Ketamine and nitrous oxide: The evolution of NMDA receptor antagonists as antidepressant agents.
Molly C Kalmoe, Alvin Janski, Charles F Zorumski, Peter Nagele, Ben J Palanca, Charles R Conway
Journal of the Neurological Sciences May 15, 2020 DOI: 10.1016/j.jns.2020.116778 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Double-blind Peer reviewed |
|---|---|
| Topics | Depression Esketamine Ketamine |
| Keywords | Nmdar Nitrous oxide Treatment resistant depression |
| Key findings | Both ketamine and nitrous oxide, as NMDAR antagonists, show rapid antidepressant effects in treatment-resistant depression, with a recent cross-over trial demonstrating nitrous oxide's efficacy in severely ill patients. |
Abstract
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.
Comparable studies
Other narrative reviews on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Long-term safety of ketamine and esketamine in treatment of depression | 2022 | Review | |
| Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms. | 2024 | Review | |
| Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. Patients with depression | 2024 | Narrative review | |
| The Possible Application of Ketamine in the Treatment of Depression in Alzheimer’s Disease | 2022 | Review |
Citations in the library
Cited by 26
- The treatment of depression — searching for new ideas Frontiers in Pharmacology October 7, 2022
- Safety considerations and risk mitigation strategies for ketamine use: a comprehensive review. Annals of Medicine and Surgery May 1, 2025
- Rapid antidepressant potential of nitrous oxide: current state and major questions. Molecular Psychiatry June 1, 2026
- The Induction of Dissociative States: A Meta-Analysis. Biological Psychiatry Global Open Science July 1, 2025
- Design, Synthesis and Biological Evaluation of Novel Ketamine Derivatives as NMDAR Antagonists. Molecules May 23, 2024
and 21 more in the library
Cites 51
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
and 46 more in the library