Nitrous oxide for the treatment of psychiatric disorders: A systematic review of the clinical trial landscape

Objective To systematically review published research studies and ongoing clinical trials investigating nitrous oxide (N2O) in psychiatric disorders, providing an up‐to‐date snapshot of the clinical research landscape. Methods A comprehensive literature search was conducted for studies published until June 2021 using the OVID databases (MEDLINE, Embase, APA PsycInfo) and the clinical trial registries (ClinicalTrials.gov, ICTRP). Results In total, five relevant published articles were identified, among which four investigated N2O for depression. One single‐dose randomized controlled trial (RCT) for treatment‐resistant depression (TRD), one triple crossover RCT comparing 50% vs. 25% N2O for TRD, and one repeated‐dose RCT for major depressive disorder (MDD) suggest that N2O has preliminary feasibility with rapid‐acting effects on symptoms of depression. From the public registries, 10 relevant ongoing clinical trials were identified. They aim to explore the use of N2O for MDD, post‐traumatic stress disorder, bipolar disorder, obsessive‐compulsive disorder, and suicidal ideation. To date, the typical treatment protocol parameters were a single session of 50% N2O delivered for 60 min, although the concentration of 25% is also being explored. Projected enrolment numbers for ongoing trials (M = 55.0) were much higher than sample sizes for published studies (M = 13.0), suggesting that there potentially will be more large‐scale RCTs published in the next few years. Conclusion Preliminary studies support the feasibility of administering N2O for depression; however, appropriate blinding is a critical challenge. Larger‐scale RCTs with repeated doses of N2O and follow‐up times beyond 1 month are needed to confirm the feasibility, therapeutic efficacy, and sustainability of response.