Effect of riluzole on cognitive and functional outcomes after severe traumatic brain injury: a randomized controlled trial

Glutamate-mediated excitotoxicity is a key mechanism of secondary neuronal injury after severe traumatic brain injury (TBI). Riluzole, a sodium–glutamate antagonist with established safety in other neurologic disorders, has demonstrated neuroprotective effects in preclinical models, but clinical evidence in TBI remains limited. In this single-center, randomized, double-blind, placebo-controlled trial, 160 adults with severe TBI (Glasgow Coma Scale ≤8) were assigned (1:1) to riluzole (50 mg twice on day 1, then 50 mg daily for 13 days) or placebo, alongside guideline-based care. The primary outcome was cognitive status measured by the Montreal Cognitive Assessment (MoCA) at day 28. Secondary outcomes included MoCA at day 14, Functional Independence Measure (FIM), daily GCS through day 14, Glasgow Outcome Scale–Extended (GOS-E) at day 28, radiographic progression, length of stay, and safety. Analyses followed the intention-to-treat principle. At day 28, MoCA scores were not significantly different between groups (median 23 vs. 22; mean difference +1.0, 95% CI −0.1 to 2.1; P=0.069). Day-14 MoCA scores were also similar (P=0.249). No significant differences were observed in FIM, GOS-E, radiographic progression, or length of stay. Adverse event rates were comparable, and no drug-related serious adverse events occurred. Adjunctive riluzole was safe but did not significantly improve short-term cognitive or functional outcomes after severe TBI. Further trials optimizing timing, dosing, and patient selection are warranted. Iranian Registry of Clinical Trials (IRCT20241230064217N1), registered on March 8, 2025. Retrospectively registered.