A dose of laughing gas may just help some people with hard-to-treat depression, suggests a new, small clinical trial published Wednesday. The study found that people who inhaled nitrous oxide reported improvements in their depression symptoms afterward. It also found that people felt similar improvements with a smaller dose as they did with a larger one, but experienced substantially fewer side effects.
Nitrous oxide (N₂O) is a colorless, non-flammable gas at room temperature that’s long been used as an anesthetic and sometimes as a recreational drug, due to the euphoria and dissociative hallucinations it can cause upon inhalation. But several years ago, Peter Nagele, a researcher and trauma anesthesiologist at the University of Chicago, and his colleagues began looking into nitrous oxide as a potential treatment for depression.
“It started with the observation that ketamine, a different anesthetic with similar mechanistic properties like nitrous oxide (likely via NMDA-receptor blockage), was found to be a rapid antidepressant that also worked in patients with treatment-resistant depression,” Nagele told Gizmodo in an email. “By connecting these dots, we hypothesized that nitrous oxide may also be an antidepressant.”
Their early research has suggested that inhaling a hour’s worth of nitrous oxide, mixed at 50% concentration with oxygen, could have “rapid and marked antidepressant effects” in patients with treatment-resistant depression. This new study, published Wednesday in Science Translational Medicine, is a Phase II controlled trial of the treatment. These sorts of trials are used to further figure out a potential drug’s efficacy and safety, oftentimes by testing out different doses.
The small trial recruited 28 participants in a crossover design, which is when all the volunteers go through each of the trial’s conditions and their responses are compared to one another (as opposed to two or more distinct groups that either take the drug or placebo). In this case, that meant the volunteers, who had depression for an average of 17.5 years, had three treatment sessions: one where they inhaled a 50% dose of nitrous oxide, another where they inhaled a 25% dose, and one where they inhaled oxygen (the placebo). Afterwards, the volunteers took surveys meant to assess their level of depression.
Ultimately, 24 people participated in at least one treatment session, and 20 took all the treatments. The team found that these volunteers on average experienced a greater improvement in depression symptoms when they took the nitrous oxide at either dose than they did after taking the placebo (based on the primary survey they completed)—an improvement that lasted for up to two weeks. They also found that both doses seemed to provide similar relief, but that people were more likely to experience side-effects like headaches, nausea, and lightheadedness from the larger dose.
The findings are based on a very small sample size, so they shouldn’t be given too much weight right now. But Nagale’s other research has suggested that for some people who haven’t responded to other treatments, nitrous oxide may trigger a profound recovery. In at least one case, published last year, a patient with severe depression seemed to experience a complete remission following a single session of 50% nitrous oxide—a remission that had endured a month later. A form of ketamine has also since become an FDA-approved depression treatment, further raising hopes that nitrous oxide could be taken seriously as an antidepressant.
Nagale and his team are planning to team up with other researchers to conduct larger trials at multiple locations (a key part of showing a drug really works), while also trying to study exactly how it seems to be affecting the brains of those with depression for the better. But it’s likely that the future of this treatment will depend on public and non-commercial funding, Nagale said, pointing to the example of ketamine.
Some doctors and patients had been using generic ketamine, taken through IV, as an experimental depression treatment for years. But Johnson & Johnson didn’t fund expensive clinical trials to secure an approval for ketamine as a depression treatment; it instead developed a patentable form taken as a nasal spray, called esketamine. That sort of commercialization isn’t something that’s possible with nitrous oxide, according to Nagale.
“It is unlikely that a pharmaceutical company will be interested, as nitrous oxide is off-patent and there is no analogue or enantiomer; it may need funding from the NIH and academic investigators taking the lead,” he said.