Psychiatric and Neurocognitive Adverse Events in Young Users of Nonmedical Nitrous Oxide

Purpose/Background: For several years, an increase in the nonmedical use of nitrous oxide (N 2 O) 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 N 2 O 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. N 2 O 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 N 2 O-induced neuropsychiatric disorders. N 2 O abuse should be considered in any young patient with psychiatric disorders of unknown origin, particularly when associated with atypical cognitive disorders.