IUPHAR Article: Psilocybin induces long-lasting effects via 5-HT2A receptors in mouse models of chronic pain

Chronic pain is a debilitating disease with current treatments lacking efficacy and safety, therefore discovery of new treatments is crucial. Initial studies suggest that psychedelics may be feasible for targeting pain, however clinical and preclinical controlled studies are necessary to further investigate that possibility. In this study we assessed the effects of two classical psychedelics psilocybin and 2,5-Dimethoxy-4-iodoamphetamine (DOI) in two models of chronic pain after systemic administration in male and female mice. Psilocybin and DOI dose-dependently reversed mechanical and cold hypersensitivity in the chemotherapy-induced peripheral neuropathy (CIPN) mouse model with different time-course of action. Similarly, psilocybin and DOI dose-dependently reversed thermal hypersensitivity in the chronic inflammatory mouse model of Complete Freud’s Adjuvant (CFA). The effects of Psilocybin and DOI in both models were mediated by activation of 5-HT2A receptors (5-HT2A R). Overall, the present study suggests that classical psychedelics psilocybin and DOI are effective in reducing pain-like behaviors via 5-HT2A R activation in two mouse models of chronic pain. • Classical psychedelics psilocybin and DOI dose-dependently reversed pain-like behaviors in two chronic pain mouse models. • In contrast to DOI, the effects of psilocybin in the two models of pain lasted for several days. • Both psilocybin and DOI are effective in reducing pain-like behaviors via 5-HT2AR mechanism.