Sustained mood improvement with laughing gas exposure (SMILE): a randomised, placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression.

Background: Nitrous oxide may possess antidepressant effects; however, limited data exist on repeated administrations and active placebo-controlled studies in treatment-resistant depression (TRD).

Aims: We aimed to test the feasibility of a randomised controlled trial examining a 4-week course of nitrous oxide or midazolam, an active placebo.

Method: In this randomised, active, placebo-controlled pilot trial, 40 participants with TRD were assigned either a 1-h inhalation of 50% nitrous oxide plus intravenous saline (n = 20) or a 1-h inhalation of 50% oxygen plus intravenous midazolam (0.02 mg/kg, up to 2 mg; n = 20) once weekly, for 4 weeks. Feasibility was assessed by examining rates of recruitment, withdrawal, adherence, missing data and adverse events. The main measure of clinical efficacy was the change in depression severity (Montgomery-Åsberg Depression Rating Scale (MADRS)) score from baseline to day 42.

Results: The recruitment rate was 22.3% (95% CI 16.9-29.0). Withdrawal rates were 10% (95% CI 2.8-30.1) in both groups and adherence rates were 100.0% (95% CI 82.4-100) in the nitrous oxide group and 94.4% (95% CI 74.2-99.0) in the placebo group. There were no missing primary clinical outcome data in either group (0.0%, 95% CI 0.0-17.6). MADRS score changed by -20.5% (95% CI -39.6 to -1.3) in the nitrous oxide group and -9.0% (95% CI -22.6 to 4.6) in the placebo group. Nearly all adverse events were mild to moderate and transient.

Conclusions: The findings support the feasibility and necessity of conducting a full-scale trial comparing nitrous oxide and midazolam in patients with TRD.