JAMA Netw Open
One psilocybin dose lifts depression, but not for long
Clinical Takeaway: Psilocybin shows promise as a rapid-acting option for patients with common (not just treatment-resistant) depression, though durability appears limited and severe persistent anxiety in a small minority warrants careful patient selection and post-dose support.
Most prior psilocybin trials enrolled patients with treatment-resistant or cancer-related depression, leaving open the question of whether the broader depression population might also benefit. This small, Swedish phase 2 trial tested a dose in adults with moderate-to-severe recurrent major depressive disorder (MDD) and is among the first to include a placebo-controlled, full 12-month follow-up.
The primary endpoint fell 7.3 points more on the blinded-rater Montgomery-Åsberg Depression Rating Scale (MADRS) score at day 8 in the psilocybin group than in the niacin active-placebo group, a clinically meaningful difference. Self-rated MADRS scores showed separation as early as day 2. Superiority on clinician-rated scores persisted through day 42, and self-reported differences held through day 102 before fading. By day 365, the between-group difference was no longer significant.
At six weeks, 53% of psilocybin recipients met remission criteria compared with 6% on niacin. By 12 months, the psilocybin remission rate remained at 53%, but the niacin group had caught up to 41%, leaving no significant between-group difference at one year. Antidepressant initiation during follow-up was similar between groups, suggesting the niacin group's late improvement wasn't explained by rescue medication.
The trial randomized 35 adults aged 20 to 65 with recurrent MDD and baseline MADRS scores of at least 22 to either a single 25 mg oral psilocybin dose or 100 mg of niacin, each paired with five psychotherapeutic support sessions. Most adverse events were mild to moderate and transient, but two participants in the psilocybin group experienced severe, persistent anxiety requiring medical attention.
"Our results suggest that psilocybin can provide rapid, clinically meaningful improvement in depression and may serve as an alternative to standard treatment when fast symptom reduction is important. However, the long-term effects are uncertain. Repeated treatments may be needed to prevent relapse," said lead author Hampus Yngwe, MD, MSc, of the Karolinska Institutet.
Source: Yngwe H. JAMA Netw Open. 2026 May 15. Short-term and late-term effects of psilocybin on symptoms in major depression: a randomized clinical trial