Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial.

This is one of the research studies I've been waiting for somebody to do. Nitrous oxide is legal and has significant similarities with ketamine, which we know can be used as an antidepressant. Earlier studies have shown that N2O might also have this ability and here's a randomized, double-blind study showing it does. Fascinating to see if working psychotherapeutically with the N2O altered state (as with ketamine) could promote still greater benefits. The authors of this free full-text study write: "Objective: Major depressive disorder (MDD) is related to glutamatergic dysfunction. Antagonists of glutamatergic N-methyl-D-aspartate receptor (NMDAR), such as ketamine, have antidepressant properties. Nitrous oxide (N2O) is also a NMDAR antagonist. Thus, this study aimed to evaluate the effects of augmenting antidepressant treatment with N2O.  Methods: This double blind, placebo-controlled randomized parallel pilot trial was conducted from June 2016 to June 2018 at the Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo. Twenty-three subjects with MDD (aged 18 to 65, on antidepressants, with a score > 17 on the 17-item-Hamilton Depression Rating Scale [HAM-D17]) received 50% N2O (n=12; 37.17±13.59 years) or placebo (100% oxygen) (n=11; 37.18±12.77 years) for 60 minutes twice a week for 4 weeks. The primary outcome was changes in HAM-D17 from baseline to week 4.  Results: Depressive symptoms improved significantly in the N2O group (N2O: from 22.58±3.83 to 5.92±4.08; placebo: from 22.44±3.54 to 12.89±5.39, p < 0.005). A total of 91.7% and 75% of the N2O group subjects achieved response (≥ 50% reduction in HAM-D17 score) and remission (HAM-D17 < 7), respectively. The predominant adverse effects of N2O treatment were nausea, vomiting, and headache.  Conclusion: N2O treatment led to a statistically significant reduction in HAM-D17 scores compared to placebo." As with ketamine, there are questions around how stable this depressive improvement is and whether psychotherapy boosts the antidepressive effects (as seems likely from the addiction literature).