Kaden L. Venugopal https://orcid.org/0000-0002-2519-9381


Introduction: Major depressive disorder (MDD) is a prevalent and complex mood disorder. Its psychotherapies often involve delayed treatment-response times, while its pharmacotherapies can cause unwanted side effects. In recent years, there has been a resurgence in psychedelic research with a specific interest in the potential of psilocybin for treating MDD. Therefore, this systematic review was performed to evaluate the effectiveness of psilocybin therapy at moderate (15±5 mg/70 kg) to high (25 ± 5 mg/70 kg) doses in the psychiatric treatment of MDD.

Methods: The review included a literature search using PubMed (Medline), SCOPUS, Web of Science, and Medline (Ovid) databases from January 1, 2013, to February 28, 2023. Seven studies were included following the inclusion and exclusion criteria (e.g., moderate to high dosing psilocybin treatment, peer-reviewed, moderate to severe depression, control/delayed treatment groups, and non-directive therapy during psilocybin sessions). Studies were excluded using PRISMA guidelines and appraised using the Critical Appraisal Skills Programme checklists.

Results: The primary outcomes assessed included changes in depression scores on validated diagnostic tools and secondary outcomes that supported depression remission (e.g., improved well-being and rumination scores, and decreased anxiety scores). Psilocybin was found to reduce depression symptoms in moderate single-dose contexts and have minimal reported side effects at high doses. A positive relationship was observed between the quality of psilocybin-induced experiences and the reduction in depressive symptoms. Additionally, a dose-response relationship was found between moderate (15±5 mg/70 kg) and high-dose psilocybin (25 ± 5 mg/70 kg), with greater improvements generally seen in higher dose conditions.

Discussion: This review suggests that psilocybin can be an effective treatment option for MDD. Psilocybin shows meaningful improvements in depression scores with the potential to treat psychiatric conditions concurrent to depression. The non-directive therapy approach during high-dose sessions enabled unique psychedelic and personal experiences, potentially allowing more profound and individualized therapy. Reported side effects were minimal, and suggestions for future studies are provided.

Conclusion: Psilocybin therapy was found to reduce depression levels and improve secondary outcomes that support depression remission, indicating efficacy for MDD and other depressive conditions. Despite seeming promising, further research is required before introducing PAP options to...

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