Approximately 5% of adults globally suffer from major depressive disorder, making it the leading cause of years lived with disability worldwide. This condition significantly impairs daily functioning, including work, social interactions, and self-care. Despite its high prevalence, a large treatment gap exists. A systematic review and meta-analysis published in The BMJ highlights the potential of high-dose psilocybin, the active compound in magic mushrooms, as a treatment for depressive symptoms, demonstrating effects comparable to the widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, escitalopram. While the results are promising, the study also points out certain limitations in current research that may affect the accuracy of these findings.
Psilocybin has gained attention for its potential therapeutic benefits in mental health, particularly in treating depression. It is a phosphorylated ester of its metabolite psilocin (4-OH-N,N-dimethyltryptamine) and is naturally found in the psychoactive mushrooms of the Psilocybe genus. Similar to other traditional psychedelics, psilocin primarily exerts its effects through agonism of serotonin 5-hydroxytryptamine type 2A (5-HT2A) receptors, a pathway implicated in depression. However, until now, only one randomized controlled trial has directly compared the efficacy of a psychedelic drug (psilocybin) with an antidepressant (escitalopram) in patients diagnosed with major depressive disorder. This lack of direct comparisons has made it challenging to draw definitive conclusions about the relative effectiveness of these treatments. To address this gap, researchers conducted an extensive search of scientific databases to identify relevant randomized controlled trials.
The inclusion criteria required that the studies assess the effects of serotonergic psychedelics (including MDMA, LSD, psilocybin, or ayahuasca) or escitalopram in adults experiencing acute depressive symptoms. Psychedelic treatments had to be administered orally without concurrent use of other antidepressants, while escitalopram trials needed to compare at least two different oral doses (up to a maximum of 20 mg/day) with a placebo. Trials that directly compared psychedelic therapy with escitalopram were also included.
The analysis included data from 811 participants (average age 42; 54% women) across 15 psychedelic trials and 1,968 participants (average age 39; 63% women) across five escitalopram trials. The findings revealed that high-dose psilocybin demonstrated a small but statistically significant effect on depressive symptoms, comparable to the effect of escitalopram. Notably, while most psychedelics outperformed placebos in psychedelic trials, only high-dose psilocybin showed a significant improvement over placebo in trials that used escitalopram as a comparator, as measured by the 17-item Hamilton Depression Rating Scale (HAMD-17). The SMD for high-dose psilocybin was 0.3, similar to that of current antidepressant drugs.
Despite these promising results, the researchers caution that several factors may have influenced the findings. For instance, placebo responses in psychedelic trials were generally lower than in escitalopram trials, which could have exaggerated the perceived effectiveness of psilocybin. Additionally, the subjective effects of psychedelic substances can compromise blinding in trials, potentially leading to an overestimation of treatment effects when compared to placebo. Furthermore, psychedelic treatment is typically accompanied by psychological support, making it difficult to isolate the direct effects of the drug itself.
The researchers also noted that the sample size for psychedelic trials was relatively small, and only the acute effects of the interventions were assessed. The long-term effects of both psilocybin and escitalopram remain unclear, and more extensive studies are needed to evaluate the sustained impact of these treatments.
In conclusion, the analysis suggests that serotonergic psychedelics, particularly high-dose psilocybin, have the potential to treat depressive symptoms with an effect size comparable to that of existing antidepressant medications. However, the study underscores the need for improved blinding methods and standardized psychotherapies to better estimate the true efficacy of psychedelics for depression and other psychiatric conditions.
References
- Hsu TW, Tsai CK, Kao YC, Thompson T, Carvalho AF, Yang FC, et al. Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis. BMJ. 2024 Aug 21;386:e078607.
- Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, et al. Trial of Psilocybin versus Escitalopram for Depression. New England Journal of Medicine. 2021 Apr 14;384(15):1402–11.
- Depressive disorder (depression) [Internet]. [cited 2024 Aug 22]. Available from: https://www.who.int/news-room/fact-sheets/detail/depression