The Cannabinoid System as a Potential Novel Target for Alcohol‐Associated Liver Disease: A Propensity‐Matched Cohort Study

Background Alcohol‐associated liver disease (ALD) is a leading cause of liver‐related morbidity and mortality, yet effective therapeutic options remain limited. Preclinical data suggest that modulation of the hepatic endocannabinoid system, particularly via cannabidiol (CBD), may reduce alcohol‐induced liver injury. Due to CBD's limited clinical use, we sought to evaluate the association between cannabis use and ALD risk among patients with alcohol use disorder (AUD). Methods Using the TriNetX US Collaborative Network, we identified adult patients with AUD between 2010 and 2022. Three cohorts were constructed: cannabis use disorder (CUD), cannabis users without cannabis abuse or dependence (CU) and non‐cannabis users (non‐CU). Outcomes included ALD, hepatic decompensation and composite all‐cause mortality over 3 years. Incidence and hazard ratios were calculated using Kaplan–Meier analysis and Cox regression. Results After matching, 33 114 patients were included in each of the CUD and non‐CU groups. Compared to non‐CU, CUD was associated with a lower risk of ALD (HR 0.60, 95% CI 0.53–0.67; p < 0.001), hepatic decompensation (HR 0.83, 95% CI 0.73–0.95; p =0.005) and all‐cause mortality (HR 0.86, 95% CI 0.80–0.94; p < 0.001) among individuals with AUD. Although CU was associated with lower risks of ALD, its risks of hepatic decompensation and all‐cause mortality were similar to those of the non‐CU cohort with AUD. Conclusion In this propensity‐matched cohort study of patients with AUD, cannabis use was associated with a reduced risk of ALD, with the greatest risk reduction seen in patients with CUD compared to CU and non‐CU. Our findings suggest that modulation of cannabinoid receptors may offer a new target for the development of pharmacological therapies for ALD.