Mental Health

Nitrous Oxide for Treatment-Resistant Depression: What’s Next?

In part 2 of this video, Charles Conway, MD, professor of psychiatry, Washington University School of Medicine, director, Center for the Advancement of Research in Resistant Mood Disorders, St Louis, Missouri, continues his summary of new research supporting the use of nitrous oxide for the treatment of treatment-resistant major depression (TRMD). Dr Conway covers possible side effects of this novel treatment, and next steps for continued research.  

Watch part 1 where Dr Conway discusses the study's methods, most significant findings, and primary applications for clinicians treating patients with TRMD.


Read the Transcript:

Dr Charles Conway: Fortunately, the nitrous oxide given in a conservative way as it's described in these papers is very safe. Like any treatment, there are things you need to think about.

Probably the two biggest things that people need to think about are, because it is a volatile gas, individuals who have certain unusual pulmonary issues like people who have openspace pulmonary lesions, and also individuals who have B12 deficiencies.

We know that abuse of nitrous oxide, individuals who sniff nitrous oxide recreationally on a consistent basis can develop brain injury from B12 deficiency. All of our studies thus far, we've looked at B12. We have not seen any reductions in serum B12 levels, but we've approached this very conservatively.

My message would be probably smart to obtain a serum B12 level before you give nitrous oxide, and then also to monitor, probably not giving serial nitrous oxide yet, because we don't know the safety of that, and also making sure that nitrous oxide is being delivered by people who know what they're doing.

There is some potential danger if an individual is giving nitrous oxide who doesn't have the proper ventilation, then the individuals who are actually giving the nitrous oxide would be breathing it in. If this happened on a recurrent basis, there potentially could be some issues.

We recommend ‑‑ this is the way we've done it so far ‑‑ that it be done by anesthesiologist in the proper setting, something like a postanesthesia care unit where there's a rebreather mechanism in place so that you're venting out the excess nitrous oxide, so the anesthesiologist and the anesthesia team aren't breathing it.

Probably the next focus of research, we've begun to look at some aspects of how this impacts the brain. No one really knows. Similar to ketamine, we don't really have a good idea. The NMDA receptor that this is likely based on is located throughout the brain. It's very hard to come up with a clear mechanism of action.

We're doing some studies. We and some other groups are doing studies of looking at how it's impacting brain function both in animals and humans. The other area that we need to pursue is a larger trial with a much greater population where we can definitively prove that this is effective.

Additionally, another logical extension would be to do studies where we look at how you do maintenance treatment. You get a patient better with nitrous oxide from depression, what do you need to do to keep them well? That's one of the struggles we're experiencing with ketamine right now. Ketamine clearly helps a lot of people, but how do you keep somebody well on ketamine?

It looks like there's quite a bit of individual difference from patient to patient. Those are big areas of needed research.

My closing message would be that this study and other studies in treatmentresistant depression are a very hopeful thing.

One of the messages to patients with treatmentresistant depression ‑‑ I've been working with these patients for about 20 years ‑‑ is that perhaps they haven't found yet something that works for them, but the science behind developing new treatments is really moving much faster than it was even 10 years ago.

There's a lot of different options, including nitrous oxide, but NMDA antagonists, neurosteroids, neurostimulation treatments, all sorts of antiinflammatory treatments. The sky is the limit. I do think as we better understand what's going on with this disorder, we'll be able to treat it better.

One of the messages that I would put forward is that there's reason for hope in this population. As most clinicians know, it's a very hopeless population. There's reasons to be cautiously optimistic about the future.


Nagele P, Palanca BJ, Gott B, et al. A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression. Sci Transl Med. 2021;13(597):eabe1376. doi:10.1126/scitranslmed.abe1376


Charles Conway, MD, received his medical degree at the University of Missouri-Columbia, and served his residency in psychiatry at Duke University Medical Center in Durham, North Carolina. He is a professor of psychiatry at the Washington University School of Medicine in St. Louis, Missouri, in addition to serving as the director of the Center for the Advancement of Research in Resistant Mood Disorders at Washington University, and the director of the Treatment Resistant Depression and Neurostimulation Clinic. His areas of clinical interest include treatment-resistant mood disorders, bipolar disorders, and mood disorders while his research expertise includes treatment-resistant depression, bipolar disorders, and neuroimaging of mood disorders.