KETAMINE COMBINED WITH DEXTROMETHORPHAN-BUPROPION FOR DEPRESSION IN THE CONTEXT OF NITROUS OXIDE MISUSE

Background: Treatment-resistant depression (TRD) affects up to a third of patients with major depressive disorder and remains difficult to manage with conventional therapies. Rapid-acting antidepressants targeting the glutamatergic system, such as ketamine, esketamine, and dextromethorphan-bupropion, have emerged as promising alternatives. Nitrous oxide, also an NMDA receptor antagonist, has demonstrated antidepressant properties in clinical trials but carries significant risks when used recreationally. Case Presentation: We describe a 27-year-old male with no prior psychiatric history who presented with escalating nitrous oxide use following the suicide of his cousin. He reported compulsive urges to continue use despite associated psychiatric symptoms. The patient endorsed depressive features without suicidal intent or psychosis. Given the limited two-week timeframe prior to his wedding, rapid-acting treatment was initiated with ketamine infusion and dextromethorphan-bupropion (Auvelity), along with naltrexone for craving management. At two-week follow-up, the patient reported abstinence from nitrous oxide, reduced irritability, and symptomatic improvement.

Discussion: This case underscores the clinical overlap between recreational nitrous oxide use and emerging therapeutic applications of NMDA receptor antagonists. Ketamine provided rapid symptom reduction, while dextromethorphan-bupropion supported early maintenance of response. The combination highlights a potential therapeutic pathway for patients who self medicate with nitrous oxide, substituting maladaptive use with evidence-based, clinically supervised interventions.