A single dose of the psychedelic substance psilocybin can rapidly reduce symptoms of depression within just a few days. This is shown by the first randomized, double-blind study of psilocybin for depression in Sweden. The effects lasted for more than three months, according to researchers at the Karolinska Institutet.
Depression is a public health problem that causes great suffering. SSRI drugs are the most common treatment, but many patients do not respond to them. It can also take several weeks to take effect, and side effects are common.
Psilocybin, found in so-called magic mushrooms, has been shown to have antidepressant effects in previous studies. However, most studies have focused on cancer-related or treatment-resistant depression. In the current phase 2 trial, JAMA network openresearchers investigated whether psilocybin could also reduce general depression.
A total of 35 patients with moderate to severe recurrent depression between the ages of 20 and 65 participated. Participants were randomly assigned to receive either a single 25 mg dose of psilocybin or an active placebo in the form of niacin, a vitamin that causes a pronounced physical response.
Both groups received psychotherapeutic support on five occasions: before, during, and after treatment. On the day of administration, participants were asked to lie down and focus inward while wearing an eye mask and listening to music through headphones.
Treatment effectiveness was measured using the MADRS (Montgomery-Asberg Depression Rating Scale). Measurements were taken on days 8, 15, 42, and 365 postdose by a physician blinded to treatment.
To participate in the study, participants were required to have a total score of at least 22 points. The primary outcome of this study was change in depressive symptoms 8 days after treatment. At this point, MADRS scores had decreased by an average of 9.7 points in the psilocybin group, compared to 2.4 points in the placebo group. This represents a 7.3 point difference between the pro-psilocybin group. This difference is considered statistically significant and clinically meaningful. The effects persisted after 15 and 42 days.
Participants also completed a self-report version of the MADRS. Their own evaluation showed antidepressant effects as early as day 2 and lasted just over three months compared to the placebo group.
After six weeks, 53 percent of participants in the psilocybin group were in remission, compared with 6 percent in the placebo group. After one year, the same proportion of the psilocybin group remained in remission, but many of the group receiving placebo also recovered, so no confirmed differences between the groups were observed by that time.
Our results suggest that psilocybin can produce rapid and clinically meaningful improvements in depression and may serve as an alternative to standard treatments when rapid symptom relief is important. ”
Hampus Yngwe, lead study author, consultant psychiatrist and PhD student in the Department of Clinical Neurosciences at Karolinska Institutet
He added: “However, the long-term effects are uncertain. Repeat treatments may be needed to prevent recurrence. This needs to be investigated in larger studies.”
Treatment was generally well tolerated. Most side effects were mild or moderate and temporary. However, two participants who received psilocybin reported severe and persistent anxiety that required medical attention.
“It is important to emphasize that the treatment is not without risks and some patients may require additional support,” says Johan Lundberg, professor at Karolinska Institutet’s Department of Clinical Neuroscience and Psychiatric Research Center, who led the study.
Research on psychedelic treatments faces methodological challenges because the substances produce powerful and easily recognizable experiences. If participants and researchers could know whether they were given psilocybin or a placebo, it would be more difficult to distinguish between treatment effects and expected effects. In the current study, nearly all participants were able to infer the treatment they received, which the researchers suggest may have influenced the results.
“Previous studies may have exaggerated treatment effects, so we want to understand how factors such as treatment expectations and lack of blinding influence the results,” Hampus-Ingwe says.
The next step in the research will be to analyze data from PET scans and blood and cerebrospinal fluid samples taken before and after administration.
“Research suggests that interactions between parts of the brain are impaired in depression, and this may be related to changes in the connections between nerve cells, known as synapses. Preclinical studies have shown that psychedelics stimulate the growth of synapses. We therefore wanted to investigate whether psilocybin alters synapse density in the brain,” Hampus-Ingwe concludes.
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Reference magazines:
Ingwe, H. others (2026) Short-term and late-term effects of psilocybin on symptoms of major depression. A randomized clinical trial. JAMA network open. DOI:10.1001/jamanetworkopen.2026.12589. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2849099.
