P.0729 Highlights of psychedelic history and current research on psilocybin application for treatment of depression – a comprehensive literature review

Summary

Psilocybin, the active compound in psychedelic mushrooms, is being re-evaluated as a treatment for depression after decades of research hiatus. It mimics serotonin and alters brain connectivity, particularly reducing default mode network activity. Since 2011, five small clinical studies involving 139 patients found that 60% experienced significant symptom reduction (58-83%), though a recent trial showed no difference from a standard antidepressant. Over 50 studies are registered, including a phase 2 trial for treatment-resistant depression. The review highlights neurobiological mechanisms, safety concerns, and the need for rigorous future research.

Study at a glance

Abstract

Introduction: Psychedelics have seen various labels: mystical sacrament aids, potential interrogation tools for the Cold War, agents for social change in the Hippie counter movement, a panacea for various mental disorders, and a tool to “hack” of the psyche. This has led to their reputation as both societal threat and a psychopharmacological breakthrough. After the loss of data on over 1000 clinical papers spanning 40000 study subjects in the 60′s, a 40-year hiatus, and a few very determined researchers, new insights of increasingly quality have been emerging from research on the potential benefits of the use of psilocybin in depression. We aim to review available data on psilocybin for treating depression, providing a bird's-eye view on the literature (historical and current), while reporting potential neurobiological, psychological and cognitive mechanisms involved, safety and methodological concerns (as well as recent advancements), emerging modalities of treatment, with a commentary on social and cultural movements occurring in parallel to the scientific endeavor to create regulated and scientifically approved treatments. Methods: Eligible studies will be identified through an electronic search of Medline and clinicaltrials.gov from inception to the date of submission. The search strategy will combine relevant standardized subject terms and text words for psychedelics, psilocybin, and depression, with relevant Boolean operators implemented. Only articles written in the English language will be included. Reference lists from eligible studies will be cross-checked to identify potential additional studies. For data synthesis, results and outcomes will be explored narratively, along reporting and critical analysis of relevant statistical data. Results: Psilocybin emulates serotonin, with special affinity for the 5-HT2A receptor. Neuroimaging studies suggest an attenuation of the default mode network and an overall increase in multiple brain area connectivity [1]. Current treatment models involve previous psychological profiling and preparation, followed by one to two sessions where administration of 25 mg of psilocybin under supervision and support from the researcher, a physician, and a therapist, with post-treatment integration. Since 2011, five clinical studies, evaluated psilocybin treatment efficacy on patients suffering from clinical depression [2,3,4]. Limited by small samples, variability of setting, timeline, and methodology, they combined number of 139 patients. Despite these limitations, 60% of patients reported significant symptom reduction (58-83%) providing promising preliminary evidence for further investment. A recent trial found no significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients, further contributing to this trend of research [5]. Over 50 studies addressing effects of psilocybin in depression have been approved on clinicaltrials.gov. One of these [6] is a phase 2 multicentered clinical trial, aiming to further evaluate the safety and efficacy of psilocybin in treatment resistant depression in a variable dose range. Conclusion: Psilocybin might become a promising approach to depression. These therapies have been (re)gaining social and cultural support, with parallel “off label” use in various spiritual and psychotherapeutic settings. There is a need for the upmost rigor in designing future research. Psilocybin might emerge as an important therapeutic tool for current and upcoming global mental health challenges in a post-COVID-19 world. No conflict of interest

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