Intravenous psilocybin administration attenuates mechanical hypersensitivity in a rat model of chronic pain

Abstract There is a renewed interest in the therapeutic potential of psychedelics, including psilocybin, in treating mental health disorders. However, there are no data on the efficacy of psilocybin in alleviating chronic pain. In this study, we investigated the effect of psilocybin on mechanical hypersensitivity and thermal hyperalgesia in a rat model of formalin-induced chronic pain. Adult male and female rats were surgically implanted with a jugular vein catheter for psilocybin or saline administration. After two weeks of post-surgical recovery and conditioning, baseline responses to mechanical (von Frey assay) and thermal (hot plate assay) stimuli were measured. Twenty-four hours after baseline measurements, rats received a subcutaneous injection of formalin (5%, 50µL) into one of the hind paws and 2h later, responses to the mechanical and thermal stimuli were measured. Twenty-four hours after formalin injection, rats received an intravenous bolus of 1 mg/kg psilocybin (n=14) or 10 mg/kg psilocybin (n=12) or saline (n=13), and approximately 3h later, responses to the mechanical and thermal stimuli were measured. Rats were tested every other day during week 1, and then weekly for the next 3 weeks. Formalin injection induced thermal hyperalgesia and bilateral mechanical hypersensitivity in the hind paws of all rats. Intravenous psilocybin produced significant attenuation (p<0.05) of the formalin-induced bilateral mechanical hypersensitivity for 28 days but had limited effect (p<0.05 only on days 1, 3, 5, and 21) on thermal hyperalgesia. These data demonstrate that a single intravenous bolus of psilocybin can attenuate indices of chronic pain in a rat model.