For many people with major depression, current treatments either don’t work or take too long to show results.
About one in three patients suffer from treatment-resistant depression, and even when medications are effective, they can take weeks to bring relief.
Now, scientists are exploring new options that could work faster—including a surprising one: nitrous oxide, also known as laughing gas.
A team led by Professor Peter Nagele at the University of Chicago has been investigating whether nitrous oxide could help treat depression.
Early clinical trials showed that even a single session of inhaling laughing gas helped patients feel better within hours, with improvements lasting up to two weeks.
Wanting to better understand how this worked, Nagele and his team dove deeper into the brain’s response to the gas.
Their new study, published in Nature Communications, reveals how nitrous oxide can trigger lasting mood improvements even though it leaves the body within minutes.
Most people know laughing gas from the dentist’s office, where it’s used to calm nerves and ease pain. But in depression research, it’s used at low doses to create a calm, sedative effect, not to cause giggles.
Nitrous oxide has been around for over 180 years, but scientists are still discovering its full potential. As Nagele puts it, it feels like uncovering a hidden mystery of an old, familiar drug.
Previous theories suggested that laughing gas and other fast-acting antidepressants like ketamine worked by blocking NMDA receptors in the brain. However, this didn’t fully explain why nitrous oxide’s benefits lasted so long after the gas was gone.
To find out more, the research team used advanced brain imaging in mice that had been exposed to chronic stress, a common model for depression. They focused on a brain area involved in emotions called the cingulate cortex. They found that nitrous oxide quickly activated specific brain cells known as layer 5 pyramidal neurons, which are usually underactive in depression.
This activation helped the brain “wake up” from its stressed, suppressed state. Instead of building new brain connections, the gas re-energized existing circuits, allowing the brain to engage more positively. The key was that nitrous oxide blocked certain potassium channels in these neurons, boosting their activity and restoring healthier brain function.
The discovery suggests that there might be more ways to treat depression than previously thought. While more research is needed, this opens the possibility of developing new medications that mimic the beneficial effects of laughing gas without needing clinical gas inhalation.
As Nagele says, understanding how laughing gas works brings scientists one step closer to creating faster, more effective treatments for people who have not found help elsewhere.
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