Nitrous oxide abuse prevalence, mechanisms, treatments and prevention

We describe major changes in the nitrous oxide market fueling recreational use with a focus on prevalence, desired effects, adverse events, treatments, and public health interventions. Nitrous oxide is currently sold with easy and discreet access for children and young adults in formulations that attract them. Over 13 million people in the United States have ever used nitrous oxide recreationally and inhalants are mostly used by pre-teen to early 20-year-olds. Poison control center calls have increased 1,300% from 2003 to 2024 and deaths have risen 6-fold from 2010 to 2023. There are many acute adverse events ranging from frostbite to asphyxia. Adverse effects from chronic use are related to cobalt oxidation which impairs vitamin B12 functioning. The resulting dysfunction of methionine synthase induces methionine deficiency frequently causing paresthesia, ataxia, unsteady gait, and cognitive issues. Less commonly, paralysis, bladder and erectile dysfunction, macrocytic anemia and thromboembolism can occur. The European Federation of Clinical Chemistry and Laboratory Medicine guidance specifies diagnostic parameters, supportive care, and replenishment of vitamin B12 levels with intramuscular cyanocobalamin. There may be a role for routine direct methionine replenishment, but it is not universally recommended. Routine folic acid supplementation is controversial and should likely be reserved for those with low serum folate concentrations. Clinicians need to be aware of this growing trend to detect adverse events from chronic nitrous oxide use and treat them before they become permanent. Clinicians can provide or advocate for public health information and regulations to prevent adverse events from occurring.