Vitamin B12 Status in Recreational Users of Nitrous Oxide: A Systematic Review Focusing on the Prevalence of Laboratory Abnormalities

The recreational use of nitrous oxide (N₂O) as "laughing gas" is a growing problem. The chronic toxicity of N₂O is mainly due to its ability to oxidize vitamin B12, making it dysfunctional as a cofactor in metabolic pathways. This mechanism plays a major role in the development of neurological disorders in N₂O users. The assessment of vitamin B12 status in N₂O users is important but challenging due to the lack of decrease in total vitamin B12 in most cases despite genuine vitamin B12 functional deficiency. Other biomarkers, such as holotranscobalamin (holoTC), homocysteine (tHcy) and methylmalonic acid (MMA), are interesting candidates to properly assess vitamin B12 status. Here, we conducted a systematic review of case series in order to assess the prevalence of abnormal values of total vitamin B12, holoTC, tHcy and MMA in recreational N₂O users, which is an important prerequisite for determining the best screening strategy in future guidelines. We included 23 case series (574 N₂O users) from the PubMed database. Total circulating vitamin B12 concentration was low in 42.2% (95% confidence interval 37.8-46.6%, n = 486) of N₂O users, while 28.6% (7.5-49.6%, n = 21) of N₂O users had low circulating concentrations of holoTC. tHcy levels were elevated in 79.7% (75.9-83.5%, n = 429) of N₂O users, while 79.6% (71.5-87.7%, n = 98) of N₂O users had increased concentrations of MMA. In summary, the increases in tHcy and MMA were the most prevalent abnormalities, and should be measured alone or in combination in symptomatic N₂O users rather than total vitamin B12 or holoTC.