The endocannabinoid signaling system in acute and chronic pancreatitis.

Mabou Tagne A.; Jamarillo J.; McMahon L.; Piomelli D. · Frontiers in physiology · 2026

**Background & Methods** This is a narrative review examining the endocannabinoid system (ECS) in acute pancreatitis (AP) and chronic pancreatitis (CP). The authors synthesized current literature on ECS organization, function in pancreatic tissue, alterations during pancreatitis, and therapeutic opportunities for targeting ECS pathways in pancreatic disorders. **Key Findings** • Cannabinoid receptors and endocannabinoid-metabolizing enzymes are widely distributed throughout exocrine and endocrine pancreatic tissue, where they regulate pancreatic function under both normal and pathological conditions. AP and CP are associated with distinct alterations in cannabinoid receptor expression and endocannabinoid ligand levels, though the functional significance of these changes remains incompletely understood. • An emerging hypothesis suggests that adaptive endocannabinoid signaling may provide resilience following pancreatic injury, with progressive disruption of this protective response potentially contributing to progression from acute to chronic pancreatitis. This mechanism could explain the pathological transition between disease states. • Clinical evidence supporting therapeutic ECS modulation in pancreatitis remains limited and often conflicting. The review identifies ECS pathway targeting as a promising therapeutic opportunity, particularly relevant given increasing cannabis use among patients with pancreatic disorders and the critical need for alternatives to opioid-based pain management strategies. **Dosage & Administration** Not reported. This is a review article that does not present clinical dosing data or administration protocols for cannabis or cannabinoid-based interventions. **Safety & Adverse Effects** Not reported. The review does not provide detailed safety profiles or specific adverse effect data for ECS-targeting therapies in pancreatitis patients. **Evidence Quality** As a narrative review, this study represents a lower level of evidence (Level 4-5). The authors acknowledge significant limitations, including incomplete understanding of the functional significance of ECS changes in pancreatitis, limited and conflicting clinical evidence, and the preliminary nature of the adaptive signaling hypothesis. The review highlights a critical gap between basic science findings demonstrating ECS involvement and clinical evidence supporting therapeutic intervention. The conclusions are largely based on preclinical studies and mechanistic observations rather than robust clinical trials, indicating substantial opportunity for future research but caution regarding current therapeutic claims.

More recent cannabis research