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Treating Severe Depression Could Be a Laughing Matter

severe depression could be laughing matter

It’s still too early to tell, but treating severe depression could be a matter of giving a dose of laughing gas. No joke. Results of a proof-of-concept clinical trial suggest that nitrous oxide could be a quick and temporary treatment for depression that has not responded to other therapy.


Although the use of laughing gas for treating depression may sound like an unusual idea, it’s not farfetched at all. That’s because nitrous oxide is an NMDA receptor antagonist. Let me explain.

An NMDA receptor antagonist is a class of substances that inhibit (antagonize) the activity of N-methyl-d-aspartate (NMDA) receptors. Dentists use the NMDA receptor antagonist nitrous oxide as an anesthetic before performing painful dental procedures.

Previous research and experience have shown that another NMDA receptor antagonist, called ketamine, has been effective as a rapid-onset treatment for depression. In fact, a new study in Psychiatry Research reports that “a single intravenous infusion of ketamine…can alleviate depressive symptoms in patients within hours.” The exact reason it works is still being investigated.

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New study on laughing gas and depression
In the new placebo-controlled, blinded, crossover trial, 20 individuals who had treatment-resistant depression were randomly assigned to receive one of the following:

  • 50% nitrous oxide and 50% oxygen for 1 hour by inhalation
  • 50% nitrogen and 50% oxygen for 1 hour by inhalation (placebo)

Since this was a crossover trial, each of the participants received both the laughing gas and the placebo on two different occasions. Here’s what the researchers reported:

  • Symptoms of depression improve significantly both at 2 hours and 24 hours after treatment when compared with the placebo group
  • Among patients who received nitrous oxide, four (20%) had at least a 50 percent reduction in symptoms and three (15%) had full remission, compared with only one response in the placebo group.
  • None of the participants reported worse depressive symptoms after nitrous oxide treatment
  • Use of nitrous oxide resulted in some temporary, mild to moderate side effects but no serious ones. Some side effects of nitrous oxide use can include nausea, vomiting, blurry vision, confusion, sweating, and lightheadedness.

The Washington University School of Medicine team also noted that about one-third of individuals suffering with clinical depression are not helped by current therapy options. The results seen in this proof-of-concept trial will lead to more research and perhaps a more effective and faster way to treat severe depression.

The fast-acting factor seen with nitrous oxide is especially appealing because current oral antidepressants can take 14 days or longer before they provide any beneficial effects. If nitrous oxide proves to be safe and effective for emergency or acute use, it could be administered to fill the gap until other medications kick in. Keep your eyes open for further research findings.

Dutta A et al. Ketamine and other potential glutamate antidepressants. Psychiatry Research 2014 Nov 13
Nagele P et al. Nitrous oxide for treatment-resistant major depression: a proof-of-concept trial. Biological Psychiatry 2014 Dec 8 online



I'm aware of people who have self medicated with nitrous oxide. I wonder if anything will come of this.