Abstract
Nitrous oxide (N(2)O) has been linked to several neuropsychiatric complications. This paper aims to systematically review reported cases of psychosis associated with N(2)O use. Additionally, five new cases of N(2)O-related psychosis are presented. A systematic search was conducted in MedLine for cases of psychosis associated with N(2)O use, from database inception to April 2025. The five new cases are thoroughly analyzed, and the Naranjo criteria were applied to assess causality in both the new cases and those identified in the systematic review. A total of 15 articles were included, encompassing 15 patients. Including these and the five newly reported cases, the current manuscript analyzes 20 individuals (17 men and 3 women) aged 20 to 45 years. Most cases reported a history of substance use disorder (mainly alcohol) and escalating N(2)O use prior to the psychotic episode. Clinical manifestations included psychotic symptoms (delusions and hallucinations) as well as other psychopathological features. Neurological complications were also commonly described. Laboratory tests showed vitamin B12 abnormalities in some cases. All patients were hospitalized; abstinence from substance use was the first intervention, and most received antipsychotic treatment. N(2)O may be associated with psychotic episodes, particularly among young, heavy users with underlying vulnerabilities. Psychiatric and neurological symptoms are frequently observed. Although outcomes vary, treatment involving abstinence, vitamin B12 supplementation, and antipsychotic medication typically leads to improvement. Further research is warranted on this topic.