To identify the optimal amantadine dosing strategy for neurological and functional recovery in traumatic brain injury (TBI).

TBI is a major cause of long-term neurological disability, and treatment options for cognitive and functional recovery are limited. Amantadine, a dopaminergic neurostimulant, shows promise, but optimal dosing remains unclear. Prior meta-analyses have not fully leveraged indirect comparisons.

We searched PubMed, EMBASE, SCOPUS, and Web of Science through September 2025 for RCTs of amantadine in TBI. Two reviewers screened studies, extracted data, and assessed quality. A frequentist network meta-analysis was conducted in R (netmeta) using a random-effects model with DerSimonian–Laird estimator. Studies compared different amantadine doses versus placebo. Primary outcomes were GCS at 7 days, DRS at 6 weeks, and MMSE at final follow-up. Language and reporting clarity were refined using ChatGPT (OpenAI, GPT-5).

Six studies (426 patients; 205 receiving amantadine) were analyzed. For GCS at 7 days (3 studies, 4 arms), 200 mg daily improved outcomes versus placebo (MD 2.50, 95% CI 1.24–3.76, p < 0.0001); 100 mg BID showed a nonsignificant trend (MD 1.83, 95% CI –0.21 to 3.87, p = 0.078), and dose escalation (200 mg × 3 days then 400 mg) was ineffective (MD 0.33, 95% CI –0.83 to 1.49, p = 0.578). For DRS at 6 weeks (2 studies), 200 mg daily was beneficial (MD 2.84, 95% CI 0.41–5.27, p = 0.022); 100 mg BID was nonsignificant (MD 1.68, 95% CI –0.98 to 4.34, p = 0.215). For MMSE, 100 mg BID improved cognition (MD 3.23, 95% CI 0.53–5.94, p = 0.019; I² = 0%).