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, Gabriella Mattina, Janneth Pazmino-Canizares, Duminda N Wijeysundera, Fatemeh Gholamali Nezhad, Vanessa K Tassone, Fathima Adamsahib, Wendy Lou, Sidney H. Kennedy, Venkat Bhat
BJPsych Open September 12, 2025 DOI: 10.1192/bjo.2025.10823 (opens in new tab) via PubMed
Summary
AI-generated from the abstractA pilot trial tested the feasibility of a four-week course of nitrous oxide compared with midazolam (an active placebo) for treatment-resistant depression. Forty participants were randomly assigned to weekly one-hour inhalations of either 50% nitrous oxide or 50% oxygen plus intravenous midazolam. Recruitment, withdrawal, adherence, and missing data rates met feasibility criteria. Depression severity, measured by the MADRS scale, changed by -20.5% in the nitrous oxide group and -9.0% in the placebo group. Adverse events were mostly mild to moderate and transient. The results support conducting a full-scale trial.
Study at a glance
| Characteristics | Randomized controlled trial Placebo-controlled Pilot study Peer reviewed |
|---|---|
| Sample size | 40 |
| Population | Participants with treatment-resistant depression |
| Interventions | Nitrous oxide Midazolam |
| Dose | 50% nitrous oxide; 0.02 mg/kg midazolam up to 2 mg |
| Duration | 4-week intervention, follow-up to day 42 |
| Topics | Depression |
| Keywords | Rct Trd Nitrous oxide Randomised controlled trial |
| Key finding | A four-week course of nitrous oxide or midazolam is feasible to study in treatment-resistant depression, with a greater reduction in depression severity observed in the nitrous oxide group. |
Abstract
Nitrous oxide may possess antidepressant effects; however, limited data exist on repeated administrations and active placebo-controlled studies in treatment-resistant depression (TRD). We aimed to test the feasibility of a randomised controlled trial examining a 4-week course of nitrous oxide or midazolam, an active placebo. 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. 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. The findings support the feasibility and necessity of conducting a full-scale trial comparing nitrous oxide and midazolam in patients with TRD.