Background <p><i>Gelsemium elegans</i> (<i>G. elegans</i>) is widely recognized as one of the most toxic plants globally, particularly harmful to humans. Some reports indicate that it is non-toxic to pigs and even has a growth-promoting effect; however, the underlying reasons for this paradox remain unclear.</p> Methods <p>Gelsenicine is the main toxic component of <i>G. elegans</i>. This study characterized gelsenicine-induced toxicity using electrophysiological recordings, molecular dynamic simulations, c-Fos immunostaining, and multi-omics technologies. Additionally, we conducted a comprehensive analysis comparing the toxic effects of gelsenicine across various animal species through examinations of tissue distribution, blood gas analysis, metabonomics, and behavioral tests.</p> Results <p>We demonstrated that gelsenicine-induced hypoxia leads to respiratory depression in mice by enhancing the effect of gamma-aminobutyric acid (GABA) on GABA receptors (GABARs). Glycine significantly ameliorated hypoxia and improved the survival of gelsenicine-poisoned mice. Under gelsenicine-induced hypoxic conditions, N-methyl-D-aspartate (NMDA) receptor function and mitochondrial energy metabolism processes were perturbed, resulting in neuronal excitotoxicity. Finally, we confirmed that pigs could tolerate hypoxia and were resistant to gelsenicine toxicity due to high concentrations of circulating glycine and low levels of NMDA receptors (NMDARs) in the hippocampus.</p> Conclusions <p>These findings suggest that hypoxic protection should be considered as a potential therapeutic strategy for gelsenicine poisoning. Our study contributes to preventing potential risks posed by <i>G. elegans</i> poisoning to human and animal health.</p> Graphical Abstract <p></p>