Psychedelic Therapies for Comorbid Major Depressive Disorder and Chronic Pain: A Review of Putative Mechanisms of Action

The review article by Kazdan, Ladha, and Husain (2026), published in Pharmacology Research & Perspectives, addresses the clinical challenge of comorbid Major Depressive Disorder (MDD) and chronic pain.

This review article by Kazdan, Ladha, and Husain (2026), published in Pharmacology Research & Perspectives, addresses the clinical challenge of comorbid Major Depressive Disorder (MDD) and chronic pain. Since these conditions frequently co-occur and exacerbate one another, the authors propose that serotonergic psychedelics (such as psilocybin, LSD, and DMT) may serve as a "unified therapeutic approach" by targeting shared underlying pathways.

The review synthesizes evidence across several biological and psychological domains to explain how a single treatment protocol might alleviate both physical pain and depressive symptoms:

Serotonergic Modulation (5-HT2A Agonism): Psychedelics primarily act on the 5-HT2A receptor. The authors highlight that these receptors are densely located in brain regions responsible for both mood regulation and the "affective dimension" of pain (how much the pain bothers the patient, rather than just the intensity).

Neuroplasticity and TrkB Signaling: The review notes that psychedelics like LSD and psilocin bind to TrkB receptors (the target for Brain-Derived Neurotrophic Factor, or BDNF) with high affinity. This promotes rapid synaptogenesis and dendritic growth, potentially "rewiring" maladaptive pathways formed by chronic pain and long-term depression.

Anti-Inflammatory Effects: Psychedelics have demonstrated potent peripheral and central anti-inflammatory properties. By reducing pro-inflammatory cytokines (e.g., TNF-α, IL-6), they may address the "neuroinflammation" that drives both central sensitization in chronic pain and the biological "sickness behavior" seen in MDD.

Network Dynamics (DMN Disruption): The authors discuss the role of the Default Mode Network (DMN), which is typically overactive in both depressive rumination and chronic pain "self-focus." Psychedelics acutely disrupt this network, potentially allowing for a "reset" of the rigid neural patterns associated with the two conditions.

Psychological Flexibility: Beyond biology, the review emphasizes that the psychedelic experience facilitates cognitive reappraisal. Patients often report moving from a state of "pain resistance" to "pain acceptance," which reduces the psychological burden and disability associated with the comorbidity.

It is worth noting limitations of this review including fragmented evidence base, role of set and setting and Mechanistic Overlap vs. Causality: While shared pathways (like BDNF or DMN activity) are involved in both conditions, it remains unclear if treating one condition leads to the improvement of the other, or if the drug acts independently on both simultaneously.

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.”

Kazdan, J., Ladha, K. S., & Husain, M. I. (2026). Psychedelic Therapies for Comorbid Major Depressive Disorder and Chronic Pain: A Review of Putative Mechanisms of Action. Pharmacology Research & Perspectives, 14(2), e70238. Read Paper

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