New study provides further support for psilocybin’s potential to treat depressive symptoms

High doses of psilocybin, the active ingredient in magic mushrooms, appear to have a similar effect on depressive symptoms as escitalopram, a selective serotonin reuptake inhibitor (SSRI), suggests a systematic review and meta-analysis published in The BMJ Today.

The results show that patients treated with high-dose psilocybin showed better responses than those treated with placebo in antidepressant trials, although the effect size was small.

The researchers point out that flaws in study design may have overestimated the effectiveness of psychedelics, but say high-dose psilocybin “appears to have the potential to treat depressive symptoms.”

Psychedelic treatments have shown promise in reducing depressive symptoms. However, to date, only one randomized controlled trial has directly compared a psychedelic drug (psilocybin) to an antidepressant (escitalopram) in patients with major depressive disorder.

Additionally, the subjective effects of psychedelics can compromise blinding, leading to overestimation of treatment effects relative to placebo. Psychedelic treatment is also typically administered with psychological support, making it difficult to isolate the direct effects of psychedelics.

To try to answer these questions, the researchers searched scientific databases to identify randomized controlled trials published up to October 12, 2023, that evaluated the effects of psychedelics or escitalopram in adults with acute depressive symptoms.

To be eligible, psychedelic treatments (including MDMA, LSD, psilocybin, or ayahuasca) had to be administered orally without the use of additional antidepressants, while escitalopram trials had to compare at least two different oral doses (maximum 20 mg/day) with placebo. Trials directly comparing psychedelic therapy to escitalopram were also included.

A total of 811 people (mean age 42 years; 54% women) were included in 15 psychedelic trials and 1,968 people (mean age 39 years; 63% women) were included in five escitalopram trials.

Effect size was expressed as a standardized mean difference (0.2–0.5 indicates a small effect, 0.5–0.8 a moderate effect, and 0.8 or more a large effect).

The researchers found that placebo responses in the psychedelic trials were lower than in the escitalopram trials. As a result, while most psychedelics performed better than placebo in the psychedelic trials on the 17-item Hamilton Depression Rating Scale (HAMD-17), only high-dose psilocybin performed better than placebo in the escitalopram trials on the HAMD-17, showing a small effect size (standardized mean difference of 0.3), which is similar to that of current antidepressant medications.

None of the interventions was associated with a higher rate of serious adverse events (including death, hospital admission, or suicide attempt) or treatment discontinuation than placebo.

The authors acknowledge several limitations to the study, including that only the acute effects of the interventions were assessed and that the long-term effects of psychedelics and escitalopram remain unclear. The sample sizes of the psychedelic trials were small, they add, and the effects of high-dose psilocybin may have been slightly overestimated compared with other treatments.

Nevertheless, they conclude: “Serotonergic psychedelics, particularly high-dose psilocybin, appear to have the potential to treat depressive symptoms. Our analysis suggests that the standardized mean difference for high-dose psilocybin is similar to that of current antidepressants, showing a small effect size.”

They add: “Improved blinding methods and standardized psychotherapies may help researchers better estimate the efficacy of psychedelics for depressive symptoms and other psychiatric disorders.”