Summary: A Phase 2 randomized clinical trial found that a single 25 mg dose of psilocybin, given with structured psychotherapeutic support, produced a rapid, statistically significant, and clinically meaningful reduction in symptoms of moderate to severe recurrent major depression.
Antidepressant effects were evident as early as day 2 by patient self-report, and by day 8 the study’s primary clinician-rated outcome showed a substantial improvement in the psilocybin group versus an active placebo. At six weeks, 53% of participants who received psilocybin reached full clinical remission. The treatment was generally well tolerated, but the study highlights persistent challenges for long-term efficacy and the difficulty of maintaining blinding in psychedelic trials.
Key Facts
- Rapid and sustained improvement: On day 8 (the primary outcome), the psilocybin group’s clinician-rated MADRS score fell by an average of 9.7 points versus a 2.4-point drop in the active placebo group, a clinically meaningful difference that remained through day 42.
- High short-term remission: At six weeks, 53% of participants receiving a single 25 mg psilocybin dose met criteria for clinical remission, compared with 6% in the active placebo (niacin) group.
- One-year follow-up: By day 365 the same 53% of the psilocybin group remained in remission, but there was no statistically confirmed group difference at that time because many participants in the placebo group had recovered over the year.
- Blinding limitations: Despite using niacin as an active physical placebo, almost all participants correctly guessed their assigned treatment, underlining how recognizable psychedelic effects can complicate interpretation of trial outcomes.
Source: Karolinska Institute
Background: Depression is a major public health problem that causes profound suffering. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments, but many people do not respond, effects can take weeks to appear, and side effects are common. Psilocybin, the active compound in so-called magic mushrooms, has shown promise as a rapid-acting antidepressant in prior studies, but most research has focused on cancer-related or treatment-resistant depression. This randomized phase 2 trial tested psilocybin in a broader sample of people with recurrent major depressive disorder (MDD).
Thirty-five adults aged 20 to 65 with moderate to severe recurrent MDD participated. They were randomized to a single oral dose of 25 mg psilocybin or an active placebo of 100 mg niacin, which produces a short-lived physical sensation. All participants received five psychotherapeutic support sessions spread across the treatment period: preparatory, dosing-day support, and post-dosing integration sessions. During the dosing session participants were encouraged to rest with an eye mask and listen to a curated music program through headphones to support inward focus.
The primary outcome was the change in depressive symptoms on the Montgomery–Åsberg Depression Rating Scale (MADRS) from baseline to day 8, assessed by clinicians blinded to treatment allocation. Secondary endpoints included MADRS scores at days 15, 42, and 365, monthly self-reported MADRS-S scores, and measures of disability, quality of life, and anxiety during 12 months of follow-up.
To enroll, participants needed a baseline MADRS score of at least 22. On day 8 the model-estimated between-group difference favored psilocybin by 7.3 points (mean drop 9.7 vs 2.4), a statistically significant and clinically meaningful benefit. Clinician-rated differences remained significant at days 15 and 42 but not at day 365.
Self-reported depressive symptoms (MADRS-S) showed a significant reduction in the psilocybin group beginning at day 2, with group-level benefits persisting for just over three months and intermittent advantages later in the year. At six weeks 53% of the psilocybin group met remission criteria compared with 6% of the placebo group; the psilocybin group’s remission rate at one year was unchanged, but the between-group difference was no longer statistically significant due to recovery in the placebo arm.
The treatment was generally well tolerated. Most adverse events were transient and rated mild to moderate. No drug-related serious adverse events occurred, but two participants who received psilocybin experienced persistent, severe anxiety that required medical attention and additional support.
Study authors emphasize that psilocybin is not without risk and that clinical supervision, screening, and integration support are essential. They also note that the pronounced subjective effects make successful blinding difficult; participants and staff often inferred the assigned treatment, which may inflate outcome differences through expectation effects. Larger trials are needed to evaluate maintenance or repeated dosing strategies to sustain benefit and to clarify how expectation and lack of blinding influence results.
