Laughing gas can potentially transform treatment for tough-to-beat depression

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 at the University of Pennsylvania, reported today 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. I felt like Indiana Jones, going back in time to crack the mystery of this ancient drug."

 Joseph Cichon, MD, PhD, Assistant Professor of Anesthesiology and Critical Care

Discovering the hidden mechanism

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 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 said. "This wasn't part of the old assumptions about nitrous oxide-and it's turning what we thought we knew upside down."

How it works: A brain wake-up call

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 explained. "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 quickly showed signs of feeling better, moving more and sipping sweet water, a mouse version of enjoying life. These effects lasted hours, and sometimes a full day. There are pores in brain cells (L5 neurons), called potassium channels or SK2 channels, that allow potassium ions to flow out of the cells and "calm" them. The nitrous gas blocks those channels, revving the cells up and waking nearby cells too. Blocking these SK2 channels keeps the brain cells buzzing, which quickly lifts mood-a new way for laughing gas to fight depression. Unlike the old NMDA theory, this is a fresh mechanism that could explain why nitrous oxide helps people with depression that resists other treatments.

Fast and full of potential

About one in three people with depression don't respond to typical antidepression medications, which can take weeks to kick in-if they work at all. Nitrous oxide acts fast and lingers longer than its five-minute stay in the body would suggest. Human trials led by Peter Nagele, MD, a Professor at the University of Chicago, and Charles Zorumski, MD, a Professor at University of Washington in St. Louis, both authors on the study, have already shown it can ease symptoms rapidly in people with treatment-resistant depression.

The catch? It's not a pill that can be taken at home. A person must make an appointment and travel to see a medical professional who is trained to administer the gas with anti-depressant dosage. Possible side effects include feeling claustrophobic from the mask and nausea from the gas. But looking ahead, Cichon sees bigger possibilities: "If we can figure out how to tweak those potassium channels directly in the brain, scientists might be able to develop new depression drugs inspired by this gas."

Digging deeper into the past for the future

This discovery isn't just about nitrous oxide-it's about learning from a drug that was thought to be fully understood. "We use it every day around the world, yet it still has secrets to share," Cichon said.

Next steps include determining how long the mood boost could last in mice and whether nitrous oxide could help rewire the brain for lasting relief. If confirmed, a drug in use for over 180 years could bring renewed hope to those struggling with depression.

The research was funded by the National Institutes of Health (R35GM151160-01) and the Brain & Behavior Research Foundation (K08GM139031, R01GM088156, R01GM151556, MH122379).