Systematic review of N-acetylcysteine as an adjunct therapy in acute stroke: Clinical outcomes, biomarker modulation, and safety

Context: Oxidative stress and neuroinflammation contribute significantly to acute stroke pathophysiology. N-acetylcysteine (NAC), a thiol-containing antioxidant and glutathione precursor, exhibits neuroprotective effects in preclinical models. However, its clinical efficacy remains unclear. Aims: To systematically evaluate the efficacy and safety of NAC as an adjunct therapy in acute stroke, focusing on neurological outcomes, biomarker modulation, and tolerability. Methods: A PRISMA-guided search of PubMed, Scopus, ScienceDirect, Google Scholar, and Cochrane Library identified randomized controlled trials (RCTs) of NAC in ischemic or hemorrhagic stroke (2013–2025). Risk of bias was assessed using the Cochrane RoB 2.0 tool. Results: Five RCTs involving 408 patients were included. NAC improved early NIH Stroke Scale (NIHSS) scores in four trials, particularly with intravenous or selenium-combined formulations. Biomarker studies reported reduced oxidative (MDA, TOS) and inflammatory markers (IL-6, ICAM-1) with increased antioxidant enzymes (SOD, GPx). Functional recovery at 90 days (mRS) was inconsistent. No significant increase in adverse events, bleeding, or mortality was observed. Conclusions: NAC may provide short-term neurological and biochemical benefits in acute stroke without added safety risks. However, its impact on long-term functional recovery remains inconclusive, warranting larger biomarker-guided trials.