A Swedish randomised trial has found that a single 25-mg dose of psilocybin produced rapid antidepressant effects in adults with moderate to severe recurrent major depressive disorder, with self-reported symptoms improving as early as day two and lasting beyond three months. By contrast, the main clinician-rated measure showed the advantage over placebo diminishing by the end of the first year. The study was published in JAMA Network Open.
Depression, or major depressive disorder, is a mental health condition characterised by persistent low mood, loss of interest or pleasure, and other emotional, cognitive, and physical symptoms that can substantially interfere with daily life. When a person experiences repeated episodes of major depression separated by periods in which symptoms improve or disappear, this is described as recurrent depression.
Antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs) are widely used to treat major depressive disorder. However, about two-thirds of patients do not achieve remission with their first SSRI, and some remain depressed despite several treatment attempts. Conventional antidepressants may take several weeks to take effect and can require long-term use to reduce relapse risk, while adverse effects can hinder adherence. These limitations have intensified interest in faster-acting treatments that might deliver relief after only one or a few administrations.
Psilocybin, a classical psychedelic, has attracted particular attention because some studies suggest that a single dose can produce antidepressant effects lasting for weeks or longer. Researchers are especially interested in whether such effects might reduce future depressive episodes and lessen the need for continuous daily medication.
However, evidence for long-term benefits remains limited because many prior studies lacked suitable control groups, used suboptimal designs, or could not fully separate treatment effects from the natural course of depression and other treatments. Blinding can be challenging with psychedelics, as participants often recognise whether they received the drug.
Rapid effects observed, but long-term edge fades
Study author Hampus Yngwe of the Karolinska Institutet led a randomised trial testing the short-term antidepressant effects of a single, oral, 25-mg dose of psilocybin in people with major depressive disorder. The researchers also followed participants for 12 months to examine longer-term effects and tolerability, and assessed how well the study’s blinding held up.
The 35 adults in Sweden had moderate to severe recurrent depression and were in a depressive episode at recruitment. Their average age was 41, and 21 were women. None had used psychedelics before, and none were taking antidepressants or receiving psychotherapy when they entered the study.
Participants were randomly assigned to receive either 25 mg of psilocybin (17 participants) or an identical-looking capsule containing 100 mg of niacin, a form of vitamin B3 (18 participants). Niacin served as an active placebo, designed to produce noticeable bodily sensations to help maintain blinding. The study was double-blind, with both participants and researchers unaware of treatment allocation. Each group also received five psychotherapeutic support sessions over 17 days, including a preparation session, the dosing session, and three follow-up sessions.
Depressive symptoms were assessed by a clinician using the Montgomery-Åsberg Depression Rating Scale (MADRS) on the dosing day and again on days 8, 15, 42, and 365. Participants also rated their own symptoms using a self-report version of the scale, daily during the first week and at regular intervals for a year, along with measures of disability, quality of life, and anxiety. Participants who were still depressed at day 42 were referred for standard treatment.
On the clinician-rated MADRS, depressive symptoms fell by about seven points more in the psilocybin group than in the niacin group by day eight, the study’s primary outcome. The psilocybin group remained ahead on days 15 and 42, but the difference was no longer statistically significant at day 365.
On the self-report measure, the psilocybin group showed a greater reduction in symptoms as early as day two, and the difference persisted through day 102, or more than three months.
By day eight, eight participants in the psilocybin group had reached remission, compared with two in the niacin group, a difference that was not statistically significant. By day 42, remission rates were 53% in the psilocybin group and 6% in the niacin group. After one year, remission rates were 53% and 41%, respectively, a difference small enough to reflect chance. The authors suggest that the remission in the niacin group may reflect the episodic nature of depression, including spontaneous remission.
Similar numbers of participants in the two groups (six and seven) started antidepressant medication during the follow-up year. Psilocybin was generally well tolerated, with mostly temporary side effects such as headache, anxiety, and hallucinations, and no serious adverse events linked to the drug. However, two participants in the psilocybin group experienced severe anxiety that persisted for weeks after dosing and required medical attention.
“In this randomized clinical trial of MDD [major depressive disorder], 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,” study authors concluded.
“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.”
The study contributes to scientific knowledge about the antidepressant potential of psilocybin. However, it should be noted that the trial involved a very small group of participants, so detected effects needed to be relatively large, and the study was not designed to draw firm conclusions about long-term outcomes.
The paper, “Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression: A Randomized Clinical Trial,” was authored by Hampus Yngwe, Pontus Plavén-Sigray, Carl Johan Ekman, Eva Henje, Anders Berglund, Mikael Tiger, Maria Beckman, and Johan Lundberg.
