Minocycline in Acute Stroke: Systematic Review and Meta-Analysis of Randomized Trials

Background: Despite advances in reperfusion therapies, acute stroke remains a leading cause of death and disability worldwide. Minocycline has emerged as a potential neuroprotective agent due to its anti-inflammatory, anti-apoptotic, and blood-brain barrier-stabilizing properties. However, randomized trials have reported inconsistent results across stroke subtypes. Research Question: Does minocycline improve neurological and functional outcomes in acute stroke without increasing adverse events? Methods We performed a systematic review and meta-analysis of randomized controlled trials comparing minocycline with placebo or standard care in acute stroke. Searches were conducted across major databases and trial registries through March 2026. Outcomes included NIH Stroke Scale (NIHSS), modified Rankin Scale (mRS), Barthel Index (BI), mortality, recurrent vascular events, hemorrhagic transformation, and neuroimaging outcomes. Frequentist random-effects meta-analysis and trial sequential analysis (TSA) were performed. Results: Nine randomized trials comprising 2,186 patients (1,086 minocycline; 1,100 control) were included. Overall, minocycline did not significantly improve 3-month NIHSS scores (MD –1.78, 95% CI –3.73 to 0.18), functional independence (mRS 0-2; RR 1.25, 95% CI 1.00-1.55), favorable functional outcome (mRS 0-1; RR 1.25, 95% CI 0.82-1.92), Barthel Index (MD 6.99, 95% CI –0.52 to 14.49), or mortality (RR 0.68, 95% CI 0.41-1.13). Subgroup analyses demonstrated significant benefit among patients with acute ischemic stroke, including improved 3-month NIHSS scores (MD –2.43, 95% CI –4.42 to –0.44), functional independence (RR 1.40, 95% CI 1.05-1.86), and Barthel Index (MD 12.34, 95% CI 5.45-19.23). No benefit was observed in intracerebral hemorrhage. Rates of recurrent vascular events, hemorrhagic transformation, hematoma volume, perihematomal edema, and MMP-9 levels were similar between groups. TSA demonstrated that available evidence remains insufficient to establish definitive benefit for neurological recovery, functional outcomes, or mortality. Conclusions: Minocycline does not significantly improve overall functional outcomes or survival after acute stroke. However, consistent signals of neurological and functional benefit were observed in acute ischemic stroke, with no apparent safety concerns. Current evidence remains underpowered for definitive conclusions, highlighting the need for adequately powered contemporary trials evaluating minocycline as an adjunct to modern reperfusion strategies.