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

Abstract

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.