Nitrous oxide has been utilized in medicine for over 150 years, with current applications in emergency medicine, dentistry, and obstetrics. It is a commonly utilized anesthetic and analgesic that is well-tolerated among adult users. Outside of medicine, nitrous oxide is a frequently inhaled recreational drug, typically used among teenagers and young adults. Within the last decade, nitrous oxide has been found to have antidepressant effects similar to ketamine, thought to be related to its effect on N-methyl-D-aspartate receptors (NMDARs). Though there is limited evidence about its therapeutic effects in mood disorders, recent studies support that nitrous oxide has the potential to treat resistant unipolar depression. In this chapter, we discuss nitrous oxide’s putative mechanism of action, administration, current use in psychiatry, and possible future psychotropic applications.