The rapid antidepressant effect of N2O lasts for at least 24 hours and up to a week. The study was recently published online in the journal Biological Psychiatry, which showed that N2O led to a positive treatment response in 20% of patients with refractory depression, with 15% experiencing symptom relief. The study involved 20 patients with refractory depression who were randomized to receive a 1-hour inhalation treatment of either a 1:1 mixture of N2O and oxygen or a 1:1 mixture of nitrogen and oxygen (as a placebo). The concentration of the inhaled gas was 44%. One week later, these patients underwent a case-crossover study. Of the 15 patients who completed the study, 3 patients discontinued N2O treatment and 2 patients discontinued treatment due to side effects of anxiety and nausea. 4 (20%) of the 15 patients who completed the trial responded positively to treatment as evidenced by a 50% or greater reduction on the HDRS-21 scale; 3 (15%) had complete remission of symptoms with HDRS scores below 7. Of the patients who received placebo, only one patient responded positively to treatment, and none were completely taken care of. Only one patient receiving placebo had a positive response to treatment, and none were completely cured. After 2 and 4 hours of N2O treatment, the patients’ depressive symptoms improved considerably compared to those receiving placebo. In this regard, N2O was considered to have better efficacy than placebo. The side effects of nausea and anxiety usually occurred at the end of the 1-hour treatment and resolved immediately after stopping treatment. The investigators concluded that dose adjustments could avoid the side effects. “By treating with a low dose of N2O, the side effects are reduced, and you can stop treatment at any time to allow the patient to recover quickly.” Unlike ketamine, which needs to be metabolized in the body, N2O is a gas that is not traceable in the body 10 minutes after treatment is stopped. The patient’s improved mood seems to have nothing to do with N2O staying in the body; it does have an effect on the brain and then leaves the body, but that effect is always there. When the patients were given N2O, they did not laugh as they were said to do when they inhaled the laughing gas; instead, they calmed down and went to sleep, thus improving their moods. Also, N2O does not cause the hallucinations and delusions that ketamine triggers, and it is not addictive. To further confirm the effects of N2O, many questions will need to be addressed in future studies. For example, the researchers noted the limitations of using the HDRS-21 scale, so a different scale, like the I-PANAS-SF or VAS, might be better. This study was only a proof-of-concept experiment, but it would be great if methods did exist that could quickly improve the status of patients with refractory depression.