Meta-Analysis of Randomized Clinical Trials Show Psilocybin for Depression, Anxiety Has Tolerable Adverse Effects

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An analysis of randomized, double-blind clinical trials found that psilocybin has a manageable adverse effect (AE) profile in the treatment of depression and anxiety disorders. The study, published in JAMA Network Open, noted that clinical trials of psilocybin to date have sought to evaluate its efficacy in treating mental health conditions—for example showing an antidepressant benefit in patients with treatment-resistant depression—without a primary focus on safety.¹

This analysis is of importance given the progress toward an FDA approval of a psilocybin-based therapy for depression. The agency recently granted breakthrough therapy designation to the deuterated psilocybin analogue CYB003 based on Phase II trial data showing sustained improvements in depression symptoms after four months.²

“Clinical studies have focused on psilocybin efficacy, resulting in studies pooling and presenting aggregate results. One recent meta-analysis investigated psilocybin adverse effects as a secondary aim, using a dose-dependent approach focused on select adverse effects,” the study authors wrote. “However, these studies have not primarily focused on or explored the adverse effect profile of psilocybin in depth. Therefore, the purpose of this study was to summarize and examine the relative risk of acute adverse effects of therapeutic doses of psilocybin in patients with depression and anxiety.”¹

To conduct the meta-analysis, the researchers evaluated trials in which participants were administered psilocybin for major depressive disorder or depression associated with other related disorders, such as cancer-related anxiety and depression. The trials compared psilocybin with placebo or a comparator, such as niacin, escitalopram, or low-dose psilocybin. All of these trials evaluated AEs associated with psilocybin while treating depression and anxiety. The primary outcome was AEs of psilocybin at high and moderate doses compared with placebo, low-dose psilocybin, or other comparator for depression and/or anxiety.

“A summary of the acute adverse effects of psilocybin in treating depression and anxiety is needed for health care professionals to identify expected adverse effects and provide effective patient counseling,” the authors wrote. “This study focused on therapeutic doses to clarify the expected adverse effects in potential future practice.”¹

Overall, six studies met the inclusion criteria, which included a total sample of 528 participants, of whom approximately 51% were female with a median age of 39.8 years. There were seven AEs observed in multiple trials that were included in the analysis.

Among the identified AEs, headache, nausea, anxiety, dizziness, and elevated blood pressure reached the level of statistical significance; however, the authors advised caution in interpreting elevated blood pressure because of its heterogeneity, which they wrote suggests potential variability. Notably, psilocybin was not associated with an elevated risk of paranoia and transient thought disorder.

“Given the psilocybin mechanism of action, these adverse effects are expected as they are similar among serotonergic antidepressants,” the study authors wrote. “The adverse effects were also anticipated based on previous survey data from adult participants who ingested active doses of psilocybin mushrooms. Additionally, data on adverse effect severity appear to align with documented psychedelic adverse effects over the past 60 years or more.”¹

In terms of study limitations, the investigators noted that the meta-analysis was based on randomized controlled trials published only in English, which limits the sample sizes. Further, the analysis focused on acute AEs reported within the first 48 hours and less stringent with time. There was also limited recent research data addressing psychedelic AEs.

“Although infrequent, the possibility of suicidality, prolonged paranoia, and persistent visual perceptual effects should be monitored over the long term,” the study authors wrote. “The effectiveness of medications and alternative treatments in managing these symptoms requires further investigation. Additionally, the role of licensed therapists in managing adverse effects presents an avenue for future research.”¹

References

1. Yerubandi A, Thomas JE, Bhuiya NMMA, Harrington C, Villa Zapata L, Caballero J. Acute Adverse Effects of Therapeutic Doses of Psilocybin: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2024;7(4):e245960. doi:10.1001/jamanetworkopen.2024.5960

2. Cybin Receives FDA Breakthrough Therapy Designation for its Novel Psychedelic Molecule CYB003 and Announces Positive Four-Month Durability Data in Major Depressive Disorder. News Release. March 13, 2024. Accessed April 11, 2024. https://www.businesswire.com/news/home/20240313731043/en