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This comorbidity poses a significant clinical challenge, resulting in greater symptom severity, higher disability, and worse prognosis than either condition alone. Current therapies often address each disorder in isolation, leaving individuals with comorbid MDD and chronic pain underserved. Serotonergic psychedelics such as psilocybin, N,N\u2010dimethyltryptamine (DMT), and Lysergic Acid Diethylamide (LSD) have reemerged as promising therapeutic targets for a range of neuropsychiatric disorders. When combined with psychological support, psychedelics show rapid and sustained antidepressant potential, and preliminary evidence supports analgesic effects. Despite substantial overlap in the biological and psychological processes underlying MDD and chronic pain, research on psychedelics for this comorbidity remains largely unexplored. This narrative review examines putative mechanisms through which psychedelics target symptoms of both MDD and chronic pain. Mechanisms considered include serotonergic modulation via the 5\u2010HT2A receptor, anti\u2010inflammatory effects, neuroplastic changes, altered brain network dynamics, psychological effects, and the influence of set and setting. While most existing evidence comes from populations with either depression or pain alone, the breadth of proposed mechanisms supports psychedelics as a unified therapeutic approach for comorbid MDD and chronic pain. This review provides a compelling rationale for future clinical trials to evaluate psychedelic\u2010assisted therapies for complex neuropsychiatric and medical conditions.<\/jats:p>","DOI":"10.1002\/prp2.70238","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T14:50:28Z","timestamp":1775487028000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Psychedelic Therapies for Comorbid Major Depressive Disorder and Chronic Pain: A Review of Putative Mechanisms of Action"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7158-6438","authenticated-orcid":false,"given":"Jordana","family":"Kazdan","sequence":"first","affiliation":[{"name":"Temerty Centre for Therapeutic Brain Intervention Centre for Addiction and Mental Health  Toronto Ontario Canada"},{"name":"Pharmacology and Toxicology, Temerty Faculty of Medicine University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim S.","family":"Ladha","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine University of Toronto  Toronto Ontario Canada"},{"name":"Department of Anesthesia Women's College Hospital  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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