; no serious adverse events were reported in the 1-mg group during day 2 to week 3. After week 3 up to week 12, serious events included suicidal behaviour in three participants in the 25-mg group; these three had prior histories of suicidal behaviour or nonsuicidal self-injury and did not show a week-3 treatment response. At baseline, passive or active suicidal ideation was present in 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). No clinically significant or consistent changes were observed in vital signs, clinical laboratory tests, or 12-lead ECGs according to the extracted text.

Goodwin and colleagues report that single-dose psilocybin given with a manualised, time-limited psychological support package was feasible in a treatment-resistant major depressive episode population followed for 12 weeks. A 25-mg dose produced a statistically significant greater reduction in MADRS score at the prespecified primary time point of week 3 compared with a 1-mg control; the 10-mg dose did not differ significantly from 1 mg. The authors note that secondary end-point results (response and remission at week 3) were generally directionally consistent with the primary outcome but that hierarchical testing rules prevent definitive claims for these endpoints, and sustained response at week 12 did not show a clear statistically significant advantage for 25 mg. In discussing safety, the investigators emphasise that adverse events such as headache, nausea, dizziness and fatigue occurred more commonly with higher doses, and that suicidal ideation, self-injury and suicidal behaviour were observed in all dose groups but were numerically more frequent in the higher-dose groups. The authors underline that some participants worsened in suicidal state, and therefore suicidality requires careful clinical vigilance in future trials. The trial was designed to address limitations of earlier studies by using a parallel-group design, multicentre recruitment, remote blinded raters, and limiting psychological support to a structured preparatory and integration protocol rather than ongoing psychotherapy. The authors observe that the week-3 response rate for 25 mg (37%) is numerically lower than response rates reported in some first-line antidepressant trials but higher than rates seen in later-line treatments in the STAR*D sequence. Pharmacokinetic and receptor-occupancy data providing dose-dependent subjective effects are offered as a possible explanation for the dose–response pattern seen here. Limitations acknowledged by the investigators include the lack of an active comparator, limited ethnic diversity of participants, exclusion of people judged at clinically significant suicide risk, and inherent difficulties in maintaining blinding because of the distinctive acute subjective effects of psilocybin (the trial did not assess participants' ability to guess dose assignment). They also note that it is unknown whether other psilocybin preparations would yield similar results. The authors conclude that larger and longer trials, including comparisons with existing treatments, are required to determine the efficacy and safety of psilocybin for treatment-resistant depression.