Psilocybin eased depression within two days, but the placebo gap closed by one year

Psilocybin has drawn interest as a potentially rapid-acting antidepressant, but most trial evidence so far has come from treatment-resistant populations rather than the broader major depressive disorder population, and long-term follow-up data has been limited. A trial published this week in JAMA Network Open, run at Sweden's Northern Stockholm Psychiatric Clinic, tracks both dimensions — speed of onset and durability out to a full year [s1].

The design

This double-blind, placebo-controlled trial enrolled participants with moderate to severe recurrent major depressive disorder between January 2021 and February 2024 [s1]. Thirty-five participants were randomized: 17 to a single 25 mg dose of psilocybin, 18 to active placebo (100 mg niacin, chosen because it produces some physical sensation, helping preserve blinding) [s1]. Both groups received five psychotherapeutic support sessions over 17 days [s1]. The primary endpoint was the between-group difference in Montgomery-Åsberg Depression Rating Scale (MADRS) score change from baseline to day 8 [s1]. Secondary endpoints tracked MADRS at days 15, 42, and 365, alongside monthly self-reported symptom, disability, quality-of-life, and anxiety measures through the full year of follow-up [s1].

What it found

The trial met its primary endpoint: a significant between-group difference in MADRS change favoring psilocybin at day 8 (mean difference −7.27, 95% CI −12.89 to −1.65, p = .01) [s1]. That advantage persisted at day 15 (mean difference −11.03, 95% CI −16.65 to −5.42, p < .001) and day 42 (mean difference −8.33, 95% CI −13.94 to −2.71, p = .004) [s1]. By day 365, though, the group difference on the clinician-rated MADRS was no longer statistically significant (mean difference −3.68, 95% CI −9.30 to 1.94, p = .20) [s1].

On the self-reported version of the same scale (MADRS-S), a significant difference emerged even earlier — by day 2 (mean difference −9.58, 95% CI −16.05 to −3.11, p = .004) — and persisted through day 102, with isolated significant differences appearing again at days 283 and 343 [s1]. Most adverse events were transient, mild to moderate, and there were no drug-related serious adverse events, though two participants in the psilocybin group experienced persistent, severe anxiety requiring medical attention [s1].

The honest headline: rapid onset, uncertain durability

This trial's most useful contribution is exactly what its title promises — data on both ends of the timeline, not just the early response most psilocybin depression trials report. The rapid onset (detectable on self-report by day 2) and the persistence through roughly six weeks on the clinician-rated measure are consistent with what prior psilocybin depression research has generally found. But the loss of statistical significance on the primary clinician-rated measure by one year is the finding that a purely promotional read of this trial would leave out, and it's a meaningfully different result than "psilocybin cures depression for a year." The self-reported measure told a somewhat more favorable story, with effects detected further into the year, including isolated significant differences at days 283 and 343 — but that divergence between clinician-rated and self-reported outcomes is itself worth noting rather than simply picking whichever number reads better.

What this doesn't establish

Thirty-five participants split across two arms is a small trial, and the isolated significant self-reported differences appearing at scattered points late in the year (283, 343) alongside non-significant points elsewhere raises the possibility that some of those late-window findings reflect statistical noise from repeated monthly testing rather than a stable, sustained drug effect — the trial doesn't apply a correction for multiple comparisons across the many monthly self-report timepoints, based on what's reported here. This is a single-dose intervention tested against a specific active placebo and specific therapeutic support protocol; it doesn't establish what would happen with repeated dosing, or how the results would look against a different comparator.

What the authors conclude

The study's authors describe the findings as showing psilocybin "may provide a rapid and relatively long-lasting antidepressant" effect [s1] — a summary that emphasizes the early and mid-term results, consistent with what the data most clearly supports, while the one-year primary-measure result complicates any claim of durable, sustained benefit through a full year.

What to watch

Larger trials designed specifically to test one-year durability with correction for repeated testing, and further characterization of which patients experienced the severe anxiety reported in two of the 17 psilocybin recipients. Psilocybin is not approved for depression; this article describes investigational drug trial results and is not medical advice.

Sources

1. Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression: A Randomized Clinical Trial — JAMA Network Open, 1 May 2026