Effect of N-Acetylcysteine on mortality in COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has prompted global interest in potential adjunctive therapies. N-acetylcysteine (NAC), a mucolytic agent that enhances intracellular glutathione synthesis, has antioxidant properties and may indirectly modulate inflammation through redox regulation. While preclinical and observational data suggest potential mortality benefits, findings from randomized controlled trials (RCTs) have been inconsistent. 

Objective: To systematically review and synthesize the evidence from RCTs evaluating the effect of NAC on mortality in patients with COVID-19. 

Methods: This systematic review and meta-analysis was conducted according to PRISMA guidelines. Six databases were searched from inception to March 21, 2025. Eligible studies were RCTs comparing NAC to placebo or standard care in adult COVID-19 patients, with mortality as a reported outcome. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane RoB 2 tool. Statistical analyses were performed with a random-effects model to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). 

Results: Ten RCTs comprising 1,424 patients were included. NAC regimens varied by dose and route. The pooled OR for mortality was 0.49 (95% CI: 0.25–0.94; I² = 67%), indicating a 51% reduction in the odds of death among patients receiving NAC. Seven studies had low risk of bias; three had some concerns, primarily due to open-label designs. 

Conclusion: NAC may reduce mortality in COVID-19 patients, particularly when administered at higher doses or via non-oral routes. Further large-scale RCTs are needed to confirm these findings and establish optimal dosing and administration strategies.