While many medications exist for treating major depression, about one in three patients don’t get better even after trying several antidepressants. This difficult condition is known as treatment-resistant depression (TRD). For these patients, waiting weeks for traditional drugs to start working can be especially painful and dangerous—especially if they are in crisis.
To solve this problem, scientists are exploring fast-acting alternatives. One promising approach comes from a surprising source: nitrous oxide, better known as “laughing gas.”
A team led by Dr. Peter Nagele at the University of Chicago, along with researchers from the University of Pennsylvania and Washington University in St. Louis, has discovered a new way this common anesthetic may help relieve depression—quickly and effectively.
Their findings, published in Nature Communications, explain how nitrous oxide works in the brain and why its effects last long after the gas has left the body.
Nitrous oxide is widely used as a pain reliever and calming agent, especially in dental clinics. At high doses, it can make people feel euphoric, but at the low doses used in depression treatment, it acts more like a gentle sedative. Patients feel calm but not giggly.
“Despite being used for over 180 years, we’re still learning what nitrous oxide can do,” said Dr. Joseph Cichon, one of the lead researchers. “It’s cheap, safe, and well known—but it turns out it might be powerful in a way we never expected.”
In earlier clinical trials, a single session of inhaling nitrous oxide gave fast relief to patients with TRD. Some felt better within hours, and the effects lasted up to two weeks. This left researchers wondering: how can a gas that exits the body in minutes have such a long-lasting impact on mood?
To answer that question, the researchers studied mice that had been exposed to long-term stress—a common model for human depression. Using advanced imaging tools, they watched brain activity in real time while the mice inhaled nitrous oxide.
They focused on a brain region called the cingulate cortex, which is involved in controlling emotions and mood. In particular, they looked at a type of brain cell called layer V pyramidal neurons (L5 neurons), which usually go quiet when a person—or a mouse—is under chronic stress or depression.
After the mice inhaled nitrous oxide, these L5 neurons suddenly lit up with activity. This happened even after the gas had left the body. The once-sluggish mice started moving around more and doing things they normally enjoy, like drinking sweet water.
The key was a type of tiny “gate” on the neurons called an SK2 channel. Normally, SK2 channels help shut neurons down, especially during stress. But nitrous oxide blocks these gates, allowing the brain cells to stay active. This reawakening of brain circuits may be why the antidepressant effect kicks in so quickly and lasts much longer than the gas itself.
“This reactivation of the brain seems to lift the fog of depression,” said Nagele. “It doesn’t require growing new brain connections. It just wakes up the ones that were shut down by stress.”
For years, scientists believed that fast-acting antidepressants like ketamine worked mainly by blocking something called NMDA receptors, which are involved in learning and memory. Nitrous oxide was thought to work the same way. But this new study suggests a different pathway is also at play—one that could lead to entirely new kinds of treatments.
“NMDA receptors still matter,” Nagele said, “but we now know that there’s another door into the brain’s emotional circuits. That’s very exciting.”
If researchers can design new drugs that copy what nitrous oxide does—especially ones that don’t require clinical supervision or gas inhalation—it could mean safer, more accessible treatments for millions of people with depression.
Still, the team cautions that more research is needed to understand how long the effects last and whether repeated doses help people stay well over time. But they are hopeful that this breakthrough could eventually help patients who have found no relief from traditional antidepressants.
This study marks a major step forward in understanding how fast-acting treatments like nitrous oxide work. For people suffering from treatment-resistant depression, a medication that brings rapid relief without weeks of waiting is life-changing. The discovery that SK2 channels—and not just NMDA receptors—play a role opens the door for a new class of antidepressants.
The fact that nitrous oxide is already widely used, safe, and inexpensive makes it an especially appealing candidate. And since the study showed how the gas activates brain circuits rather than building new ones, future treatments could work faster and with fewer side effects.
In short, laughing gas may no longer be just for the dentist—it could be the key to unlocking faster, more effective care for people battling severe depression.
If you care about depression, please read studies about vegetarianism linked to higher risk of depression, and Vitamin D could help reduce depression symptoms.
For more information about health, please see recent studies that ultra-processed foods may make you feel depressed, and these antioxidants could help reduce the risk of dementia.
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