Exploring the Effects of Psilocybin on Depression and the Mediating Role of the 5-HT2A Receptor: A Systematic Review

Abstract Background: Major depressive disorder (MDD) is a significant public health concern, and current treatments often have limitations in effectiveness and adherence. Psilocybin, a psychedelic compound found in certain mushrooms, is being explored as a potential treatment for depression. It primarily acts through the serotonin 5-HT2A receptor but interacts with 5-HT1A and 5-HT2C receptors. Its precise mechanisms remain under investigation. Objectives: (1) To consolidate evidence on psilocybin’s efficacy and safety for depression, (2) to identify limitations in the literature, and (3) to highlight areas needing further research. Methods: This systematic review follows PRISMA guidelines and analyzes 20 studies, including randomized controlled trials (RCTs) and open-label studies. The studies cover various populations, including individuals with treatment-resistant depression, different dosing regimens, and adjunctive therapies. Results: Psilocybin therapy shows substantial and rapid antidepressant effects, often after one or two sessions with psychological support. Improvements are sustained for weeks or months in many cases. Psilocybin is generally well-tolerated, with mild adverse effects such as anxiety during administration and transient headaches, which are manageable in controlled settings . Conclusions: Psilocybin demonstrates promise as a novel treatment for depression, especially for individuals unresponsive to conventional antidepressants. Further research is needed to refine dosing, explore long-term effects, and understand its mechanisms of action.