Psilocin, the Psychoactive Metabolite of Psilocybin, Modulates Select Neuroimmune Functions of Microglial Cells in a 5-HT2 Receptor-Dependent Manner

Psilocin, the active metabolite of psilocybin, can reduce certain inflammatory activities of microglia, the brain's immune cells, without affecting tumor necrosis factor secretion. In microglia-like cell lines, psilocin at non-toxic concentrations significantly inhibited phagocytosis, reactive oxygen species release, and nitric oxide production. These inhibitory effects on reactive oxygen species and nitric oxide were similar to those of selective 5-HT2R agonists 25I-NBOH and Ro60-0175, and were blocked by 5-HT2R antagonists cyproheptadine and risperidone, indicating the role of 5-HT2 receptors. Psilocin is suggested as a potential drug candidate for neuroimmune disorders like neurodegenerative diseases where reactive microglia contribute.

Study at a glance

Abstract

Neuroinflammation that is caused by microglia, the main immune cells of the brain, contributes to neurodegenerative diseases. Psychedelics, including psilocybin and lysergic acid diethylamide (LSD), possess certain anti-inflammatory properties and, therefore, should be considered as drug candidates for treating neuroinflammatory pathologies. When ingested, psilocybin is rapidly dephosphorylated to yield psilocin, which crosses the blood–brain barrier and exerts psychotropic activity by interacting with the 5-hydroxytryptamine 2A receptors (5-HT2ARs) on neurons. Since microglia express all three 5-HT2R isoforms, we hypothesized that, by interacting with these receptors, psilocin beneficially modulates select neuroimmune functions of microglia. We used microglia-like cell lines to demonstrate that psilocin, at non-toxic concentrations, did not affect the secretion of tumor necrosis factor (TNF) by immune-stimulated microglial cells, but significantly inhibited their phagocytic activity, the release of reactive oxygen species (ROS), and nitric oxide (NO) production. The inhibitory activity of psilocin on the latter two functions was similar to that of two selective 5-HT2R agonists, namely, 25I-NBOH and Ro60-0175. The role of this subfamily of receptors was further demonstrated by the application of 5-HT2R antagonists cyproheptadine and risperidone. Psilocin should be considered a novel drug candidate that might be effective in treating neuroimmune disorders, such as neurodegenerative diseases, where reactive microglia are significant contributors.