Efficacy and safety of minocycline in acute ischemic stroke: an updated systematic review and meta-analysis with trial sequential analysis of randomized controlled trials

Background Acute ischemic stroke (AIS) remains a leading cause of death and disability worldwide. Because neuroinflammation contributes substantially to ischemic brain injury, minocycline has been investigated as a potential adjunctive therapy owing to its anti-inflammatory and neuroprotective properties. Methods This systematic review and meta-analysis (PROSPERO: CRD420261340165 ) was conducted in accordance with PRISMA guidelines. We included randomized controlled trials (RCTs) enrolling adults with AIS that compared oral or intravenous minocycline plus standard care versus placebo plus standard care. The primary outcome was functional outcome assessed by the modified Rankin Scale (mRS) at 90 days. Random-effects meta-analysis with Hartung-Knapp adjustment was performed, and trial sequential analysis (TSA) was conducted for all-cause mortality. Results Five RCTs involving 2,073 patients were included. Minocycline did not significantly improve excellent functional outcome (mRS ≤1; RR 1.52, p =0.271), functional independence (mRS ≤2; RR 1.32, p =0.214), or moderate functional outcome (mRS ≤3; RR 1.05, p =0.282) at 90 days compared with placebo. Likewise, no significant differences were observed in early neurological improvement at day 7 (NIHSS; p =0.248) or functional independence at 90 days assessed by the Barthel Index ( p =0.246). Minocycline was associated with lower all-cause mortality (RR 0.71, 95% CI 0.57–0.89; p =0.01); however, TSA indicated that the available evidence remains underpowered and insufficient for definitive conclusions. No significant differences were found in recurrent stroke or hemorrhagic transformation. Conclusion In conclusion, our findings suggest that minocycline is biologically credible, but it did not demonstrate a consistent benefit in functional or neurological outcomes after AIS (very low-to-low certainty evidence). Minocycline was associated with reduced all-cause mortality (moderate-certainty evidence), although trial sequential analysis indicates this finding remains inconclusive. With respect to the specific safety outcomes assessed—all-cause mortality, recurrent stroke, and hemorrhagic transformation—our findings do not raise safety concerns; however, safety was not comprehensively evaluated across the broader spectrum of known minocycline-associated adverse effects (e.g., hepatic toxicity, gastrointestinal intolerance, hypersensitivity reactions, vestibular symptoms), which were not systematically reported across the included trials. We therefore view minocycline as a promising adjunct that now needs better targeted, biomarker-informed, reperfusion-aware trials rather than immediate universal use in acute ischemic stroke.