Nitrous oxide has been used for nearly 200 years for anesthesia and pain relief. Dentists often administer "laughing gas" to people undergoing tooth extractions, root canals and other procedures, because it eases anxiety and the awareness of pain. It's also been used for the same purpose during labor for nearly 100 years, most commonly in Europe and Australia.
In recent years, the sedative gas — which is inhaled through a mask or nose piece — has been studied as a possible treatment for depression. New research from the University of Pennsylvania offers deeper insight into why nitrous oxide seems to help people who have not found relief through several commonly prescribed antidepressants.
MORE: More than 50 local researchers sign letter protesting Trump administration for 'gutting' science
People are diagnosed as having treatment-resistant depression when two or more antidepressants don't ease the symptoms of major depression. A 2021 study found that people who breathed in a mixture of nitrous oxide and oxygen for one hour had significant relief from treatment-resistant depression. Sometimes, it alleviated symptoms for weeks. But the reason for this was not fully understood.
The Penn Medicine study found laughing gas seems to impact a group of neurons that help regulate behavior and emotion. Brain images show these neurons are underactive in mice and humans with stress-related depression. But the laughing gas seems to activate those neurons in mice, stimulating them out of stress-related lethargy, the new study found.
"Most anesthetics calm the brain, then the effects of the anesthetic fade away," Dr. Joseph Cichon, one of the study's authors, said in a news release. "But this one flips a switch – those cells start firing like crazy, and they keep going even after the gas is gone. That was a total surprise."
The mice became more active and sipped sugar water, something they enjoy. The nitrous oxide seemingly blocks certain channels in the brain that usually silence the neurons. Those cells remained activated, stimulating the surrounding brain circuit into a more "energized" state, the researchers said.
"It helps reactivate neural circuits dulled by stress and depression without needing to form entirely new brain connections," said Dr. Peter Nagele, a University of Chicago researcher who has conducted prior research on nitrous oxide and depression, and co-authored the new study.
But nitrous oxide does not come in pill form. People have to see a provider trained to administer the gas at antidepressant levels. More research into how long the positive effects of nitrous oxide last on mice and whether it has the potential to rewire the brain is needed, Cichon said.
Also, nitrous oxide abuse – commonly known as doing "whippets" – is on the rise. More than 13 million people in the United States have misused nitrous oxide in their lifetimes, according to the 2023 National Survey on Drug Use and Health. Fatal nitrous oxide poisonings shot up by 110% between 2019 and 2023, according to the Centers for Disease Control and Prevention.
Last month, the U.S. Food and Drug Administration put out an advisory that warned people not to inhale nitrous oxide products that can lead to blood clots, asphyxiation and death. The FDA had observed an increase in reports of health complications from people misusing nitrous oxide.
The products have been available on Amazon, eBay, Walmart and at smoke shops and gas stations under a variety of names including Baking Bad, Cosmic Gas, Galaxy Gas, HOTWHIP, InfusionMax, MassGass, Miami Magic and Whip-it!