A single dose of psilocybin eased depression within days, but its edge over placebo faded within a year

A randomized clinical trial conducted in Sweden found that a single 25-mg dose of psilocybin produced rapid antidepressant effects in patients with moderate to severe recurrent major depressive disorder. On a self-report measure, the effects appeared as early as the second day after dosing and lasted for more than three months, although by one year the difference between groups had faded on the main clinician-rated measure. The paper was published in JAMA Network Open.

Depression, or major depressive disorder, is a mental health condition characterized 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, such a condition is called 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. Mainstream antidepressant medications may also take several weeks to produce effects. They frequently need to be taken for years to reduce the risk of relapse, while adverse effects can make long-term treatment difficult. These limitations have increased interest in faster-acting treatments that might produce improvement 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 several weeks or longer. Researchers are especially interested in whether such effects might also reduce the risk of future depressive episodes and lessen the need for continuous daily medication.

However, evidence for long-term benefits remains limited because many previous studies lacked suitable control groups, used suboptimal designs, or could not fully separate treatment effects from the natural course of depression and other treatments. Psilocybin’s strong effects can also make it easy for participants to tell whether they received the drug, which can undermine blinding.

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Study author Hampus Yngwe of the Karolinska Institutet and his colleagues conducted a randomized clinical trial to test the short-term antidepressant effects of a single, oral, 25-mg dose of psilocybin in people with major depressive disorder. They also followed participants for 12 months to examine longer-term effects and tolerability, and tested how well the study’s blinding held up.

Study participants were 35 adults in Sweden with moderate to severe recurrent depression who were in a depressive episode at the time of recruitment and were recruited through social media and online ads. 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, a substance that produces noticeable bodily sensations, such as flushing, and was intended to make it harder for participants to tell which capsule they had received. The study was double-blind, meaning that neither participants nor the researchers assessing them were told who received which capsule. Both groups 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 then 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 measure, depressive symptoms fell by about 7 points more in the psilocybin group than in the niacin group by day 8, the study’s main 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 2, and the difference persisted through day 102, or more than three months.

By day 8, 8 participants in the psilocybin group had reached remission, compared with 2 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 that it could reflect chance. Remission in the psilocybin group held steady from the first week onward, while in the niacin group it rose from 12% to 41% over the year, which the authors suggest reflects the episodic nature of depression, including the potential for spontaneous remission.

Similar numbers of participants in the two groups (6 and 7) 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 the scientific knowledge about the antidepressant potential of psilocybin. However, it should be noted that the study was conducted on a very small group of participants, so any effects needed to be quite large to be detected, and the trial was not designed to draw firm conclusions about long-term effects.

Blinding also largely failed. At the end of the study, 94% of participants in the psilocybin group and all of those in the niacin group who answered correctly guessed which treatment they had received, and the clinicians rating symptoms guessed correctly for most participants as well. Because depression was measured through interviews and self-reports, knowing which treatment they had received may have influenced how participants and raters judged symptoms, and recruitment through social media may have drawn people with high expectations for the treatment.

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.