Efficacy and safety of nitrous oxide for patients with treatment-resistant depression, a randomized controlled trial

Sustained Mood Improvement with Laughing Gas Exposure (SMILE): Study protocol for a randomized placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression

“…Nitrous oxide is emerging as a potentially effective and fast-acting treatment to mitigate TRD [13][14][15][16][17]. Here, we present the protocol for a pilot, six-week, double-blind RCT comparing a 4-week regimen of weekly administered nitrous oxide to the active placebo, midazolam, in patients with TRD.…”

“…The primary objective of the study is to assess feasibility, and the secondary objective is to assess the preliminary efficacy of nitrous oxide in reducing symptoms of depression 42 days following treatment initiation. Currently, few RCTs have examined nitrous oxide treatment for TRD, with studies showing ameliorative effects of a single administration of nitrous oxide on symptoms of depression 2 to 24 hours post-treatment [13][14][15][16], and in some studies 1-2 weeks post-treatment [14,15,17]. Yet, it remains unknown whether repeated treatments can produce cumulative amelioration of depressive symptoms over a follow-up period past two weeks and in comparison to an active placebo, like midazolam.…”

“…Currently, several studies have examined nitrous oxide treatment in the context of psychiatric disorders [12], including randomized controlled trials (RCTs) in TRD demonstrating rapid antidepressant effects of nitrous oxide [13][14][15][16][17]. Indeed, reductions in symptoms of depression have been observed as early as 2 hours post-treatment and sustained for 24 hours [14][15][16], with a subset of studies demonstrating effects at one or two weeks following nitrous oxide administration [14,15,17]. However, this line of evidence has been based on work that lacks adequate blinding of participants.…”

“…Midazolam has also been widely used as an active placebo in studies testing ketamine in TRD [15], further supporting the use of midazolam as a more appropriate placebo for nitrous oxide trials in TRD. In addition to the lack of optimal blinding, current studies investigating nitrous oxide in TRD [13][14][15][16][17] have not conducted follow up past two weeks, and have only examined a single administration of nitrous oxide, rather than repeated administrations over time. While a recent RCT that included both patients with TRD and non-TRD suggests that repeated administrations of nitrous oxide over four weeks may produce cumulative amelioration of depressive symptoms [19], this study also lacked adequate blinding; and it is unclear whether these results can be translated to patients with TRD specifically.…”

Persistent Brain Connectivity Changes in Healthy Volunteers Following Nitrous Oxide Inhalation

“…Its psychomimetic effects and noncompetitive antagonism of NMDA receptors (NMDARs) have led to comparisons with ketamine ( 1 , 2 ). Recently, nitrous oxide has shown promise in the treatment of major depressive disorder ( 3 , 4 , 5 , 6 ), posttraumatic stress disorder ( 7 ), alcohol withdrawal ( 8 ), and bipolar depression ( 9 , 10 ). Despite widespread and longstanding use, mechanistic understanding of nitrous oxide’s effects on the brain have not been fully elucidated.…”