Abstract
OBJECTIVE: The aim of this study was to evaluate the efficacy of N-acetylcysteine, compared to placebo, in reducing alcohol use among treatment-seeking adolescents and young adults with alcohol use disorder (AUD). METHOD: Between March 2019 and February 2024, a fully powered, double-blind, parallel, randomized, placebo-controlled, intent-to-treat clinical trial was conducted in an outpatient setting among treatment-seeking young people 15 to 25 years of age who met criteria for AUD. Participants (N = 126; mean [SD] age, 21.0 [2.4] years; 78 [62%] female) were randomized in a 1:1 ratio to an 8-week course of 2,400 mg/day (administered as 1,200 mg twice daily) of N-acetylcysteine (n = 65) or placebo (n = 61) and were followed for 6 months total. All participants received weekly clinician-led alcohol intervention sessions, including elements of motivational interviewing and goal setting. Adverse events were assessed by the medical clinician, and medication adherence videos were observed asynchronously by study staff to confirm medication taking. The primary efficacy endpoint was reduction in alcohol use (total standard drinks during the last 4 weeks of treatment), compared between the N-acetylcysteine and placebo groups. Secondary outcomes included number of drinking days, heavy drinking days, and drinks per drinking day during the last 4 weeks of treatment. RESULTS: Video-confirmed medication adherence (overall, 82.7%) and rates of adverse events did not differ between groups. There were no overall differences in primary or secondary alcohol use outcomes between participants in the N-acetylcysteine versus placebo group (primary efficacy endpoint: 37.9 [SE = 3.8] standard drinks over the last 4 weeks of treatment in the N-acetylcysteine group vs 42.6 [6.3] in the placebo group; risk ratio = 1.19, 95% CI = 0.89, 1.61, p = .24); however, baseline AUD severity modified treatment efficacy. In participants with moderate to severe AUD, N-acetylcysteine significantly reduced alcohol consumption compared to placebo (31.7 vs 44.4 standard drinks over the last 4 weeks of treatment, p = .01) but not frequency of alcohol use. In participants with mild AUD, N-acetylcysteine did not significantly reduce alcohol use compared to placebo. CONCLUSION: N-acetylcysteine may be a useful adjunctive treatment for moderate to severe AUD, but it is potentially less suitable for mild cases. In exploratory analyses, N-acetylcysteine was effective in reducing alcohol consumption among youth with moderate to severe AUD, but not among those with mild AUD; nor was there an effect on frequency of alcohol use for any group. This could be especially relevant for adolescents, who typically drink less often than adults but tend to consume larger amounts of alcohol when they do drink; thus, changes in alcohol consumption may be more impactful than changes in frequency. These findings highlight the importance of considering AUD severity in both clinical treatment planning and the design of youth AUD trials. Because individuals with more severe AUD are the most likely to seek treatment, trials may consider oversampling youth with moderate to severe AUD to improve the relevance and effectiveness of interventions. Future studies should consider similar stratified approaches to evaluate other potential treatments for adolescents and young adults with AUD. CLINICAL TRIAL REGISTRATION INFORMATION: N-Acetylcysteine for Adolescent Alcohol Use Disorder; https://clinicaltrials.gov/study/NCT03707951.