The effect of nitrous oxide on severe depression

A Phase 2 clinical trial has found a 60-minute treatment session with the gas nitrous oxide can deliver significant and rapid improvements in patients with treatment-resistant depression, and the research indicates these benefits can last for at least two weeks.

Since its discovery in the late 18th century nitrous oxide has played a notable role in the history of anesthesia. Perhaps best known for its use in dentistry, it is often anecdotally referred to as “laughing gas” due to the nature of its euphoric sedation when administered in mild concentrations.

Over the last few years the rapid anti-depressant qualities of ketamine, another old anesthetic, were discovered and thought to be due to the blocking of a protein receptor in the brain called N-methyl-D-aspartate (NMDA). Back in 2014 a team of researchers wondered whether nitrous oxide could have the same antidepressant effect considering it has a somewhat similar action on the brain.

An early proof of concept trial offered compelling clues the gas could indeed rapidly relieve symptoms of depression. Subsequent preliminary research suggested the gas could also potentially treat post-traumatic stress disorder (PTSD) and alcoholism.

This new study set out to investigate whether lower doses of nitrous oxide than previously tested were effective for depression, and whether the benefits from a single treatment last for several weeks. Each of the 24 subjects recruited for the trial completed three treatment sessions, each one hour long, spaced a month apart. Alongside a placebo session breathing only oxygen, the subjects tested 25 percent and 50 percent nitrous oxide concentrations.

The researchers found 85 percent of the subjects showed significant improvements to their depression symptoms after a single nitrous oxide treatment and, most importantly, the lower dose was almost as effective as the higher dose but with substantially fewer negative side effects.

“Some patients experience side effects – it’s a small subset, but it’s very real – and the main one is that some people get nauseated,” explains co-senior investigator on the trial, Charles Conway. “But in our study, only when people got the 50 percent dose did they experience nausea. When they received 25 percent nitrous oxide, no one developed nausea. And that lower dose was just about as effective as the higher dose at relieving depression.”

Peter Nagale, a senior investigator on the trial, says the duration of treatment effect was another exciting finding. Previous research had only followed participants for up to 24 hours, whereas this study found the anti-depressant effects of a single nitrous oxide treatment lasted between two and four weeks.

“The reduction in side effects was unexpected and quite drastic,” says Nagele, “but even more excitingly, the effects after a single administration lasted for a whole two weeks. This has never been shown before. It’s a very cool finding.”

As this is a completely new kind of treatment modality for depression much more work is needed to understand the best and safest ways for it to be administered. However, Nagele and Conway think there could be a useful place for nitrous oxide in the future of depression therapy, especially as a rapid fast-acting treatment for severely depressed patients dealing with suicidality.

“One potential advantage to nitrous oxide, compared with ketamine, is that because it’s a volatile gas, its anesthetic effects subside very quickly,” says Conway. “It’s similar to what happens in a dentist’s office when people drive themselves home after getting a tooth pulled. After treatment with ketamine, patients need to be observed for two hours following treatment to make sure they are OK, and then they have to get someone else to drive them.”

The study was published in the journal Science Translational Medicine.

Sources: Washington University School of Medicine in St. Louis, University of Chicago Medicine

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