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

Karim S. Ladha,Jiwon Lee,G. Mattina,J. Pazmino-Canizares,D. Wijeysundera,Fatemeh Gholamali Nezhad,Vanessa K. Tassone,Fathima Adamsahib,Wendy Lou,S. Kennedy,Venkat Bhat

Published 2025 in BJPsych Open

ABSTRACT

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.

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