Deciphering psilocybin: Cytotoxicity, anti-inflammatory effects, and mechanistic insights

Psilocybin and its active metabolite psilocin show different cytotoxic and immunomodulatory effects on mouse macrophages. Psilocybin is nearly twice as cytotoxic as psilocin, with LC50 values of 12 ng/ml and 28 ng/ml, respectively. In resting macrophages, both compounds triggered significant release of the pro-inflammatory cytokine TNF-α after 4 hours, with lower doses inducing higher levels than higher doses. Only the highest dose of psilocin increased the anti-inflammatory cytokine IL-10 in resting cells. In LPS-activated macrophages, psilocin reduced TNF-α more than psilocybin in both pre-treatment and post-treatment. Psilocin, but not psilocybin, significantly increased IL-10 in post-treatment, indicating that psilocin exerts anti-inflammatory effects on classically activated macrophages.

Study at a glance

Abstract

A decade of clinical research has indicated psilocybin's effectiveness in treating various neuropsychiatric disorders, such as depression and substance abuse. The correlation between increased pro-inflammatory cytokines and the severity of neuropsychiatric symptoms, along with the known anti-inflammatory potential of some psychedelics, suggests an immunomodulatory role for psilocybin. This study aims to understand the mechanism of action of psilocybin by investigating the cytotoxic and immunomodulatory effects of psilocybin and psilocin on both resting and LPS-activated RAW 264.7 murine macrophages. The study evaluated the cytotoxicity of psilocybin and psilocin using an LDH assay across various doses and assessed their impact on cytokine production in RAW 264.7 cells, measuring cytokine expression via ELISA. Different doses, including those above and below the LC50, were used in both pre-treatment and post-treatment approaches. The LDH assay revealed that psilocybin is almost twice as cytotoxic as psilocin, with an LC50 of 12 ng/ml and 28 ng/ml, respectively. In resting macrophages, both psilocybin and psilocin triggered significant release of TNF- α after 4 h, with the lowest doses inducing higher levels of the cytokine than the highest doses. IL-10 expression in resting cells was only triggered by the highest dose of psilocin in the 4-hour incubation group. In LPS-stimulated cells, psilocin reduced TNF- α levels more than psilocybin in pre-treatment and post-treatment, with no significant effects on IL-10 in pre-treatment. Psilocin, but not psilocybin, induced a significant increase of IL-10 in post-treatment, leading to the conclusion that psilocin, but not psilocybin, exerts anti-inflammatory effects on classically activated macrophages.