Current Understanding on Psilocybin for Major Depressive Disorder: A Review Focusing on Clinical Trials

Psilocybin shows promise for treating depression and anxiety, with notable safety profiles. A review of eleven clinical trials—six open-label and five double-blinded randomized trials—found that psilocybin, a 5-HT2A receptor agonist, may reduce depressive symptoms by increasing glutamate transmission, reducing brain inflammation, and decreasing default mode network activity. In treatment-resistant depression, a pilot study reported significant symptom reductions after two sessions, with sustained improvements and high remission rates. Among cancer patients, two trials showed reductions in anxiety and depression lasting over six months. In major depressive disorder, psilocybin produced rapid depression reductions with higher remission rates than escitalopram. A dose-response trial found that 25 mg, but not 10 mg, was superior to 1 mg. Further research should explore optimal dosages and long-term effects.

Study at a glance

Abstract

Previous studies suggested effectiveness of psilocybin in the field of mental health. FDA designated psilocybin as a "breakthrough therapy" for the treatment of treatment-resistant depression (TRD) in 2018. This paper provided a review of psilocybin's potential role in treatment of depression by focusing on published clinical trials. Studies showed that psilocybin, an agonist on 5-HT2A receptors, manifests antidepressant and anxiolytic effects by increasing glutamate transmission, reducing brain inflammation, decreasing default mode network activity. In terms of clinical trials, eleven studies (six open-label and five double blinded randomized clinical trials [DB-RCTs]) trials exploring psilocybin's impact on depression were found. Among open-label studies, a pilot study on TRD patients demonstrated significant reductions in depressive symptoms after two psilocybin sessions. Psilocybin also improved cognitive bias associated with depression. Extension studies confirmed sustained improvements and high remission rates. Among five DB-RCTs, two showed that psilocybin led to significant reductions in anxiety and depression in cancer patients, and the improvements sustained for over six months. In MDD, psilocybin showed rapid reductions in depression, with higher remission rates compared to escitalopram in a DB-RCT. Another DB-RCT showed that psilocybin induced higher decrease in depression around 6 hours after their administrations than placebo. The last DB-RCT showed that in patients with TRD, a single dose of psilocybin 25 mg, but not psilocybin 10 mg, resulted in superior antidepressant effect than psilocybin 1 mg. Overall, psilocybin showed promise in treating depression and anxiety, with notable safety profiles. Further research should explore optimal dosages and long-term effects.