Classic Psychedelics in Pain Modulation: Mechanisms, Clinical Evidence, and Future Perspectives.

Millions worldwide suffer from chronic pain, a complex condition often accompanied by depression and anxiety, highlighting the urgent need for innovative treatments. Classic psychedelics, including psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), primarily act on serotonin 5-HT_2A receptors and have emerged as potential modulators of pain perception and mood regulation. These substances may offer an alternative to conventional analgesics, such as opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), by influencing neuroplasticity, descending pain modulation pathways, and inflammatory processes. Evidence from case studies, preclinical research, and early phase clinical trials suggests that psychedelics may alleviate pain in conditions such as cluster headaches, migraines, fibromyalgia, and chronic pain syndromes. However, the exact mechanisms underlying their analgesic properties are yet to be fully understood. While psychedelics show promise in reshaping pain management strategies, rigorous randomized controlled trials are needed to establish their safety, efficacy, and optimal dosing. This review highlights the therapeutic potential of psychedelics for chronic pain and emphasizes the necessity of further research to validate their role in modern pain medicine.