The Effects of Psilocybin on Lipopolysaccharide-Induced Inflammation in THP-1 Human Macrophages

Psilocybin, a compound from Psilocybe mushrooms known for activating serotonin 5-HT2A receptors, reduces inflammation in immune cells. In laboratory experiments, human THP-1 monocytes were turned into macrophages and then stimulated with lipopolysaccharide (LPS) to trigger an inflammatory response, followed by adenosine triphosphate (ATP) to activate the NLRP3 inflammasome. Psilocybin exposure produced a dose-dependent inverse correlation with the production of proinflammatory cytokines and proteins. The compound likely mediates these anti-inflammatory effects by influencing key signaling pathways, including NF-κB, IL-6/TYK2/STAT3, and TYK2/STAT1.

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Abstract

Psilocybin, an innate compound produced by mushrooms belonging to the Psilocybe genus, is primarily known for its agonistic effects on the serotonin 5-HT2A receptor. This receptor’s functioning is involved in many neurological processes. In the context of this research, our primary aim was to comprehensively investigate the influence of psilocybin as a serotonin receptor agonist on the intricate cascade of events involved in THP-1 macrophages stimulated by lipopolysaccharide (LPS). THP-1 monocyte cells were subjected to differentiation into macrophages through a controlled incubation with phorbol 12-myristate 13-acetate (PMA). The next step involved the induction of an inflammatory response by exposing THP-1 macrophages to 500 ng/mL LPS for 4 h. Subsequently, we triggered the activation of the second phase of the NLRP3 inflammasome by introducing adenosine triphosphate (ATP) immediately following LPS stimulation. Our findings have revealed a dose-dependent inverse correlation between psilocybin exposure and the production of LPS-induced proinflammatory cytokines and proteins. Our work indicates that psilocybin likely mediates these responses by influencing key signaling pathways, including NF-κB, IL-6/TYK2/STAT3, and TYK2/STAT1.