Nitrous Oxide: an emerging novel treatment for treatment-resistant depression

This review (2021) explores the possibilities of using Nitrous Oxide (NO2) for treating treatment-resistant depression (TRD). The use of NO2 as a psychiatric intervention is discussed along with its possible mechanism of action. Its antidepressant effects are believed to be mediated through the NMDA receptor.


“Stemming from the results of the historic STAR-D trial, it is evident that a significant subset of individuals (20–25%) with major depressive disorder (MDD) do not respond to conventional antidepressant medications. As a result, an emphasis has been placed on the development of novel therapeutics for MDD over the last two decades. Recently, substantial research efforts have been focused on the use of ketamine as an antidepressant whose mechanism of action is via the N-methyl-d-aspartate (NMDA) receptor. Another potential therapeutic compound of interest is nitrous oxide, which has been utilized for more than a century in multiple fields of medicine for its analgesic and anesthetic properties. Recent clinical studies suggest that nitrous oxide may be effective for treatment-resistant depression. In this review, we will discuss the administration of nitrous oxide as a psychiatric intervention, current use in psychiatry, putative mechanisms of action, and future directions highlighting knowledge gaps and other potential utilities in the field of psychiatry.”

Authors: David F. Quach, Victoria C. de Leon & Charles R. Conway

Authors Highlights

•Nitrous oxide is emerging as a therapeutic for treatment-resistant depression.

•Recent studies indicate that it is fast-acting with effects lasting up to 2 weeks.

•Its antidepressant activity is thought to be mediated through the NMDA receptor.

•It has a favourable side effect profile with a long history of safe use in medicine.


As the name suggests, there is a significant unmet need when it comes to treating treatment-resistant depression (TRD). This significant subset of people living with major depressive disorder (MDD) remains unresponsive to conventional antidepressant medications such as SSRIs. Given this unmet need, researchers are continuously searching for new treatments. In the realm of psychedelic research, this particular subset of people with depression has been the main focus of researchers and industry players alike. Ketamine is already available off-label to those with TRD while trials with psilocybin have shown great promise in alleviating symptoms of this disorder. This promise has spurred research into the possibilities of using other psychedelic compounds as well as the potential off-label use of readily available medications.

The present paper is one of the first to make a case for the use of Nitrous Oxide (NO2) to treat TRD. NO2, also known as laughing gas, is a gas that is commonly used for general anaesthesia, procedural sedation, dental anaesthesia, and to treat severe pain. The authors of this paper argue that NO2 could be used for TRD given its antagonism at the NMDA receptor, which is the same property through which the antidepressant effects of ketamine are believed to be mediated.

The main findings

  • Recent studies using NO2 to treat TRD directly or as an adjunctive therapy found that is a fast-acting antidepressant with effects that can last up to two weeks in certain individuals.
  • As well as the NMDA receptor, NO2 has been shown to act on other recepors such as opioid recepots which may explain its potential pain relieving effects.
  • Compared to ketamine, NO2 has different electrophsyiological effects at the NMDA receptor and from a safety perspective, there have been no reports of pychosis related to NO2.

Overall, the present study provides food for thought on the possibilities of using NO2 to treat TRD. While further research is clearly needed to establish dosing protocols, the safety profile, mechanisms of action and more, the fact NO2 is widely used means it could be a cheap alternative to alleviate the symptoms of TRD in comparison to the costs of other psychedelic therapies.

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Nitrous Oxide: an emerging novel treatment for treatment-resistant depression

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Published in
Journal of the Neurological Sciences
December 16, 2021
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Study details

Compounds studied
Nitrous Oxide

Topics studied
Treatment-Resistant Depression

Study characteristics
Literature Review Theory Building

0 Humans


Institutes associated with this publication

Washington University School of Medicine
Located in St. Louis Missouri, researchers at the Washington University School of Medicine have conducted a number of studies with psychedelics inlcuding ketamine, psilocybin and nitrous oxide.

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