A single dose of psilocybin alleviated depression within days, but its advantage 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 administration and lasted for more than three months, although after a year the difference between the groups faded on the primary clinician-rated measure. The document was published in Open JAMA Network.

Depression, or major depressive disorder, is a mental health problem characterized by persistent low mood, loss of interest or pleasure, and other emotional, cognitive, and physical symptoms that can significantly interfere with daily life. When a person experiences repeated episodes of major depression separated by periods during 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 multiple treatment attempts. Traditional antidepressant medications may also take several weeks to produce their effects. They often need to be taken for years to reduce the risk of relapse, while side effects can make long-term treatment difficult. These limitations have increased interest in faster-acting treatments that could produce improvement after only one or a few administrations.

Psilocybin, a classic psychedelic, has attracted particular attention because some studies suggest that a single dose can produce antidepressant effects lasting several weeks or longer. Researchers are particularly interested in whether such effects could also reduce the risk of future depressive episodes and decrease the need for ongoing daily medications.

However, evidence of long-term benefits remains limited because many previous studies lacked appropriate control groups, used suboptimal designs, or failed to completely separate treatment effects from the natural history of depression and other treatments. The powerful effects of psilocybin may also make it easy for participants to know whether they received the drug, which can undermine blinding.

Study author Hampus Yngwe of Karolinska Institutet and colleagues conducted a randomized clinical trial to test the short-term antidepressant effects of a single oral dose of 25 mg of psilocybin in people with major depressive disorder. They also followed participants for 12 months to examine long-term effects and tolerability, and tested whether the study was blinded.

Study participants were 35 Swedish adults with moderate to severe recurrent depression, who were in a depressive episode at the time of recruitment and were recruited via social media and online advertisements. Their average age was 41 years, and 21 were women. None had previously used psychedelics, and none were taking antidepressants or undergoing psychotherapy at the time of entry into 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 more difficult for participants to know which capsule they had received. The study was double-blind, meaning neither the participants nor the researchers evaluating them knew who received which capsule. Both groups also received five sessions of psychotherapeutic support 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 day of administration and then on days 8, 15, 42, and 365. Participants also rated their own symptoms using a self-report version of the scale, daily for the first week, then at regular intervals for a year, as well as measures of disability, quality of life, and of anxiety. Participants who were still depressed on day 42 were referred to standard treatment.

By the clinician-rated measure, depressive symptoms decreased about 7 points more in the psilocybin group than in the niacin group on day 8, the main outcome of the study. The psilocybin group remained ahead on days 15 and 42, but the difference was no longer statistically significant by 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 until day 102, more than three months.

By day 8, 8 participants in the psilocybin group had achieved remission, compared to 2 in the niacin group, a difference that was not statistically significant. At day 42, remission rates were 53% in the psilocybin group and 6% in the niacin group. After one year, the remission rates were 53% and 41%, respectively, a difference small enough that it could reflect chance. Remission in the psilocybin group remained stable from the first week, while in the niacin group it increased from 12% to 41% over the year, which the authors say reflects the episodic nature of depression, including the potential for spontaneous remission.

A similar number of participants in both groups (6 and 7) started antidepressant treatment during the year of follow-up. Psilocybin was generally well tolerated, with mostly temporary side effects such as headache, anxiety, and hallucinations, and no serious drug-related adverse events. However, two participants in the psilocybin group experienced severe anxiety that persisted for weeks after administration and required medical attention.

“In this randomized clinical trial in MDD (major depressive disorder), a single dose of psilocybin was associated with rapid antidepressant effects, observed as early as day 2 and persisting for more than 3 months on secondary outcomes; psilocybin was generally well tolerated, but some people required additional support after administration due to anxiety,” the study authors concluded.

“These results suggest that psilocybin may have a rapid and relatively long-lasting antidepressant effect in major depressive disorder, warranting further research into repeat dosing or adjunctive treatment strategies.”

The study contributes to 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 the effects had to be quite large to be detected, and the trial was not designed to draw definitive 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 clinicians assessing symptoms also guessed correctly for most participants. Because depression was measured through interviews and self-reports, knowing what treatment they received may have influenced how participants and raters judged symptoms, and recruiting through social media may have attracted people with high expectations of treatment.

The article, “Short- and long-term effects of psilocybin on symptoms of 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.