Psychiatric and neurocognitive adverse events in young users of nonmedical nitrous oxide (2026)

Purpose/Background: For several years, an increase in the nonmedical use of nitrous oxide (N2O) has been observed in France, among adolescents and young adults, sometimes associated with severe adverse events.
Methods/Procedures: Analysis of spontaneous reports (SRs) concerning neuropsychiatric adverse events in N2O users, received by the Montpellier addictovigilance centre between 2022 and June 2024, and discussion of the underlying pharmacological mechanisms.
Findings/Results: Nineteen severe SRs were analysed, mainly in men (73.6%, mean age: 23.1 +/- 7.3 y) and concerned psychiatric disorders (n = 11), neurocognitive disorders (n = 2), or both (n = 6). Associated consumptions were mainly cannabis (38.9%). Reported symptoms were psychiatric (mainly behavioural disorders, n = 14; delusion, n = 10), and/or neurocognitive (mainly memory disorders, n = 5; spatiotemporal disorientation, n = 3; cognitive slowing, n = 3). Vitamin B12 dosage was performed in 11 cases (<145 pmol/l: 4 cases, mean: 245.4 +/- 118 pmol/l), homocysteine in 10 cases (>15 µmol/l: all cases, mean: 80.3 +/- 54 µmol/l), methylmalonic acid in 6 cases (>0.5 µmol/l: 4 cases, mean: 1.2 +/- 1.7 µmol/l), and vitamin B9 (<8.83 nmol/l: 2 cases, mean: 16.2 +/- 9.7 nmol/l). When performed (n = 8), magnetic resonance imaging revealed white matter abnormalities with punctiform hyperintensities in 6 cases. Twelve have received long-term antipsychotic medication, and 9 vitamin supplementation. N2O combines potentially neurotoxic mechanisms: psychoactive (glutamatergic receptor antagonist, opioid/GABAergic effects), biochemical (disruption of vitamin B12 metabolism) and anoxic.
Implications/Conclusions: These observations highlight the importance and uniqueness of N2O-induced neuropsychiatric disorders. N2O abuse should be considered in any young patient with psychiatric disorders of unknown origin, particularly when associated with atypical cognitive disorders. [Author's abstract]