Psilocybin and psilocin regulate microglial immunomodulation and support neuroplasticity via serotonergic and AhR signaling.

Psilocybin and its active metabolite psilocin suppress the pro-inflammatory cytokine TNF-α and increase levels of the neuroplasticity marker BDNF in activated microglia. These effects are mediated through 5-HT2A, 5-HT2B, 5-HT7, and TrkB signaling. AhR activation is required for psilocin-induced BDNF upregulation but not for TNF-α suppression. IL-10 levels remain unchanged under normal conditions but rise when serotonergic, TrkB, or AhR signaling is blocked, indicating a compensatory anti-inflammatory shift. The compounds promote a microglial phenotype that reduces inflammation and supports neuroplasticity via distinct receptor-specific pathways.

Study at a glance

Abstract

Psilocybin, a serotonergic psychedelic, has demonstrated therapeutic potential in neuropsychiatric disorders. While its neuroplastic and immunomodulatory effects are recognized, the underlying mechanisms remain unclear. This study investigates how psilocybin and its active metabolite, psilocin, influence microglial inflammatory responses and neurotrophic factor expression through serotonergic and AhR signaling. Using in vitro models of resting and LPS-activated microglia, we evaluated the effects of psilocybin and psilocin on the expression of pro-inflammatory cytokines (TNF-α), anti-inflammatory cytokines (IL-10), and neuroplasticity-related markers (BDNF). Receptor-specific contributions were assessed using selective antagonists for 5-HT2A, 5-HT2B, 5-HT7, TrkB, and AhR. Psilocybin and psilocin significantly suppressed TNF-α expression and increased BDNF levels in LPS-activated microglia. These effects were mediated by 5-HT2A, 5-HT2B, 5-HT7, and TrkB signaling, while AhR activation was required for psilocin-induced BDNF upregulation but not TNF-α suppression. IL-10 levels remained unchanged under normal conditions but increased significantly when serotonergic, TrkB, or AhR signaling was blocked, suggesting a compensatory shift in anti-inflammatory pathways. Psilocybin and psilocin promote a microglial phenotype that reduces inflammation and supports neuroplasticity via receptor-specific mechanisms. Their effects on TNF-α and BDNF depend on distinct serotonergic and neurotrophic pathways, with AhR playing a selective role in psilocin's action. These findings clarify the receptor-mediated dynamics of psilocybin's therapeutic effects and highlight alternative anti-inflammatory pathways that may be relevant for clinical applications.