Psychedelic Therapies for Comorbid Major Depressive Disorder and Chronic Pain: A Review of Putative Mechanisms of Action.
Pharmacology research & perspectives April 1, 2026 Jordana Kazdan, Karim S. Ladha, M. Ishrat Husain
Major Depressive Disorder and chronic pain often co-occur, worsening symptoms and prognosis, yet treatments typically address each condition separately. Serotonergic psychedelics like psilocybin, DMT, and LSD show promise for both depression and pain. This narrative review examines mechanisms—including 5-HT2A receptor modulation, anti-inflammatory effects, neuroplasticity, altered brain network dynamics, and psychological influences—that could target both conditions simultaneously. The authors argue that existing evidence supports psychedelics as a unified therapeutic approach for comorbid MDD and chronic pain, providing a rationale for future clinical trials.