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

Abstract

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.

Keywords: LSD; chronic pain; classic psychedelics; psilocybin; serotonin 5-HT2A receptors.

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Illustration of the pain transmission pathway with four stages of nociceptiontransduction, transmission, modulation, and perceptionwithin the ascending (blue) and descending (red) neural pathways. Peripheral nociceptors initiate transduction (I) by converting noxious mechanical, thermal, or chemical stimuli into electrical signals. The transmission (II) of these impulses occurs via primary afferent neurons to the spinal cord’s dorsal horn, subsequently reaching higher brain centers. The modulation (III) of nociceptive signals is achieved primarily through descending pathways originating in the brainstem (e.g., the periaqueductal gray (PAG) and rostroventral medulla (RVM)), where neurotransmittersserotonin, norepinephrine, and endogenous opioidsmediate either the enhancement or the suppression of nociceptive transmission. , Conscious pain perception (IV) arises from the cortical integration of nociceptive input with its emotional and cognitive context. , At multiple levels, particularly in modulation (III) and perception (IV), serotonergic activitymediated in part through 5-HT₂A receptor signalingcritically influences pain intensity and emotional perception. Created with BioRender.

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Diagram illustrates the downstream signaling cascades initiated by LSD binding to 5-HT₂Rs and TrkB receptors. Created in BioRender.