Summary: A Phase 2 randomized clinical trial demonstrates that a single 25 mg dose of psilocybin, combined with psychotherapeutic support, provides rapid, statistically significant, and clinically meaningful reduction in symptoms of common, recurrent depression.
The study showed that an antidepressant effect was noticeable as early as day two, with 53% of the psilocybin group reaching remission at six weeks. While the treatment was generally well-tolerated, researchers noted long-term efficacy challenges and highlighted the ongoing methodological hurdle of patient blinding in psychedelic research.
Key Facts
- Rapid and Lasting Impact: On day 8 post-dosing (the primary outcome target), the psilocybin group’s depression rating score dropped by an average of 9.7 points compared to just 2.4 points in the placebo group, a clinically meaningful difference that persisted through day 42.
- High Remission Rates: At the six-week mark, 53% of participants who received the single psilocybin dose achieved full clinical remission, compared to only 6% of those in the active placebo group.
- Uncertain One-Year Outlook: By day 365, the same 53% of the psilocybin group remained in remission, but no significant group difference remained because a large portion of the placebo group had naturally recovered over the year.
- The Blinding Problem: Despite using niacin as an active physical placebo, almost all participants correctly guessed their assigned group, highlighting a methodological challenge where expectations might partially inflate treatment scores.
Source: Karolinska Institute
Depression is a public health problem that causes great suffering. SSRI drugs are the most common treatment, but many patients do not benefit from them. Their effect can also take several weeks to kick in and side effects are common.
Psilocybin, found in so-called magic mushrooms, has shown antidepressant effects in previous studies. However, most studies have focused on cancer-related or treatment-resistant depression. In the current phase 2 study, published in JAMA Network Open, the researchers investigated whether psilocybin can also alleviate common depression.
A total of 35 people aged 20 to 65 with moderate to severe recurrent depression took part. Participants were randomly assigned to receive either a single dose of 25 mg of psilocybin or an active placebo in the form of niacin, a vitamin that causes a noticeable physical reaction.
Both groups received psychotherapeutic support on five occasions: before, during and after treatment. On the day of dosing, participants were asked to lie down and focus inwardly whilst wearing an eye mask and listening to music via headphones.
The effect of the treatment was measured using the MADRS (Montgomery–Åsberg Depression Rating Scale). The measurements were taken by doctors who were blinded to the treatment on days 8, 15, 42 and 365 following dosing.
To be included in the study, participants were required to have a total score of at least 22 points. The primary outcome of the study was the change in depressive symptoms eight days after treatment. At this point, the MADRS score had decreased by an average of 9.7 points in the psilocybin group, compared with 2.4 points in the placebo group.
This represents a group difference of 7.3 points in favor of psilocybin. The difference was statistically significant and is considered clinically meaningful. The effect persisted even after 15 and 42 days.
Participants also completed a self-report version of the MADRS. Their own assessments showed an antidepressant effect as early as day two, which persisted for just over three months compared to the placebo group.
After six weeks, 53 per cent of participants in the psilocybin group were in remission, compared with six per cent in the placebo group. After one year, the same proportion of the psilocybin group remained in remission, but by then no confirmed difference between the groups was observed, as many of those who had received the placebo had also recovered.
”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.”, says the study’s lead author Hampus Yngwe, consultant psychiatrist and PhD student at the Department of Clinical Neuroscience, Karolinska Institutet. He continues:
”However, the long-term effects are uncertain. Repeated treatments may be needed to prevent relapse. This needs to be investigated in larger studies.”
The treatment was generally well tolerated. Most side effects were mild or moderate and transient. However, two participants who received psilocybin reported severe and persistent anxiety that required medical attention.
“It is important to emphasise that the treatment is not risk-free and that some patients may need extra support,” says Johan Lundberg, professor at the Department of Clinical Neuroscience and the Centre for Psychiatry Research, Karolinska Institutet, who led the study.
Research into psychedelic treatments faces methodological challenges because the substances produce strong and easily recognisable experiences. If participants and researchers can tell whether psilocybin or placebo was given, it becomes harder to separate the effect of the treatment from that of expectations.
In the current study, almost all participants were able to guess which treatment they had received, which may have influenced the outcomes, the researchers suggest.
“We want to understand how factors such as treatment expectations and lack of blinding affect the results, as previous studies may have exaggerated the treatment effects,” says Hampus Yngwe.
The next step in the research is to analyse data from the PET scans, as well as blood and cerebrospinal fluid samples collected before and after dosing.
”Research suggests that the interaction between parts of the brain is impaired in depression and that this may be linked to changes in the connections between nerve cells, known as synapses.
