Therapeutic Effects of Low-Dose Psilocybin in Depression and Other Mental Disorders: A Systematic Review.

Introduction: High-dose psilocybin has shown potential in treating various psychiatric disorders, but its perceptual and cognitive effects, along with the risk of adverse events, highlight the need for alternative treatment approaches. One such approach is the use of low-dose psilocybin, which does not significantly alter cognition or perception. While low-dose psilocybin has garnered growing interest in the psychiatric community, its therapeutic efficacy remains unclear and warrants further investigation. This systematic review aims to evaluate the efficacy and safety of low-dose-whether in the form of microdosing or low-dose control conditions in clinical trials-psilocybin for mental disorders. Methods: We conducted a systematic review of all empirical evidence involving low-dose psilocybin in human subjects for psychiatric treatment from inception to June 2024. We also searched for relevant registered clinical trials on clinicaltrials.gov. Results: We identified five registered clinical trials and six publications, including randomized controlled trials (RCTs) (3, 50%), secondary outcome studies (2, 33%), and case report (1, 16%). Four studies (66%) included concurrent psychotherapy. Doses ranged from 1-3 mg per 70 kg as a single dose or 0.1-0.2 g of dried psilocybin-containing mushrooms every 3 days for up to 3 years. Two RCTs studied treatment-resistant depression with 1, 10, and 25 mg psilocybin doses. In the 1 mg group, 18% of participants showed a significant response, 8% achieved remission, and the Montgomery-Åsberg Depression Rating Scale score improved by -5.4 (95% confidence interval [CI]: -8.1 to -2.7) at week 3, though only 10% maintained this by week 12. Another study found transient improvements in anxiety and cognitive function with 1 mg. One trial reported no significant improvement with 1-3 mg doses, though 12% achieved anxiety remission and 16% depression remission. An RCT comparing 25 mg to 1 mg plus escitalopram found higher response rates with 25 mg than 1 mg group, although no significant difference in rumination or thought suppression between groups was observed. Conclusion: The empirical evidence for the efficacy of low-dose psilocybin in treating mental disorders is limited. The current research is constrained by a lack of well-designed studies that compare low-dose psilocybin to placebo. To better understand its potential, future research should include large, rigorous RCTs specifically focused on assessing low-dose protocols.