Classic Psychedelics for Chronic Pain: A Critical Review of the Literature and Practical Advice for Clinicians.

Chronic pain is common, costly, and for many, remains inadequately treated by existing pharmacologic and non-pharmacologic approaches. In parallel with growing dissatisfaction with conventional therapies, classic serotonergic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), ayahuasca, N,N-dimethyltryptamine (DMT), and mescaline, administered alone or within psychedelic-assisted therapy models, have re-emerged as potential therapeutic tools for a range of health conditions, including chronic pain. In this review, we examine putative mechanisms of action relevant to pain, including effects on neuroplasticity, inflammation, large-scale brain network dynamics, and higher-order psychological processes, such as pain acceptance and cognitive flexibility. We also briefly overview findings from relevant preclinical models for pain. We then summarize recent observational studies and early-phase clinical trials that highlight preliminary signals of benefit across multiple pain conditions, including fibromyalgia, migraine, cluster headache, and other chronic pain syndromes. In addition, we critically evaluate safety considerations, contraindications, drug-drug interactions, and key regulatory challenges that will shape both research and clinical implementation of psychedelics for chronic pain. Finally, we offer pragmatic guidance for clinicians to work more skillfully with patients choosing to use these substances on their own. Although the existing literature suggests mechanistic plausibility and promising preliminary outcomes, the field is limited by small sample sizes, functional unblinding, and a lack of large, well-controlled randomized trials. We conclude by outlining critical methodological priorities and future research directions needed to rigorously evaluate the potential role of psychedelic compounds in the treatment of chronic pain.