| Summary: | Psilocybin-containing mushrooms, commonly known as magic mushrooms, have been used since ancient and recent times for depression and to improve quality of life. However, their anti-inflammatory properties are not known. The study aims at investing cytotoxicity; antioxidant; and, for the first time, anti-inflammatory effects of <i>Psilocybe natalensis</i>, a psilocybin-containing mushroom that grows in South Africa, on lipopolysaccharide-induced RAW 264.7 macrophages. Macrophage cells were stimulated with lipopolysaccharide and treated with different concentrations of <i>Psilocybe natalensis</i> mushroom extracted with boiling hot water, cold water and ethanol over 24 h. Quercetin and N-nitro-L-arginine methyl ester were used as positive controls. Effects of extracts on the lipopolysaccharide-induced nitric oxide, prostaglandin E<sub>2</sub>, and cytokine activities were investigated. Phytochemical analysis, and the antioxidant and cytotoxicity of extracts, were determined. Results showed that the three extracts inhibited the lipopolysaccharide-induced nitric oxide, prostaglandin E<sub>2</sub>, and interleukin 1β cytokine production significantly in a dose-dependent manner close to that of the positive controls. A study proposed that ethanol and water extracts of <i>Psilocybe natalensis</i> mushroom were safe at concentrations used, and have antioxidant and anti-inflammatory effects. Phytochemical analysis confirmed the presence of natural antioxidant and anti-inflammatory compounds in the mushroom extracts.
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