Laughing gas: An old drug’s new trick to fight depression
Researchers at the Perelman School of Medicine have uncovered how nitrous oxide, an anesthetic used worldwide since the 19th century, could help lift mood fast in people with depression that resists other treatments.
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Nitrous oxide—better known as “laughing gas”—can potentially transform treatment for tough-to-beat depression. This centuries-old anesthetic gas targeted specific brain cells in mice and quickly reduced symptoms, according to new research from the Perelman School of Medicine, reported in Nature Communications.
“Nitrous oxide is the oldest anesthetic we’ve got—it’s been used worldwide for over 180 years, costs about $20 a tank, and yet we’re still learning what it can do,” says Joseph Cichon, an assistant professor of anesthesiology and critical care. “I felt like Indiana Jones, going back in time to crack the mystery of this ancient drug.”
First discovered for its giddy, mood-lifting effects (hence the nickname “laughing gas”), nitrous oxide was a go-to anesthetic in the 19th century. For years, it was widely understood to work by blocking certain receptors (called NMDA receptors) which are in nearly all brain cells and are known to play a big role in how brain cells communicate, especially in managing pain.
Cichon’s team, however, found something different. After hundreds of experiments and a process of elimination, they zeroed in on a group of brain cells called layer 5 (L5) neurons, which lie deep in the grey matter of the brain, in an area called the cingulate cortex helping regulate emotions and behavior. “We were trying to unlock the secrets of these layer 5 neurons,” Cichon says. “This wasn’t part of the old assumptions about nitrous oxide—and it’s turning what we thought we knew upside down.”
The Penn team, working with researchers from the University of Chicago and Washington University in St. Louis, tested nitrous oxide on mice who were exposed to stressful conditions. After breathing the gas for an hour through masks, the mice’s L5 neurons, sprang to life within minutes. “Most anesthetics calm the brain, then the effects of the anesthetic fade away,” Cichon explains. “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.”
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