A tiny phase II clinical trial published on June 9 in the journal Science Translational Medicine indicated that nitrous oxide (often known as “laughing gas” in the dentist’s office) may help some people with treatment-resistant depression reduce their symptoms. Researchers have been interested in approaches that act faster than traditional depression medications, such as SSRIs, which can take up to six weeks to begin working. 17 million adults in the United States suffer from depression for which common treatments don’t seem to work, and researchers have been interested in approaches that act faster than traditional depression medications, such as SSRIs, which can take up to six weeks to begin working.
“There was no medicine that could immediately treat depression symptoms until the discovery of ketamine,” says lead author Peter Nagele, a trauma anesthesiologist at the University of Chicago. Ketamine, like nitrous oxide, is considered a “promising” new therapy option, but it can have major adverse effects, such as increased blood pressure, delusion, and addiction, according to Nagele. Nitrous oxide, like ketamine, blocks a brain receptor known as the NMDA receptor, suggesting that it could have an antidepressant effect. Gas for giggling According to Nagele, “might be the oldest drug we use in medicine, older than aspirin”—it began as a party drug in 18th century England, hence the name—and it is regarded less dangerous in terms of adverse effects.
This phase II experiment followed a phase II “proof-of-concept” experiment involving 20 people, the results of which were reported in 2015 and revealed that nitrous oxide could have fast-acting antidepressant benefits. However, according to Nagele, “a lot of crucial concerns remained unanswered,” such as whether a lower dose of nitrous oxide would work as effectively with fewer side effects (some patients suffered nausea or vomiting), and how long the anti-depressant benefits would continue.
Twenty persons with treatment-resistant depression took part in the experiment, which was designed to answer such issues. The bulk of those who took part were women, and 96 percent of those who took part were white. The participants were given two different dosages of nitrous oxide (as well as a placebo of ordinary oxygen) to inhale for one hour. The patients’ moods were assessed before and after inhalation, with the final assessment taking place four weeks after the last treatment.
Senior author Charles Conway, a professor of psychiatry at Washington University, told STAT News, “I don’t expect to see new things work because I’ve worked with these folks for so many years.” “However, the patients in this study, some of whom I’ve known for a long time, improved.”
The researchers discovered that both doses were equally beneficial, however, the lower amount produced fewer side effects like nausea and headaches. 85 percent of patients had improved by the end of the three-month study. Eight of the 20 persons went into remission, rating in the healthy range on a depression scale, and 11 of the 20 persons saw their depression score drop by more than half.
“And we proved for the first time that these effects would endure for two weeks in many patients,” Nagele says.
The study had certain drawbacks, according to the researchers: it was difficult to prevent participants from identifying the placebo therapy, and several patients modified their antidepressant dosage during the trial.
Ravi Das, a psychopharmacologist at University College London, told NBC News, “The fundamental restriction is that it’s a tiny study.”
Other specialists told STAT News that nitrous oxide, like other brain-based medicines, might be overused and that there is insufficient safety data on long-term use. Because the participants were nearly all white, Lisa Harding, a psychiatrist at Yale School of Medicine, told STAT News that future trials should involve a more varied group of patients.
“It’s great to see preliminary findings like this,” Nagele adds, “but the results must be replicated in much larger, more diversified, and preferably multinational clinical trials.”