Planned next steps include analysis of PET imaging and blood and cerebrospinal fluid samples collected before and after dosing to explore biological mechanisms. Preclinical evidence suggests psychedelics can promote synaptic growth, and investigators will examine whether psilocybin affects synaptic density in humans.
The trial was conducted by Karolinska Institutet in collaboration with the Brain Stimulation Clinic at Northern Stockholm Psychiatry, Stockholm Region. Funding was provided by Norrsken Mind and the Swedish Research Council. One investigator reports a personal honorarium from Janssen-Cilag.
Facts about the MADRS:
The Montgomery–Åsberg Depression Rating Scale (MADRS) assesses depression severity on a 0–60 scale. Higher scores indicate more severe symptoms:
* 0–12: no or very mild depression
* 13–19: mild depression
* 20–34: moderate depression
* 35–60: severe depression
Key Questions Answered:
A: In this trial, yes. Participants reported measurable symptom relief as early as two days after a single psilocybin dose, whereas typical SSRIs often take several weeks to show benefit.
A: Psilocybin is not risk-free. Most adverse effects were mild and transient, but two participants experienced severe, persistent anxiety requiring medical treatment, indicating the need for careful screening and clinical oversight.
A: Unlikely. Although over half of the psilocybin group remained in remission at one year, the overall group difference was not sustained at day 365. Authors suggest repeated treatments or maintenance strategies may be necessary to prevent relapse.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full.
- Additional context was added by editorial staff.
About this psychopharmacology and depression research news
Author: Press Office, Karolinska Institute
Source: Karolinska Institute
Contact: Press Office – Karolinska Institute
Image: The image is credited to Neuroscience News
Original Research (open access): “Acute and Late Effects of Psilocybin on Symptoms in Major Depression: a randomized clinical trial” by Hampus Yngwe, Pontus Plavén-Sigray, Carl Johan Ekman, Eva Henje, Anders Berglund, Mikael Tiger, Maria Beckman, and Johan Lundberg. DOI: 10.1001/jamanetworkopen.2026.12589
Abstract
Title: Acute and Late Effects of Psilocybin on Symptoms in Major Depression: a randomized clinical trial
Importance: Psilocybin has been proposed as a rapid-acting antidepressant with effects emerging within two weeks and lasting beyond six weeks, but randomized clinical trial data in a general MDD population are limited.
Objective: To evaluate short-term and long-term antidepressant effects of psilocybin therapy in patients with major depressive disorder.
Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial enrolled participants with moderate to severe recurrent MDD at the Northern Stockholm Psychiatric Clinic from January 26, 2021, to February 19, 2024. Statistical analyses were conducted between February 20, 2024, and June 20, 2025.
Interventions: Participants received a single dose of psilocybin (25 mg) or active placebo (niacin, 100 mg) plus five psychotherapeutic support sessions over 17 days.
Main Outcomes and Measures: The primary endpoint was the between-group difference in change in MADRS score from baseline to day 8. Secondary endpoints included MADRS at days 15, 42, and 365, monthly MADRS-S self-reports, and measures of disability, quality of life, and anxiety during the 365-day follow-up.
Results: Thirty-five participants (21 female; mean age 41.0 years) were randomized, 17 to psilocybin and 18 to niacin. The primary endpoint was met: the model-estimated mean between-group difference in MADRS change on day 8 favored psilocybin (−7.27; 95% CI, −12.89 to −1.65; P = .01). Significant between-group differences persisted on days 15 and 42 but not on day 365. Self-reported MADRS-S scores showed significant benefit for psilocybin beginning at day 2 and persisting through approximately three months. Most adverse events were transient and mild to moderate; two participants reported persistent severe anxiety requiring medical attention. No drug-related serious adverse events were reported.
Conclusions and Relevance: In this randomized trial, a single 25 mg dose of psilocybin with psychotherapeutic support produced rapid antidepressant effects detectable by day 2 and sustained benefits on secondary outcomes for more than three months. Psilocybin was generally well tolerated, but some individuals required additional clinical support for anxiety. These findings support further research into repeat dosing and maintenance strategies to sustain benefit in MDD.
Trial Registration: ClinicalTrials.gov Identifier: NCT04630964