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The combination of inhaled oxygen and intravenous midazolam is utilized as an active placebo control in the SMILE (Sustained Mood Improvement with Laughing Gas Exposure) clinical trial. This multi-center study, led by Women's College Hospital and St. Michael's Hospital, investigates the efficacy of nitrous oxide as an adjunctive treatment for adults with treatment-resistant depression. Midazolam, a short-acting benzodiazepine and GABA-A receptor agonist, is administered at a low dose (0.02 mg/kg) to induce mild sedative effects that mimic the subjective experience of nitrous oxide, thereby maintaining the double-blind nature of the trial. Oxygen serves as the sham inhalational vehicle. This specific combination is not a therapeutic candidate for commercial development but is a methodological component of a Phase 3 psychiatric research protocol.
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