Classic Psychedelics for Treating Chronic Pain: Mechanism and Clinical Translation

Abstract

Chronic pain is a complex disorder of central nervous system maladaptation, perpetuated not only by ascending nociceptive transmission but also by entrenched prior expectations. Conventional analgesics typically fail to reverse this cognitive rigidity and the ensuing pathological cycles. Classic psychedelics, however, are emerging as a promising avenue to help address this therapeutic impasse. This narrative review provides a comprehensive overview of the emerging science of psychedelics, encompassing their biological binding targets, potential neural mechanisms and clinical applications, in the context of chronic pain. We synthesize the therapeutic potential of classic psychedelics and critically examine the discrepancies between clinical outcomes and foundational mechanistic research. Furthermore, we evaluate key translational barriers, particularly compromised blinding and expectancy bias, and highlight the necessity for developing novel validation strategies. Ultimately, these new insights compel a fundamental rethinking of how biological neuroplasticity and subjective psychological experiences independently or synergistically drive analgesia, thereby offering a paradigm-shifting perspective for the translation of psychedelics into evidence-based analgesic therapeutics.