Psychoactive substances, historically taken to parties, increasingly appear to be suitable tools for the treatment of mental illness.
In Phase III clinical trials, MDMA has been shown to be a highly effective treatment for post-traumatic stress disorder, and in recent studies, oral ketamine has been shown to significantly reduce suicidal ideation.
Nitric oxide, or nitrous oxide, now joins the ranks. A new trial with 24 participants in the United States has found that a low dose of this gas can relieve symptoms of depression that are otherwise resistant to current drugs.
Even better, the benefits seem to last for several weeks and come with very few side effects.
“The reduction in side effects was unexpected and quite drastic, but even more exciting were the effects after a single administration for a full two weeks,”
“This has never been shown before. It’s a very cool find.”
When nitrous oxide was first discovered in the late 1700s, chemists in England held laughter gas parties for an elite crowd. The festivities were sold as ‘experiments’ at the time to find out how the drug actually worked.
Partygoers reported feeling euphoric and pain-free, which is why nitric oxide was soon adapted for use in dentistry and surgery. Hundreds of years later, most of us know the drug as an anesthetic or sedative.
In the last few years, however, researchers have re-examined this drug and its use in clinical settings.
In 2015, a principle-to-principle study showed that inhaling a gas consisting of 50 percent nitrous oxide in just one hour has rapid antidepressant effects. Depression decreased markedly the day after treatment for most volunteers; among those whose mood was checked a week later, however, the results did not seem to last. While there were no serious side effects, many participants reported feeling nauseous, dizzy, or paranoid.
But new follow-up study suggests this does not have to be the case. In a recent randomized phase II clinical trial, 24 volunteers with treatment-resistant major depression were randomly assigned to three different treatments staggered over three months with one month between each treatment.
The first treatment involved an hour-long dose of nitric oxide (50 percent), the second involved an hour-long dose of the drug (25 percent), and the last involved a placebo.
Not everyone in the study responded equally to each treatment, and there was a strong placebo effect for some. That said, the majority of people in the trial showed a high response rate and symptom improvement over three months.
These benefits are greater than those observed with other traditional antidepressants, researchers say, and they appear to last longer than we previously thought.
Two weeks after each treatment, the researchers found that those who had received nitrous oxide at both doses showed lasting benefits compared to when they received placebo.
However, the higher dose of nitrous oxide was, on average, associated with four times more side effects. A lower dose mostly slept patients.
“This study was motivated by observations from research on ketamine and depression,” Nagele explains.
“Like nitrous oxide, ketamine is an anesthetic, and there has been promising work to use ketamine in a subanesthetic dose to treat depression. We wondered if our previous concentration of 50 percent had been too high. Maybe by lowering the dose we could find the ‘Goldilocks site’ that maximizes clinical benefit and minimizes adverse side effects. “
The sample size of the current study is small, and because researchers only followed up with patients after two weeks, it is unclear whether the effects of the first nitric oxide treatment were carried over to the next battle with nitrous oxide.
This can strengthen the lasting effect of the drug, which means that several doses of nitrous oxide can be beneficial as a long-term treatment.
A single hour of nitrous oxide, on the other hand, can not last that long.
Much more research is needed before we can take advantage of this drug for clinical depression in a safe and effective way, but given the number of millions of people who do not respond to current antidepressants, alternative treatments are needed.
“This has just been pilot studies,” Nagele says. “But we need acceptance from the larger medical community for this to become a treatment that is actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we will have to to show society how to deliver this treatment safely and effectively. ”
The study was published in Scientific translational medicine.