No evidence of immediate or persistent analgesic effect from a single dose of psilocybin in three mouse models of pain

The psychedelic psilocybin may have lasting therapeutic effects for patients with chronic pain syndromes. Some preclinical data suggest these putative benefits derive from direct analgesic effects; however, this possibility has not been comprehensively tested in preclinical models. Here, we evaluated the analgesic properties of a single exposure to psilocybin at acute and chronic time points in Complete Freund's Adjuvant-induced inflammatory pain, spared nerve injury model of neuropathic pain, and acid-induced muscle pain. Across these models, we tested a range of doses (0.3, 2, and 10 mg/kg i.p.) in male and female mice using multiple behavioral assays evaluating sensory aspects (von Frey, cold plate, Hargreaves, thermal place preference, and muscle withdrawal threshold) and functional aspects of pain (marble burying). We further tested the effects of psilocybin on the affective dimension of pain in a surgical model of acute pain (mouse grimace scale). Except for cold sensitivity, we found no effect of psilocybin across pain models, behavioral assays, drug doses, or sex. The apparent reduction in cold sensitivity may be explained by profound hypothermia induced by psilocybin rather than true analgesia.