Psychedelic Therapies for Comorbid Major Depressive Disorder and Chronic Pain: A Review of Putative Mechanisms of Action.
Jordana Kazdan, Karim S Ladha, Muhammad Ishrat Husain
Pharmacology Research & Perspectives April 1, 2026 DOI: 10.1002/prp2.70238 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Peer reviewed |
|---|---|
| Topics | Depression LSD Psilocybin Psychedelic-assisted therapy |
| Keywords | Chronic pain Mood Psychedelics |
| Key findings | Psychedelics may target symptoms of both MDD and chronic pain through shared mechanisms including serotonergic modulation, anti-inflammatory effects, neuroplastic changes, and altered brain network dynamics. |
Abstract
Major Depressive Disorder (MDD) and chronic pain are independently debilitating conditions that frequently co-occur. 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-dimethyltryptamine (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-HT2A receptor, anti-inflammatory 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-assisted therapies for complex neuropsychiatric and medical conditions.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Psychedelics may target symptoms of both MDD and chronic pain through shared mechanisms including serotonergic modulation, anti-inflammatory effects, neuroplastic changes, and altered brain network dynamics.
Synthesized
Comparable studies
Other narrative reviews on LSD for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Registered clinical studies investigating psychedelic drugs for psychiatric disorders. Registered clinical trials on clinicaltrials.gov evaluating psychedelics for... | 2021 | Review | n = 70 |
| Top Ten Tips Palliative Care Clinicians Should Know About Psychedelic-Assisted Therapy in the Context of Serious Illness. Palliative care clinicians and patients | 2022 | Review | |
| Serotonergic psychedelics for depression: What do we know about neurobiological mechanisms of action? | 2023 | Narrative review | |
| Role of psilocybin in the treatment of depression | 2016 | Review |