Background: Monosodium glutamate (MSG) represents one of the most extensively studied and controversially debated food additives in modern nutrition science. While regulatory agencies worldwide have established its safety at typical dietary levels, emerging research continues to reveal complex neurobiological mechanisms through which MSG may exert neurotoxic effects under specific conditions.

Methods: This comprehensive analysis synthesizes experimental evidence from cellular, animal, and human studies examining MSG neurotoxicity mechanisms. We evaluated current regulatory perspectives, safety assessments, and emerging therapeutic approaches targeting glutamate-induced excitotoxicity through systematic review of literature published between 2010-2024.

Results: MSG induces neurotoxicity primarily through NMDA receptor-mediated excitotoxicity, leading to calcium influx, oxidative stress, and neuroinflammation. Animal studies demonstrate dose-dependent neuronal damage in hypothalamic and hippocampal regions, with neonatal exposure producing more severe effects due to immature blood-brain barrier function. The threshold for neurotoxic effects varies significantly across species and developmental stages, from 0.5 mg/kg in neonatal animals to 12 mg/kg in human clinical studies. Multiple neuroprotective strategies show promise, with N-acetylcysteine demonstrating the highest efficacy (score 9/10) in clinical trials, followed by various natural compounds targeting oxidative stress pathways.

Conclusion: While MSG appears safe at typical dietary levels, high-dose exposure or compromised blood-brain barrier integrity may precipitate neurotoxic effects. Understanding these mechanisms is crucial for developing targeted neuroprotective strategies and refining safety guidelines for vulnerable populations.

Keywords: Monosodium Glutamate, Neurotoxicity, Excitotoxicity, NMDA receptors, Neuroprotection, Blood-brain barrier