Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial

Of 1529 prescreened individuals, 347 consented, and 104 were randomised and received study drug (51 assigned to psilocybin, 53 to niacin). Due to a dispensing error one participant assigned to psilocybin received the comparator, yielding 50 participants who actually received psilocybin and 54 who received niacin in the safety population. Baseline characteristics were broadly balanced: mean age ~41 years, 50% women, 89% White, prior lifetime psychedelic use reported by about 20% of each group, median duration of current episode measured in many months (median 53 weeks for psilocybin, 81 weeks for niacin), and a low prevalence of TRD (approximately 12.5% of the ITT sample). By day 43, 1 participant in the psilocybin group and 9 in the niacin group had withdrawn or been lost to follow‑up; no withdrawals were attributed to AEs. On the primary outcome, psilocybin produced greater reduction in depressive symptoms than niacin from baseline to day 43: mean difference in MADRS change −12.3 (95% CI −17.5 to −7.2), P < .001. The key secondary end point at day 8 also favoured psilocybin: mean difference −12.0 (95% CI −16.6 to −7.4), P < .001. Similar between‑group differences were observed at days 15 and 29 and in multiple imputation sensitivity analyses. More participants randomised to psilocybin achieved sustained depressive symptom response across the postdose visits, although the extracted text does not provide the complete ITT counts for sustained response. In the per‑protocol population (n = 81), results were similar; here the difference in sustained remission reached statistical significance (12/44 [27%] psilocybin vs 3/36 [8%] niacin; adjusted absolute difference 18.9% [95% CI 3.0%–34.9%]; OR 4.0 [95% CI 1.0–15.7]; P = .04). Exploratory outcomes showed improvements with psilocybin in clinician global severity, self‑reported depressive and anxiety symptoms, and quality of life, with no evidence of increased emotional blunting. Safety analyses showed higher rates of adverse events in the psilocybin group. Across the study through day 43, 44/50 (88%) participants receiving psilocybin and 33/54 (61%) receiving niacin reported at least one AE. From dosing day through day 9, 41/50 (82%) psilocybin participants experienced at least one drug‑related treatment‑emergent AE (TEAE) versus 24/54 (44%) in the niacin arm (absolute difference 38% [95% CI 20.6%–41.3%]; relative incidence 1.8). Severe drug‑related AEs through day 9 occurred in 4/50 (8%) psilocybin recipients (examples included migraine, headache, illusion, panic attack with paranoia) and in none of the niacin recipients. The most common solicited events were headache (33/50 [66%] vs 13/54 [24%]; difference 42% [95% CI 27.3%–57.6%]; RI 2.7) and nausea (24/50 [48%] vs 3/54 [6%]; difference 42% [95% CI 24.5%–59.3%]; RI 8.6). Visual perceptual effects were reported on the dosing day by 22/50 (44%) psilocybin participants and after the dosing day by 3/50 (6%); all resolved by study end. No serious treatment‑emergent adverse events were reported, and no instances of clinically confirmed active suicidal behaviour occurred during the trial; suicidal ideation increases were reported in one psilocybin and five niacin participants between baseline and end of trial. No clinically significant changes in vital signs or laboratory tests were observed.

Raison and colleagues interpret these results as evidence that a single 25‑mg dose of psilocybin administered with standardised psychological support produced statistically and clinically meaningful reductions in depressive symptoms compared with an active niacin placebo, with improvements apparent by day 8 and maintained through the 6‑week primary end point. The reported between‑group difference of 12.3 MADRS points at day 43 is larger than typical active‑placebo differences cited in the depression literature and the absolute MADRS reduction in the psilocybin group was described by the authors as exceeding thresholds commonly used to indicate substantial clinical improvement. Psilocybin also improved psychosocial functioning (SDS) and several exploratory measures including anxiety and quality of life, and did not increase emotional blunting. The investigators note several caveats. First, they acknowledge the likelihood of some degree of functional unblinding from psilocybin's acute psychoactive effects, and that the study did not formally assess blinding success; centralised remote raters were used to mitigate this risk but may not fully remove it. Second, the choice of niacin as an active placebo could have affected placebo responses; the authors observe that placebo response in this trial was larger than with an inert placebo in other studies but smaller than typical daily‑pill placebo rates. Third, the 6‑week follow‑up provides longer observation than some recent trials but still leaves open questions about longer‑term durability of effect, especially given the low proportion of participants with treatment‑resistant depression in this sample. Fourth, fidelity to the psychosocial support protocol was not assessed, so between‑participant variability in therapeutic support cannot be excluded as a contributor to outcomes. Finally, the sample lacked racial and ethnic diversity and was generally of higher socioeconomic status, limiting generalisability; the authors emphasise the need for future trials that actively recruit underrepresented groups. In terms of safety, psilocybin was generally well tolerated with most AEs mild or moderate and concentrated around the dosing period, but it was associated with higher overall and severe AE rates compared with niacin. The authors caution that psychedelics may produce adverse effects not fully captured by standard scales and stress the importance of continued careful safety monitoring in future studies. They recommend further large‑scale, longer‑term, and more diverse trials, consideration of alternative comparators that better preserve blinding (for example ketamine), and evaluation of the contribution of psychological support to clinical outcomes.

In this multicentre, randomised Phase II trial, a single 25‑mg dose of psilocybin given with protocolised psychological support produced clinically and statistically significant reductions in depressive symptoms and improvements in functional disability compared with a 100‑mg niacin active placebo at 6 weeks, without any serious treatment‑emergent adverse events. Psilocybin was associated with higher rates of overall, solicited and severe AEs, most occurring around the dosing session and resolving by study end. The authors conclude these results add to evidence that psilocybin, when administered with psychological support, may hold promise as a novel intervention for MDD, while underscoring the need for longer‑term, larger, and more diverse studies and for improved assessment of blinding and psychological‑support fidelity.