N-acetylcysteine for patients with alcohol use disorder, post-traumatic stress disorder, and their co-occurrence: a systematic review of placebo-controlled randomized trials

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INTRODUCTION: Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are thought to be significant global contributors to the burden of mental illness. According to recent WHO epidemiological estimates, 3.9% of people worldwide have experienced PTSD at some point in their lives; this number rises to roughly 5.6% among those who have experienced trauma. NAC has shown promise in reducing PTSD symptoms and cravings in veterans, according to recent trials. Our analysis aims to resolve the conflict between results and determine whether NAC is an effective add-on therapy for PTSD, AUD, and co-occurring PTSD/AUD. METHODS: We conducted this study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, following our protocol (CRD420251170956). We searched PubMed, Scopus, Cochrane CENTRAL, Embase, EBSCO, and the Web of Science for relevant studies. Only randomized placebo-controlled trials were included. The primary outcomes were severity of PTSD and alcohol craving, while secondary outcomes were anxiety, depression, and alcohol use patterns and biomarkers. RESULTS: Seven randomized, double-blind, placebo-controlled trials were included in this meta-analysis, enrolling a total of 566 participants. There were no significant differences between NAC and placebo in craving (SMD= -0.40, 95% CI [-1.05, 0.25], P = 0.22, I² = 56.1%). Regarding PTSD severity, the PCL scale pooled analysis demonstrated no significant difference between NAC and placebo (SMD = 0.04, 95% CI [-0.40, 0.48], P = 0.8) (I² = 65.9%, P = 0.05), while the CAPS scale pooled analysis demonstrated no significant difference between NAC and placebo (SMD = -0.13, 95% CI [-0.50, 0.24], P = 0.49) (I² = 54.8%, P = 0.109). Leave-one-out sensitivity analysis showed that exclusion of the Back et al. (2025) study resulted in a significant effect favoring NAC (SMD = -0.35, 95% CI [-0.70, -0.01], P = 0.04), with no observed heterogeneity (I² = 0%). CONCLUSION: Our meta-analysis indicates that N-acetylcysteine, when compared to placebo, does not demonstrate consistent efficacy in reducing the primary symptoms of AUD or PTSD in broad patient populations. However, the treatment is relatively safe. A noteworthy signal of potential efficacy for PTSD symptoms emerged in a sensitivity analysis, suggesting that the therapeutic promise of NAC should not be entirely dismissed. CLINICAL TRIAL NUMBER: Not applicable.

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