Psilocybin ameliorates neuropathic pain-like behaviour in mice and facilitates gabapentin-mediated analgesia

Abstract Chronic pain states remain challenging to control with current drug therapies. Here, we demonstrate that a single dose of psilocybin produces a sustained anti-nociceptive effect in chronic neuropathic pain models in male and female mice, mediated primarily by 5-HT 2A receptors. Critically, psilocybin significantly potentiates the analgesic efficacy of gabapentin, a standard-of-care treatment, representing the first preclinical evidence that a psychedelic can serve as a pain-network primer for existing analgesics. This finding represents a novel therapeutic strategy with potential clinical application, particularly for the 30-50% of neuropathic pain patients who fail gabapentin monotherapy. Our data demonstrate that a single psilocybin injection produces sustained month-long changes that enhance gabapentin efficacy in a preclinical model of human pain. Together, these findings indicate that psilocybin both acutely enhances analgesia and induces lasting changes that amplify gabapentin efficacy weeks later. Such a translation is notable in chronic pain management, where most analgesics require chronic dosing and lose efficacy through tolerance. These findings establish psilocybin as a potential therapeutic addition for pain management by enabling longer-lasting changes in pain-processing networks and enhancing the utility of established treatments.