Groundbreaking research at the University of Pennsylvania demonstrates that a single dose of psilocybin, the psychoactive compound in psychedelic mushrooms, rapidly and sustainably alleviates pain hypersensitivity and anxiodepressive-like symptoms in mouse models of chronic pain. This work elucidates specific brain circuit modulation by psilocybin, mediated via serotonin receptor activity, and opens avenues for non-opioid alternatives to treat comorbid chronic pain and mood disorders, affecting millions worldwide.