BACKGROUND:Traumatic brain injury is a global burden. We aimed to perform a meta-analysis to determine the efficacy of amantadine for cognitive performance after traumatic brain injury. METHODS:The systematic review was prospectively registered on the International Prospective Register of Systematic Reviews website under the registration number CRD42017080044. We used Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to report the steps of meta-analysis. The search included electronic databases (PubMed, PsycINFO, Embase, Cochrane Library databases, CENTRAL, ProQuest and ClinicalTrials.gov trial registry). Critical care medicine journals and clinical neurology specialty were searched using www.scimagojr.com. There was no publication date restriction. Two authors assessed studies' relevance and extracted data. Studies were assessed for quality using the Cochrane risk of bias tool. Data were analyzed using Comprehensive Meta-analysis Program versions 2.0 and 3.0. RESULTS:Twenty-six studies out of 3,440 records were included in the systematic review, of which only 14 clinical trials and 6 observational studies were included in the meta-analysis. Amantadine significantly enhanced the cognitive function relative to control group (mean difference [MD], 0.50; 95% confidence interval [CI], 0.33-0.66; p < 0.001, 16 studies, 1,127 participants, low certainty evidence). Consistent significant difference in favor of amantadine relative to control group was found (MD of 0.79 [95% CI, 0.34-1.24], very low certainty evidence, for cohort studies vs. MD of 0.40 [95% CI, 0.25-0.56], moderate certainty evidence, for RCTS). Starting amantadine in the first week after TBI had a significant effect on improving cognitive function (MD, 0.97; 95% CI, 0.45-1.49; 16 studies, 1,127 participants, low certainty). Amantadine showed a better effect when administered for less than 1 month (MD, 0.83; 95% CI, 0.56-1.11; low certainty) and to patients below 18 years of age (MD, 0.66; 95% CI, 0.32-0.99; low certainty) or to patients with less severe traumatic brain injury (MD, 0.40; 95% CI, 0.18-0.62; low certainty). No statistically significant difference existed between amantadine and the control concerning the adverse events (OR, 1.74; 95% CI, 0.88-3.44; p = 0.11, moderate certainty). Metaregression of the different clinical parameters, which are onset of treatment, age, and severity of traumatic brain injury, showed a statistically significant relation between onset of treatment and the effect size of amantadine. The relation between the other two parameters and the effect size of amantadine showed a marginal statistical significance. CONCLUSION:Amantadine may improve the cognitive function when used after TBI. Further research with high validity is needed to reach a solid conclusion about the use of amantadine in traumatic brain injury.