Endocannabinoid system modulators for abdominal pain in irritable bowel syndrome and inflammatory bowel disease: A systematic review of efficacy and safety.

Aim: To systematically review the benefits and harms of cannabis, cannabinoids, cannabis-based medicines, and other pharmacological endocannabinoid system (ECS) modulators for visceral abdominal pain in inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS). Methods: We included randomised controlled trials (RCTs) comparing ECS modulators with placebo or other interventions in IBD or IBS. We searched CENTRAL, MEDLINE (PubMed), EMBASE, WHO ICTRP and ClinicalTrials.gov (29/07/2025). Primary outcomes: proportions of participants with ≥30% and ≥50% reductions in pain intensity. Secondary outcomes: change in pain, physical or emotional functioning, quality of life, gastrointestinal health, and adverse events. We assessed risk of bias using Cochrane RoB-2 and certainty using GRADE. We synthesised findings narratively; due to insufficiently comparable data, meta-analysis was not possible. (PROSPERO: CRD42025616728). Results: We included 14 studies (796 participants). One study reported our primary outcome while all reported at least one secondary outcome. Palmitoylethanolamide + polydatin improved pain, symptom severity (moderate certainty) and emotional and physical functioning (low certainty) in IBS. THC and CBD showed benefits across pain, quality of life, emotional and physical functioning, and disease activity in IBD (low to very low certainty). Adverse events were predominantly mild-to-moderate; severe neurologic events were reported for CBD-dominant botanical extract. Risk of bias ranged from low to high. Conclusion: Evidence for ECS modulators in IBS or IBD visceral abdominal pain is heterogeneous with very low to moderate certainty, limiting conclusions regarding efficacy and safety. Larger, well-designed RCTs using clinically relevant pain outcomes are needed to inform therapeutic development.