Multiple treatments for treatment-resistant depression, from brain stimulation to ketamine to psychedelics, may all work in part by modulating the endocannabinoid system, positioning it as a unifying therapeutic target.
People interested in the neuroscience of depression treatment, and anyone following endocannabinoid system research.
Multiple TRD treatments all modulate the endocannabinoid system
What the researchers found
This review synthesizes evidence that diverse non-monoaminergic treatments for treatment-resistant depression all influence the endocannabinoid system. Brain stimulation (rTMS, ECT) elevates anandamide and 2-AG levels, correlating with clinical improvement. Ketamine and esketamine modulate CB1 receptors. Psilocybin restores 2-AG and enhances CB1 expression in mood-related brain regions, while LSD affects the broader endocannabinoidome in the prefrontal cortex and hippocampus.
Why it matters
Treatment-resistant depression affects roughly a third of people with depression. Understanding why very different treatments (electrical stimulation, ketamine, psychedelics) can all be effective could lead to better-targeted therapies. The endocannabinoid system may be the common thread connecting these diverse approaches.
The numbers in context
Approximately one-third of depression patients are treatment-resistant. The review covers rTMS, ECT, ketamine, esketamine, psilocybin, and LSD, all showing ECS modulation.
How the study worked
Narrative review drawing from preclinical and clinical literature on the endocannabinoid system's role in depression and its involvement in non-monoaminergic treatments effective for treatment-resistant depression.
What this study cannot tell us
Narrative review, not systematic. Much of the ECS evidence comes from preclinical models. The causal direction is not established. Limited human data on ECS biomarkers during treatment.
How to read the evidence
Moderate: synthesizes substantial preclinical and some clinical evidence, but narrative rather than systematic approach.
When this study was published
Published in 2025.
The bigger picture
If the endocannabinoid system truly serves as a shared pathway for multiple antidepressant treatments, it could shift how treatment-resistant depression is understood and treated. Rather than trying different medications hoping one works, clinicians might eventually target ECS function directly.
Questions still open
- Could direct ECS-targeting drugs treat depression more effectively than current options?
- Do individual differences in ECS function predict which treatment-resistant patients respond to which treatments?
- Would combining ECS-targeted approaches with existing treatments improve outcomes?
Common questions
Is the endocannabinoid system involved in depression?
Could cannabis-based treatments help with treatment-resistant depression?
Read the original research
Endocannabinoids, depression, and treatment resistance: Perspectives on effective therapeutic interventions.
Psychiatry research, 352, 116697
Citation
Rosa, Ilenia; Padula, Lorenzo Pio; Semeraro, Francesco; Marrangone, Carlotta; Inserra, Antonio; De Risio, Luisa; Boffa, Marta; Zoratto, Francesca; Borgi, Marta; Guidotti, Roberto; Lorenzo, Giorgio Di; D'Addario, Claudio; Pettorruso, Mauro; Martinotti, Giovanni. (2025). Endocannabinoids, depression, and treatment resistance: Perspectives on effective therapeutic interventions.. Psychiatry research, 352, 116697. https://doi.org/10.1016/j.psychres.2025.116697
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