• Giovanni Addolorato, Hannu Alho, Paula Bresciani M De Andrade, Otto Michael Lesch, Lei Liu, and Bankole Johnson.
• Department of Medical and Surgical Sciences, Università Cattolica di Roma, Rome, Italy; Internal Medicine and Alcohol Related Disease Unit, Columbus-Gemelli Hospital, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Electronic address: giovanni.addolorato@unicatt.it.
• Eur. J. Intern. Med. 2024 Sep 1; 127: 434943-49.

BackgroundThe increasing prevalence of alcohol use disorder (AUD) and the parallel surge in alcohol-associated liver disease (ALD) emphasize the urgent need for comprehensive alcohol management strategies. Low-dose ondansetron (AD04, a 5-HT3 antagonist) was shown recently to be a promising treatment for AUD with a specific genotypic profile (5-marker). The liver safety of AD04 has never been evaluated in subjects with AUD. The aim of the present study was to assess the liver safety profile of AD04 compared with placebo in subjects with AUD.MethodsLiver biochemical parameters were assessed in subjects with AUD with a 5-marker genetic profile who participated in a Phase 3 randomized controlled trial and received either twice-daily, low-dose AD04 (ondansetron 0.33 mg twice daily) or matching placebo, combined with brief psychosocial counseling. ALT, AST, GGT, Serum Bilirubin, MCV, and Prothrombin were evaluated at weeks 0, 12, and 24. Adverse cardiac events, general well-being, and study completion were also assessed.ResultsLow-dose AD04 did not significantly change biochemical markers of liver injury, such as ALT, AST, and Serum Bilirubin. While patients with AUD displayed elevated GGT levels, typically associated with increased alcohol consumption, this parameter remained unaffected by low-dose AD04. Notably, no significant adverse effects were observed due to oral low-dose AD04 treatment.ConclusionsLow-dose AD04 has the potential to be a safe treatment option for subjects with AUD and ALD, indicating the need for an RCT for this specific cohort. Such a trial would pave the way for the design of a precision treatment for combined AUD with ALD.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

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