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Laughing Gas Relieves Symptoms of Treatment-Resistant Depression, New Study Finds

By Alexander Beadle

Published: Jun 22, 2021   
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Low doses of nitrous oxide – more commonly known as laughing gas – can significantly improve symptoms in people with treatment-resistant depression (TRD), according to new data from researchers at the Washington University School of Medicine in St. Louis and the University of Chicago.

Results from a new phase 2 clinical trial, published in the journal Science Translational Medicine, indicate that inhaling a mixture of 25 percent nitrous oxide and oxygen can provide long-lasting symptom relief to those who have found other antidepressants ineffective, with negligible side effects. This builds on previous work that showed the effectiveness of a fifty percent nitrous oxide mixture in reducing symptoms of TRD, but which carried a much greater risk of undesirable side effects.

While the phase 2 trial is somewhat limited by its relatively small sample size, the researchers believe that these promising results demonstrate the need for a larger, multi-center study comparing the antidepressant effects of nitrous oxide to placebo.

Forty percent of participants entered remission after treatment

Twenty-four patients were enrolled in the trial, which involved three one-hour treatment sessions. In one session the patients were given a mixture to inhale that was half nitrous oxide and half oxygen. In another session, the mixture was 25 percent nitrous oxide and 75 percent oxygen, with the final session using an oxygen-only placebo. These sessions were given in a random order to each patient, leaving approximately one month between sessions. Symptoms were assessed using the Hamilton Depression Rating Scale (HDRS-21) and compared across a set of follow-up exams given at the 24-hour, 1-week, and 2-week marks.

Of the 20 patients that completed all of the follow-up exams, 17 patients’ TRD symptoms improved enough by the end of the trial that their clinical classification fell by at least one degree (from severe to moderate depression, for instance). Eleven patients (55 percent) experienced significant improvement in at least half of their reported symptoms.

Astonishingly, eight patients (40 percent) were considered to be “in remission” after undergoing nitrous oxide treatment, meaning that their reported symptoms no longer met the requirements for a clinical depression diagnosis.

“Our primary goals in this study were twofold: to determine whether a lower dose of nitrous oxide might be just as effective as doses we’d tested previously – and it was for most patients – and we also wanted to see how long the relief lasted,” explained senior investigator Peter Nagele, in a statement. Nagele is a professor and chair of the Department of Anesthesia and Critical Care at the University of Chicago.

“In a proof-of-concept study several years ago, we assessed patients for 24 hours. In this study, we continued to assess them for two weeks, and most continued to feel better,” Nagele said.

Balancing positive effects against undesirable side effects

In addition to monitoring the long-term impact of these sessions on depression symptoms, the researchers also sought to evaluate any changes in side-effect risk between the two nitrous oxide dosages.

They found that the antidepressant effects of the 50 percent nitrous oxide mixture were stronger at the two-week follow-up exam, with an average reduction of −7.00 in the participants’ HDRS-21 scores versus a −5.19 reduction for the 25 percent nitrous oxide mixture. However, the higher dose nitrous oxide sessions were also associated with numerous reports of adverse events, most commonly nausea.

Though the 25 percent dosage was slightly less effective at this final time point, there was a substantial decline in reports of adverse effects. This roughly comparable efficacy combined with its better side effect profile may make low dose nitrous oxide a much more appealing treatment option for real-world use.

“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,” Charles Conway, a professor of psychiatry at Washington University and one of the study’s senior investigators, said in a statement. “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.”

The need for alternative antidepressants

Around one-third of patients diagnosed with major depressive disorder (MDD) find that traditional antidepressants do nothing to alleviate their symptoms. With roughly 350 million people worldwide living with MDD, finding effective alternative methods of treatment is of critical importance.

“A large percentage of patients don’t respond to standard antidepressant therapies – the patients in this study had failed an average of 4.5 antidepressant trials – and it’s very important to find therapies to help these patients,” said Conway. “That we saw rapid improvements in many such patients in the study suggests nitrous oxide may help people with really severe, resistant depression.”

Traditional antidepressant medications block receptors in the body that respond to the neurotransmitters serotonin and norepinephrine. But nitrous oxide works differently to traditional antidepressants, by blocking certain molecules on nerve cells called N-methyl-D-aspartate (NMDA) receptors.

This is the same mode of action used by the psychedelic compound ketamine, which has recently made waves as a novel treatment for TRD. A nasal spray formulation of esketamine, the chemical enantiomer of ketamine, has received approval from the US Food and Drug Administration (FDA) and the European Commission for use in treating TRD.

“One potential advantage to nitrous oxide, compared with ketamine, is that because it’s a volatile gas, its anesthetic effects subside very quickly,” Conway said. “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.”

Given the promise indicated by this phase 2 trial, the researchers suggest that a larger, multi-center study that would compare the effects of both ketamine and nitrous oxide to placebo would be important future work.


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