LPS-Induced Liver Inflammation Is Inhibited by Psilocybin and Eugenol in Mice

<b>Background/Objectives:</b> Liver inflammatory diseases are a major global health burden and are often exacerbated by inflammation driven by lipopolysaccharides (LPS) through toll-like receptor 4 signaling. This study evaluates the anti-inflammatory effects of psilocybin and eugenol in an LPS-induced liver inflammation model in C57BL/6J mice. <b>Methods:</b> Mice were treated with psilocybin (0.88 mg/kg) and/or eugenol (17.59 mg/kg) either before (pre-treatment) or after (post-treatment) LPS injection. <b>Results:</b> Psilocybin and eugenol, individually and in combination, significantly reduced the LPS-induced mRNA levels of pro-inflammatory cytokines, with post-treatment administration exhibiting stronger effects than pre-treatment. Psilocybin alone displayed the most pronounced anti-inflammatory response, especially for <i>IL-1β</i>, <i>IL-6</i>, and <i>MCP-1</i>, while its combination with eugenol in 1:50 ratio demonstrated similar results, with strongly reduced <i>COX-2</i> and <i>TNF-α</i>. Histological analysis revealed improved nuclear circularity and reduced inflammatory infiltration in the treatment groups. Eugenol alone showed potential adverse effects, including increased <i>MCP-1</i> and <i>GM-CSF</i>, but this was mitigated by the co-administration of psilocybin. <b>Conclusions:</b> These findings highlight psilocybin and its combination with eugenol as promising therapies for hepatic inflammation, suggesting their application in treating acute and chronic liver diseases. Future research should explore their long-term effects, the mechanisms underlying their anti-inflammatory actions, and their therapeutic efficacy in humans.