Effect of adjunctive minocycline on functional recovery and safety in acute ischemic stroke: a systematic review and meta-analysis

Neuroinflammation drives secondary brain injury after acute ischemic stroke. Minocycline, a tetracycline antibiotic with anti-inflammatory properties, has shown promise in preclinical and early-phase trials. The recent EMPHASIS trial necessitates an updated evidence synthesis. We aimed to evaluate the efficacy and safety of adjunctive minocycline in AIS. We systematically searched PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library through April 30, 2026, for RCTs of minocycline in adult AIS patients within 72 h of onset. Primary outcomes were mRS 0–2 and 0–1 at 3 months. Pooled effect sizes were calculated as risk ratios or mean differences with 95% CIs. Heterogeneity was assessed using I²; certainty of evidence was rated using GRADE. Seven RCTs ( n = 2,246) were included. For mRS 0–2, the pooled estimate was directionally neutral (RR 1.04, 95% CI 0.86–1.26; I² = 67%). For mRS 0–1, the pooled estimate did not reach statistical significance (RR 1.09, 95% CI 1.00–1.19; I² = 0%). Early neurological improvement (NIHSS at 5–7 days) yielded interval crossing zero; The pooled 3‑month NIHSS confidence interval did not cross zero, with substantial heterogeneity across studies. The Barthel Index showed no significant difference at any assessed time point. Safety outcomes were imprecise, with wide confidence intervals that preclude firm inference on either harm or benefit. This updated meta-analysis does not support a consistent, robust functional benefit of adjunctive minocycline after acute ischemic stroke. The overall certainty of evidence was rated low to very low by GRADE. Current randomized evidence is insufficient to support a change in clinical practice. Future adequately powered trials with standardized dosing, uniform placebo control, and prospective reporting of reperfusion status are required before firm inferences on either efficacy or safety can be drawn.