N-methyl-d-aspartate receptor (NMDAR) antagonists, including ketamine and nitrous oxide, are currently intensely studied as rapid-acting antidepressant agents. Interestingly, both of these compounds are also drugs of abuse. Intravenous ketamine, a dissociative anesthetic that induces complex downstream effects via NMDARs, rapidly reduces depressive and suicidal symptoms in treatment-resistant depression (TRD), as demonstrated by several trials. Recently, the United States Food and Drug Administration (FDA) approved an intranasal version of ketamine (esketamine) for TRD. The United States Drug Enforcement Agency (DEA) lists ketamine as a Class III scheduled drug (moderate-low potential for physical and psychological abuse). The FDA has established a Risk Evaluation and Management Strategy (REMS) program to ensure proper drug storage, handling, dispensing, and monitoring intranasal esketamine to minimize misuse/abuse opportunities. Nitrous Oxide is a colorless, odorless, gas that has been in medical use for over 150 years. The mechanisms of action of nitrous oxide are not fully understood; however, it is known to act as a non-competitive inhibitor of NMDA-type glutamate receptors. Currently, nitrous oxide is used for inhalational general anesthesia and analgesia for short procedures. Inhaled nitrous oxide is also used recreationally, primarily by teens and young adults, but is not believed to have strong addiction potential. In contrast to ketamine, nitrous oxide is not a controlled substance and can be legally purchased without a prescription. A recent double-blind, prospective, cross-over study demonstrated that nitrous oxide reduced depressive symptoms in a group of severely ill TRD patients. Though this is a promising initial study, further investigation is needed.Copyright © 2020 Elsevier B.V. All rights reserved.