Nitrous oxide (N 2 O) toxicity is a concern common to several medical fields. Here, retrospective study of four N 2 O abuses with neurological signs in the emergency practice provides a preliminary basis for a metabolic Discussion/Review. This latter highlights N 2 O abuse as pathology of DNA/RNA/protein methylations, for instance consistent with impairments of protein arginine methyltransferases involved in myelinogenesis and myelopathy in patients. Basically, pathogenesis starts with oxidation by N 2 O of coordinated cobalamine cobalt ions at enzyme sites with impairments of vitamin-B12-dependent pathways. Methionine synthase (methylcobalamine) and methymalonyl-CoA mutase (adenosylcobalamine) are inactivated and cofactor-depleted, respectively. The number of impacted pathways (folate cycle, methylation cycle, S -adenosylmethionine-dependent methyltransferases, transulfuration pathway, Krebs cycle fueling by methylmalonyl-CoA, glutathione synthesis) explains the variety of potential research/laboratory markers, and may provide new clues and future angles to explore N 2 O toxicity. Overall, homocysteine measurements obviously help diagnosis of N 2 O abuses. Additional markers may include vitamin-B12, methionine, methylmalonate, dimethylglycine, sarcosine, S -adenosylmethionine to S -adenosylhomocysteine ratio, various S -adenosylamino acids, S -adenosylmethionine-dependent cellular methylations, and additional analytes (propionylcarnitine, propionylglycine, cystathionine and derived metabolites, methylated amino acids [eg arginine], betaine). • Recreational use of N 2 O can reach 100 to 300 cartridges/day, and cause neurological deterioration. • N 2 O by oxidising the coordinated cobalt ion disrupts cobalamin (vitamin B12)-dependent pathways. • N 2 O disrupts folate, methylation cycles; DNA, RNA, protein methylations; glutathione synthesis. • Laboratory markers include increased plasma homocysteine and numerous metabolites reviewed. • Treatment of abuse is cessation of N 2 O consumption and supplementation with vitamins B12 and B6. [ABSTRACT FROM AUTHOR]