Endocannabinoid System in Sepsis: A Scoping Review

Sepsis is a life-threatening syndrome marked by a dysregulated host response to infection, resulting in systemic inflammation, organ dysfunction, and high mortality globally. Despite advancements in supportive care, effective immunomodulatory therapies remain elusive, necessitating exploration of novel biological pathways and subsequent therapeutic development. The endocannabinoid system (ECS), which regulates immune function and homeostasis, has emerged as a key modulator of immunological and metabolic pathways central to sepsis pathophysiology. The ECS mediates its effects through endogenous ligands, G-protein-coupled cannabinoid receptors (CB1 and CB1), and regulatory enzymes that control its synthesis and degradation. Following PRISMA-ScR guidelines, this scoping review synthesizes current evidence on the mechanistic roles of ECS components in experimental and clinical models of sepsis, identifies knowledge gaps, and delineates future areas of work. A comprehensive literature search across multiple databases without restrictions on date or publication type was executed to ensure broad coverage of original studies investigating ECS mechanisms and their intersection with sepsis and septic shock. Across 53 studies, CB2 receptor activation was consistently associated with anti-inflammatory process, organ-protective outcomes, and increased survival rates against septic challenges in preclinical rodent models. CB1 receptor activation trends, however, showed context dependent outcomes. Central antagonism improved hemodynamics and survival rate, but peripheral effects varied with cell type and timing. Non-canonical ECS components (TRPV1, GPR55, PPAR-α, FAAH, MAGL) also contributed to neuroimmune and metabolic regulation. Limited clinical data linked ECS lipid profiles and gene expression with sepsis severity and outcomes. Collectively, ECS modulation, particularly CB2 agonism, TRPV1 activation, and FAAH/MAGL inhibition, shows promise in mitigating sepsis-induced inflammation and organ dysfunction. However, complex, context-dependent effects, especially involving CB1, highlight the need for precision-targeted therapeutic approaches. Further preclinical research is needed to expand generalizable trends to allow translational research to refine ECS-based interventions for sepsis management.