To evaluate the efficacy and safety of memantine, an NMDA receptor antagonist, in ALS treatment.

ALS is a progressive neurodegenerative disorder in which glutamate-mediated excitotoxicity via NMDA receptor overactivation has been proposed as a pathogenic mechanism. Memantine, approved for Alzheimer’s disease, has been investigated as a potential ALS therapy, but trial results have been inconsistent. Understanding its efficacy and limitations may inform future neuroprotective strategies.

A comprehensive search of PubMed, Scopus, and Web of Science was conducted up to December 15, 2024. Inclusion criteria included randomized controlled trials (RCTs) or single-arm clinical trials investigating Memantine in ALS. Meta-analyses were performed using a random-effects model in RevMan.

The search yielded 193 records, with five clinical trials (317 ALS patients) meeting inclusion criteria. These included three RCTs and two pilot studies, all conducted in Western countries. Memantine was well-tolerated, consistent with its safety profile in Alzheimer’s disease. While early pilot trials suggested potential benefits, all three RCTs failed to demonstrate significant effects. Notably, Pal’s RCT, the largest study with 183 participants in the Memantine group and 186 in the placebo group, found no differences in functional decline (measured by ALSFRS-R) or biomarkers, including neurofilament light chain. Meta-analysis of ALSFRS-R monthly change revealed no difference between Memantine and placebo (mean difference = 0.01, 95% CI [-0.08 to 0.11], p=0.81).

Current evidence does not support memantine (up to 40 mg/day) as an effective therapy for ALS. Its failure may reflect the pathological heterogeneity of ALS, suboptimal dosing, or the predominance of non-glutamate mechanisms such as TDP-43 proteinopathy and neuroinflammation. Future research should focus on biomarker-driven patient selection, earlier intervention, and combination therapies targeting multiple disease pathways. While NMDA antagonism alone appears insufficient, it may still hold potential within precision medicine strategies for defined ALS subgroups.