Endocannabinoid Signaling and Mood Regulation.
Aditya Rayasam, Cecilia J. Hillard
The Annual Review of Pharmacology and Toxicology October 12, 2026 DOI: 10.1146/annurev-pharmtox-052825-085837 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Key findings | Preclinical and healthy-human evidence largely indicates that endocannabinoid signaling dampens acute stress responses and that enhanced endocannabinoid tone can reduce chronic-stress effects on avoidance and anhedonia. However, FAAH inhibitors have largely failed to demonstrate efficacy and CB1 receptor agonists show only modest effects in mood disorders; the authors argue that closing the gap between model systems and patients is needed to advance therapeutic potential. |
Abstract
The endocannabinoid (eCB) signaling system is a local regulator of synaptic activity across brain circuits involved in the regulation of emotional behaviors. Preclinical studies predominantly show that eCB signaling dampens acute stress responses, although notable exceptions exist. Various forms of chronic stress downregulate eCB signaling, and enhanced eCB tone can reduce the effects of chronic stress on avoidance behaviors and anhedonia. Studies in healthy humans generally align with these preclinical findings. Type 1 cannabinoid receptors (CB1Rs) and fatty acid amide hydrolase (FAAH), the enzyme that degrades the eCB N-arachidonoylethanolamine (AEA), are present in circuits that regulate emotion, and pharmacological and genetic manipulations of these proteins affect anxiety, stress responses, and reward. However, FAAH inhibitors have largely failed to demonstrate efficacy, and CB1R agonists have only modest effects in individuals with mood disorders. Advancing the therapeutic potential of CB1R/eCB signaling likely will require a deeper understanding of the factors contributing to inconsistencies between model systems and individuals with mood disorders.