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.
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.