A brief critique of excitotoxicity in amyotrophic lateral sclerosis

The excitotoxicity hypothesis has been significantly influential in amyotrophic lateral sclerosis (ALS) research for over thirty years but has seen limited clinical success. Here, the evidence supporting excitotoxicity in ALS is re-examined from first principles, motivated by a critical question: What if excitotoxicity does not underlie ALS pathogenesis? Rather than presenting a definitive answer, this article aims to foster critical discourse by systematically investigating core assumptions and proposing a competing hypothesis grounded in fundamental cellular neurophysiology. The goal of this article is to stimulate open academic dialog, encourage consideration of alternative mechanisms, and inspire investigations that may yield greater insight into ALS pathobiology.