Study Suggests Promise of Psilocybin in Treating Depressive Symptoms

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Several clinical trials have previously demonstrated the efficacy of psychedelics for patients with clinical depression, including psilocybin, lysergic acid diethylamide, and ayahuasca; and entactogens, such as 3,4-methylenedioxymethamphetamine (MDMA). However, concerns have arisen regarding overestimated effect sizes of psychedelics due to the issues of blinding and response expectancy in clinical trials. According to authors of a study published by The BMJ, only one double blind, head-to-head randomized controlled trial has directly compared a psychedelic drug (psilocybin) with an antidepressant drug (escitalopram) for patients with major depressive disorder.

In this study, the researchers aimed to assess the comparative efficacy and acceptability of oral monotherapy with psychedelics, such as psilocybin, LSD, MDMA, and ayahuasca as monotherapies, vs. escitalopram, a common SSRI antidepressant, for treating depressive symptoms. To find accurate results, the researchers implemented a search of the Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PsycINFO, ClinicalTrial.gov, and World Health Organization’s International Clinical Trials Registry Platform databases. Participants studied were adults over the age of 18 years with clinically diagnosed depression or life-threatening diagnoses and terminal illness with depressive symptoms; and adults with assessment of treatment response using standard, validated, and internationally recognized instruments, such as the Hamilton Depression Rating Scale (HAMD-17). The overall goal of the study was the change in depressive symptoms at the end of treatment compared with controls.¹

In total, data from 811 patients were included across 15 psychedelic trials and 1,968 patients were a part of five escitalopram trials.^1,2

Results found that high-dose psilocybin provided a superior reduction in depressive symptoms compared to both placebo and escitalopram, with improvements significantly exceeding the minimal important difference on the HAMD-17. Other psychedelics, such as ayahuasca, also showed favorable effects but were less consistent across all measures.

Additionally, the study found that psychedelics had a higher placebo response than antidepressant trials, possibly as a result of compromised blinding in psychedelic studies caused by the noticeable effects of these substances. Due to these findings, the researchers raised concerns about the reliability of some reported results in prior psychedelic trials, especially those without strong placebo control. The study was adjusted for this reason, and still indicated that psychedelics, particularly psilocybin, outperformed escitalopram.¹

“In patients with major depressive disorder, ayahuasca, low dose psilocybin, high dose psilocybin, escitalopram 10 mg, and escitalopram 20 mg were associated with greater effectiveness than the placebo response in antidepressant trials,” explained the study authors. “However, when compared with extremely low dose psilocybin, only high dose psilocybin was associated with better effectiveness; the standardized mean difference decreased from 0.38 (compared with placebo response in antidepressant trials) to 0.30 (compared with extremely low dose psilocybin). As such, the effectiveness of psilocybin should be considered with concomitant psychotherapeutic support in people with major depressive disorder. The effect size of high dose psilocybin was similar with antidepressant trials of patients with major depressive disorder showing a mean standardized mean difference of 0.3.”

Despite the study’s successful outcome, the authors acknowledged that there were a number of limitations. One of which was that the trial worked on extracting the acute effects of the interventions, with the long-term effects of psychedelics and escitalopram remain unclear. Additionally, the randomized control trial’s MDMA patients were predominantly diagnosed with post-traumatic stress disorder, while those in the rials on escitalopram were patients with major depressive disorder.¹

“Serotonergic psychedelics, especially high dose psilocybin, appeared to have the potential to treat depressive symptoms. However, study designs may have overestimated the efficacy of psychedelics. Our analysis suggested that the standardized mean difference of high dose psilocybin was similar to that of current antidepressant drugs, showing a small effect size. Improved blinding methods and standardized psychotherapies can help researchers to better estimate the efficacy of psychedelics for depressive symptoms and other psychiatric conditions,” concluded the authors of the study.

References

1. 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. June 20, 2024. Accessed August 22, 2024. https://www.bmj.com/content/386/bmj-2023-078607

2. New study provides further support for psilocybin’s potential to treat depressive symptoms. EurekAlert! August 21, 2024. Accessed August 22, 2024. https://www.eurekalert.org/news-releases/1055099