“In preclinical studies, psychedelics have been shown to stimulate synaptic growth. We therefore want to investigate whether psilocybin alters synaptic density in the brain”, concludes Hampus Yngwe.
The study was conducted in collaboration between Karolinska Institutet and the Brain Stimulation Clinic within Northern Stockholm Psychiatry, Stockholm Region.
Funding: The research was funded by Norrsken Mind and the Swedish Research Council. Johan Lundberg declares a personal honorarium from Janssen-Cilag.
Facts about the MADRS:
The MADRS (Montgomery–Åsberg Depression Rating Scale) is used to assess the severity of depressive symptoms. The scale ranges from 0 to 60 points, with higher scores indicating more severe depression:
* 0–12 points: no depression or very mild depression
* 13–19 points: mild depression
* 20–34 points: moderate depression
* 35–60 points: severe depression
Key Questions Answered:
A: Yes, based on these findings. Traditional SSRIs can take several weeks to offer relief, whereas participants in this study self-reported a noticeable antidepressant effect just two days after a single dose.
A: It is not entirely risk-free. While most side effects were mild and temporary, two participants in the psilocybin group experienced severe and persistent anxiety that required medical intervention. This underscores the necessity of clinical supervision.
A: Likely no. Although over half the psilocybin group stayed in remission for a year, lead author Hampus Yngwe emphasizes that the long-term effects remain uncertain and repeated maintenance treatments may be required to permanently prevent relapses.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this psychopharmacology and depression research news
Author: Press Office
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 randomised clinical trial” by Hampus Yngwe, Pontus Plavén-Sigray, Carl Johan Ekman, Eva Henje, Anders Berglund, Mikael Tiger, Maria Beckman, and Johan Lundberg. JAMA Network Open
DOI:10.1001/jamanetworkopen.2026.12589
Abstract
Acute and Late Effects of Psilocybin on Symptoms in Major Depression: a randomised clinical trial
Importance
Psilocybin has been proposed as a rapid-acting antidepressant (onset <2 weeks) with sustained effects (>6 weeks), but evidence from randomized clinical trials remains limited, particularly in the broader major depressive disorder (MDD) population.
Objective
To assess short-term and long-term antidepressant effects of psilocybin therapy in patients with MDD.
Design, Setting, and Participants
This double-blind, placebo-controlled randomized clinical trial of participants diagnosed with moderate to severe recurrent MDD was conducted at the Northern Stockholm Psychiatric Clinic between January 26, 2021, and February 19, 2024. Statistical analysis was performed from February 20, 2024, to June 20, 2025.
Interventions
Participants received a single dose of psilocybin (25 mg) or active placebo (niacin, 100 mg) and 5 psychotherapeutic support sessions during 17 days.
Main Outcomes and Measures
The primary end point was between-group difference in change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 8. Secondary end points included MADRS scores on days 15, 42, and 365, as well as monthly self-reports (MADRS-S) of depressive symptoms, disability, quality of life, and anxiety throughout the 365-day follow-up.
Results
The study included 35 participants (21 [60%] female; mean [SD] age, 41.0 [10.1] years) diagnosed with moderate to severe recurrent MDD, with 17 randomized to the psilocybin group and 18 to the niacin group.
The study met its primary end point with a significant mean between-group difference (model estimated) in change in MADRS score on day 8 (−7.27; 95% CI, −12.89 to −1.65; P = .01) in favor of psilocybin. The between-group difference was significant also on days 15 (mean difference, −11.03; 95% CI, −16.65 to −5.42; P < .001) and 42 (mean difference, −8.33; −13.94 to −2.71; P = .004) but no longer on day 365 (mean difference, −3.68; −9.30 to 1.94; P = .20).
For MADRS-S, the psilocybin group had a significantly greater reduction beginning at day 2 (mean difference, −9.58; 95% CI, −16.05 to −3.11; P = .004), with group differences persisting through day 102 (mean difference, −6.60; 95% CI, −13.01 to −0.19; P = .04) and then isolated effects at days 283 and 343. Most reported treatment-emergent adverse events were transient and of mild to moderate severity.
No drug-related serious adverse events were reported. Two participants in the psilocybin group reported persistent, severe anxiety that required medical attention.
Conclusions and Relevance
In this randomized clinical trial of MDD, a single dose of psilocybin was associated with rapid antidepressant effects, observed by day 2 and persisting for more than 3 months on secondary outcomes; psilocybin was generally well tolerated, but some individuals required additional support after dosing due to anxiety.
These results suggest that psilocybin may provide a rapid and relatively long-lasting antidepressant effect on major depressive disorder, warranting further investigation into repeated dosing or adjunctive treatment strategies.
Trial Registration
ClinicalTrials.gov Identifier: NCT04630964
