Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain

Chronic pain and mood disorders co-occur, exacerbate one another and share neurobiological mechanisms, but whether a single intervention could promptly alleviate both conditions remains unclear. Here, in two chronic pain models, we show that a single dose of psilocybin induces a rapid and sustained reversal of both mechanical allodynia and anxiodepression-like states in adult male and female mice. Using local psilocin injections, the key active metabolite of psilocybin, we show that the engagement of prefrontal cortical circuits is critical for the concurrent alleviation of both conditions. Two-photon calcium imaging reveals that psilocin rapidly normalizes chronic pain-associated hyperactivity in anterior cingulate cortex layer 2/3 pyramidal neurons. Pharmacologic manipulations with full agonists of 5-HT2A and 5-HT1A receptors replicated some, but not all, of psilocin’s cellular and behavioral effects, suggesting that psilocin’s actions arise from partial agonism at these receptors within shared circuits governing pain and mood processing. Hammo et al. show that a single dose of psilocybin rapidly and sustainably relieves both chronic pain and anxiodepressive-like behaviors in mice by restoring prefrontal activity through partial agonism at 5-HT2A and 5-HT1A receptors.