Researchers from the University of Chicago Medicine and Washington University published the results of their phase 2 clinical trial in Science Translational Medicine in early June.
Nitrous oxide has been used in medicine for about 150 years and known for even longer. Its long medical history and well-documented mechanisms of action led the researchers behind the recent study to wonder if it could treat depression.
Following a Hunch
Peter Nagele, MD, chair of anesthesia and critical care at the University of Chicago Medicine and an author of the study, tells Verywell that the team was “following a hunch,” about nitrous oxide.
The gas shares properties with ketamine, a dissociative anesthetic (which is now also being tested to relieve treatment-resistant depression). Nagele’s team wanted to see if the two treatments had comparable effects.
“That was really just trying to connect dots,” says Nagele. “And we followed up on that hunch.”
Answering Unanswered Questions
In a previous study, Nagele and colleagues tested the effects of giving 20 patients 50% nitrous oxide gas for an hour.
“The study from five years ago was designed to really just the test if there’s a signal,” says Nagele, adding that the team also wanted to see if there was evidence that the nitrous oxide could treat depression.
“We found that the answer was yes, but there were a lot of unanswered questions,” says Nagele. Some of those questions were how long the effects would last and if a smaller concentration of nitrous oxide could work.
The New Study
In previous experiments, the researchers had determined that one inhalation session with higher doses of nitrous oxide gas helped to relieve the symptoms of treatment-resistant depression.
The new study found that when given at 25% inhaled concentration (half the previous dose) the laughing gas was nearly as effective as the 50% inhaled concentration dose.
The reduced dose also produced fewer side effects and relief lasting for much longer than the researchers expected—some participants experienced improvements for about two weeks.
More Effective, Fewer Side Effects
For the second study, Nagele and colleagues tested the effects of a one-hour inhalation session on 20 people again—but this time, they used a 25% nitrous oxide gas session. They also looked at the participants’ depression scores for longer—two weeks instead of just 24 hours (as they did in the first study).
At the end of the two weeks, they found that the participants experienced a fraction of the side effects that the first group had. In addition, some participants even showed depression relief for the entire two weeks after the single 25% nitrous oxide inhalation session.
“One of the take-home messages is that a lower concentration is about as effective as a 50% concentration,” says Nagele.
Don’t Try This at Home
While the results of the research are promising, it’s important to remember the medical context in which the treatment is being explored. Nagele acknowledges that nitrous oxide can also be used as a recreational drug—which he says that his team’s study in no way condones or advocates for.
Although they found that the treatment led to speedy improvements in patients’ depressive symptoms—lasting for at least 24 hours when compared to placebo—many patients experienced negative side effects, such as vomiting, nausea, and headaches.
Laughing gas is used recreationally because its pain-relieving and euphoric effects appear quickly after inhalation and disappear in just a few minutes. A 2015 study found that nitrous oxide use among clubbers and ravers in the United Kingdom ranged anywhere from 40% to 80%.
Nagele adds that when used recreationally, it’s hundred percent nitrous oxide. “Pure gas, no oxygen. And there’s a lot of unwanted side effects related to this that are just not there with medically-used nitrous or nitrogen-oxygen mix.”
Bottom line? Nagele warns: “Don’t try this at home.”
Still, considering that millions of people with depression do not respond to the standard treatment, experimental findings may lead to experimental treatment on a case-by-case basis.
Nagele says that when options like antidepressants do not help someone with depression, “then it’s clear that novel treatments may be very beneficial, too.”
New Uses for Old Drugs
Regardless of what the future brings, Nagele says that his team’s study is an exciting reminder that innovation sometimes comes in old packages.
While we know that carbon dioxide emissions pose a threat, nitrous oxide is 300 times more potent than carbon dioxide and depletes the ozone layer even more.
“One benefit about these old drugs is that we’ve known them for a long time,” says Nagele, adding that this familiarity means that the medical community has a sound understanding of effects and risks. “Not every drug or every novelty comes from a novel molecule. It could be just finding new uses for old drugs.”
In addition to its promise as a depression treatment, other researchers are wondering if laughing gas could help curb the opioid epidemic in the United States.
