Psilocybin as a lead candidate molecule in preclinical therapeutic studies of psychiatric disorders: A systematic review

Psilocybin is the main psychoactive compound found in hallucinogenic/magic mushrooms and can bind to both serotonergic and tropomyosin receptor kinase b (TrkB) receptors. Psilocybin has begun to show efficacy for a range of neuropsychiatric conditions, including treatment‐resistant depression and anxiety disorders; however, neurobiological mechanisms are still being elucidated. Clinical research has found that psilocybin can alter functional connectivity patterns in human brains, which is often associated with therapeutic outcomes. However, preclinical research affords the opportunity to assess the potential cellular mechanisms by which psilocybin may exert its therapeutic effects. Preclinical rodent models can also facilitate a more tightly controlled experimental context and minimise placebo effects. Furthermore, where there is a rationale, preclinical researchers can investigate psilocybin administration in neuropsychiatric conditions that have not yet been researched clinically. As a result, we have systematically reviewed the knowledge base, identifying 82 preclinical studies which were screened based on specific criteria. This resulted in the exclusion of 44 articles, with 34 articles being included in the main review and another 2 articles included as Supporting Information materials. We found that psilocybin shows promise as a lead candidate molecule for treating a variety of neuropsychiatric conditions, albeit showing the most efficacy for depression. We discuss the experimental findings, and identify possible mechanisms whereby psilocybin could invoke therapeutic changes. Furthermore, we critically evaluate the between‐study heterogeneity and possible future research avenues. Our review suggests that preclinical rodent models can provide valid and translatable tools for researching novel psilocybin‐induced molecular and cellular mechanisms, and therapeutic outcomes. We conducted a literature review to assess the mechanisms, efficacy and therapeutic value of psilocybin, with a focus on the peer‐reviewed preclinical literature. As a result, we identified 35 papers based on our search criteria. Psilocybin seems to display the most efficacy for depressive‐like and anxiety‐like behaviours, but also shows considerable therapeutic value for compulsive‐spectrum and fear‐related disorders. Psilocybin seems to exert its therapeutic effects by altering functional connectivity patterns and modulating neuroplasticity (including associated molecular and cellul