What is the efficacy and safety of psilocybin in patients with major depressive disorder?

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What is the efficacy and safety of psilocybin in patients with major depressive disorder?

In a recent study published in JAMA Journal, researchers report the results of a randomized clinical trial that evaluated various clinical aspects, including the safety, timing, magnitude, and durability of the antidepressant psilocybin in patients with major depressive disorder.

survey: Single-dose psilocybin treatment for major depressive disorder. Image credit: 24K-Production/Shutterstock.com


Psilocybin is a psychedelic that has recently gained significant research interest as a potential therapeutic option for major depressive disorders.

This interest is also fueled by the limitations of pharmacological treatments currently approved for the treatment of major depressive disorders and the observation that the antidepressant effects of psilocybin appear to be longer-lasting than the actual presence of psilocybin in the body.

However, due to various factors, such as inadequate sample size, assessment of studies by unblinded raters, insufficient assessment of potential adverse effects of psilocybin use, and study design issues, there is a lack of clarity regarding the efficacy of psilocybin use for the treatment of major depressive disorder. .

Furthermore, studies involving large sample sizes have only examined short-term endpoints of the therapeutic use of psilocybin, and the long-term impact and efficacy of psilocybin use for the treatment of major depressive disorders remains unclear.

About the research

In the current study, researchers conducted a multi-blind, randomized control trial to compare the results of psilocybin and active placebo niacin in terms of factors such as time of onset, six-week safety profiles, and duration of beneficial effects. All assessments were performed by centralized assessors who were blinded.

This phase II clinical trial was conducted between December 2019 and June 2022 at 11 sites in the United States (US) with informed consent obtained from all participants. Participants were recruited through a variety of means, from the study website to advertisements and patient advocate lists.

Adults between the ages of 21 and 64 who were medically healthy and met diagnostic criteria for major depressive disorder, with at least one episode of depressive disorder in the past two months, were recruited for the study.

Only those individuals with a Montgomery-Asberg Depression Rating Scale (MADRS) score of 28 or greater and 30% or less improvement during a screening period of one to five weeks were included in the study to give possibility of dose reduction or administration of placebo.

Participants were excluded if they had a personal or family history of mania or psychosis, a moderate to severe drug or alcohol use disorder, suicidal tendencies in the past year, required strict adherence to their psychotropic medication, or were have used a psychedelic drug in the previous five months or more than ten times in their lifetime.

The interventions that were compared were a 25-milligram dose of psilocybin versus a 100-milligram dose of niacin in capsules, which appeared to be identical.

The primary outcome studied was the difference between the two groups in the MADRS score between baseline and day 43, which was assessed by the central rater.

The primary secondary outcome was the change in MADRS score between baseline and day 8. Other secondary outcomes included difference in Sheehan Disability Scale score between baseline and day 43, the proportion of participants who had a sustained response in depressive symptoms, and sustained remission of depressive symptoms.

The seriousness, severity, and relationship of adverse events to interventions were also monitored.


The findings suggest that treatment of major depressive disorder with psilocybin results in sustained and clinically meaningful reductions in functional impairment and depressive symptoms, with no serious adverse effects reported.

In the psilocybin intervention group, there were marked improvements in depressive symptoms during the first eight days. This was then maintained over the six weeks of follow-up, confirming a rapid onset and sustained mode of action.

Other beneficial effects of psilocybin noted in the study included improvements in psychosocial function, supported by significant differences in Sheehan Disability Scale scores, and reductions in general anxiety, illness severity, and depressive symptoms, as well as improvements in overall quality of life.

Furthermore, the emotional blunting associated with other standard antidepressants was not observed with psilocybin treatment.

The drug was also well tolerated, with only a few mild-to-moderate adverse reactions reported, and the overall incidence of adverse reactions was lower than in other studies examining the use of psilocybin.


The findings suggest that the use of psilocybin for the treatment of major depressive disorder is a safe and effective alternative for treating the symptoms of major depressive disorder.

Results reported sustained and clinically significant reductions in functional impairment and depressive symptoms, without serious adverse effects.

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