To evaluate the effectiveness of early administration of excitatory amino acid (EAA) inhibitors on long-term neurological outcomes in adults with acute moderate to severe traumatic brain injury (TBI).

Systematic review and meta-analysis of randomised controlled trials (RCTs).

MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, WHO International Clinical Trials Registry Platform and ClinicalTrials.gov from inception to January 2026.

RCTs comparing EAA inhibitors with placebo, standard care or any other interventions were included. Trials enrolled adult patients (≥18 years) with moderate to severe TBI (Glasgow Coma Scale score ≤12) receiving the intervention within the acute phase of care (first week).

Pairs of reviewers independently screened trials, extracted data, assessed the risk of bias (RoB) with the Cochrane RoB tool 2 and graded the certainty of evidence using the Grades of Recommendation, Assessment, Development and Evaluation approach. Random effects models were used for all effect measures and trial sequential analyses (TSA) were performed for each outcome.

The primary outcome was long-term neurological function at 6 months (or the nearest earlier time point), assessed with the Glasgow Outcome Scale (GOS) or extended version (GOS-E), using the classical definitions of an unfavourable outcome (GOS 1–3 or GOS-E 1–4).

28 trials enrolling 4238 patients were included. Early administration of EAA inhibitors was not associated with reduced unfavourable neurological outcomes (relative risk 0.93 (95% CI (0.84 to 1.03); I²=40%; 15 trials, n=3613, moderate certainty). No statistically significant difference was observed based on EAA inhibitor type, timing or duration of administration, RoB or TBI severity. Mortality, intensive care unit lengths of stay and mean intracranial pressure were not statistically different between groups, but hospital length of stay was reduced in the EAA inhibitors group. The early use of EAA inhibitors was not associated with adverse events (low certainty). TSA showed insufficient power for the primary outcome.

In adults with moderate to severe TBI, the early administration of EAA inhibitors was not associated with a reduction of unfavourable neurological outcomes. Further high-quality and adequately powered RCTs are required to clarify their role in TBI management.

CRD42025635527.