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 (N₂ O) 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 N₂ O for depression. One single-dose randomized controlled trial (RCT) for treatment-resistant depression (TRD), one triple crossover RCT comparing 50% vs. 25% N₂ O for TRD, and one repeated-dose RCT for major depressive disorder (MDD) suggest that N₂ O 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 N₂ O 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% N₂ O 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 N₂ O for depression; however, appropriate blinding is a critical challenge. Larger-scale RCTs with repeated doses of N₂ O and follow-up times beyond 1 month are needed to confirm the feasibility, therapeutic efficacy, and sustainability of response.