Regarding “The molecular mechanisms through which psilocybin prevents suicide: evidence from network pharmacology and molecular docking analyses”

Psilocybin is a prodrug that is rapidly converted in the body to psilocin, the active compound responsible for its subjective and therapeutic effects. The authors of the reviewed manuscript used computational network pharmacology and molecular docking to investigate how psilocybin might prevent suicide, but they incorrectly treated psilocybin as the active agent. In humans, psilocybin's effects correlate with psilocin plasma concentration and serotonin 2A receptor occupancy, and cryo-EM structures of psilocin bound to that receptor are available. Therefore, discussing psilocybin's binding to proteins is nonsensical for understanding its therapeutic actions in humans.

Study at a glance

Abstract

Clinical investigations into the therapeutic actions of psilocybin have been the focus of much attention in recent years as duly cited in the manuscript.The authors of the present manuscript discuss potential targets through which psilocybin may help prevent suicide using computational network pharmacology coupled with molecular docking investigations.Unfortunately, the manuscript contains the following oversight: Psilocybin is rapidly converted to psilocin in plasmai.e., psilocybin is a prodrug of psilocin, see Fig. 1 [1].The acute subjective effects of psilocybin are correlated with the plasma concentration and serotonin 2 A receptor occupancy of psilocin [2] and the authors also reference this study in the manuscript (Reference 66).Therefore, any therapeutic effects elicited by psilocybin can be attributed to the active metabolite psilocin, and potentially the metabolites of psilocinnot psilocybin.Furthermore, CryoEM structures of Psilocin in complex with the serotonin 2 A receptor are also available [3].Thus, the discussion on the binding of psilocybin to various proteins in the present manuscript is nonsensical in the context of trying to shed light on the therapeutic effects of Psilocybin in humans.