Depression that resists traditional treatments may have a surprising new contender: laughing gas.
Researchers have discovered that nitrous oxide, commonly used as an anesthetic, can quickly lift mood and activate brain circuits dulled by stress, effects that may last long after the gas has left the body. By unlocking a novel brain mechanism involving specific neurons and potassium channels, this study points to an entirely new path for fast-acting depression treatments.
Searching for Faster, More Effective Depression Treatments
While many medications and therapies are available for major depression, about one in three patients don’t respond to standard treatments. This condition, known as treatment-resistant depression (TRD), doesn’t improve with first-line antidepressants. Even when traditional drugs do help, they often take weeks to show effects, delaying relief for people who may be in urgent need.
To address this gap, scientists have started exploring fast-acting alternatives that work differently in the brain. Inspired by promising results with ketamine, a team led by Peter Nagele, MD, Professor of Anesthesia and Critical Care and Psychiatry and Behavioral Neuroscience at the University of Chicago, turned their attention to another anesthetic: nitrous oxide, commonly known as laughing gas.
Laughing Gas Shows Surprising Promise in Early Trials
Early clinical trials suggested that laughing gas could quickly relieve symptoms in patients with TRD. To better understand how this works, Nagele and his colleagues conducted a new study, published today (April 3) in Nature Communications, to investigate what happens in the brain during and after nitrous oxide treatment.
“Figuring out how the observed antidepressant effects work at a neural and molecular level is an important step toward clinical acceptance and implementation,” said Nagele, the senior author of the new paper.
A New Use for a Familiar Anesthetic
Most people associate laughing gas with dentists’ offices, where it’s used to ease anxiety and dull pain. While its nickname hints at euphoric effects, at the low doses used for depression research, it acts as a sedative, giving people a temporary feeling of calm rather than making them feel giddy.
“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,” said first author Joseph Cichon, MD, PhD, an assistant professor of Anesthesiology and Critical Care at the University of Pennsylvania. “I felt like Indiana Jones, going back in time to crack the mystery of this ancient drug.”
In the preliminary clinical trials led by Nagele and researchers at Washington University in St. Louis, even a single inhalation session could bring positive change to patients who hadn’t responded to other treatments, with effects lasting up to two weeks in some cases.
“The results were striking,” Nagele said. “We saw people who had been struggling for years experience meaningful improvement within hours that lasted for weeks. It made us wonder what, exactly, was happening in the brain to cause this.”
Rethinking What Activates Antidepressant Effects
For years, scientists assumed the antidepressant effects of both nitrous oxide and ketamine were tied to the drugs’ ability to block specific proteins on brain cells involved in memory and learning: N-methyl-D-aspartate (NMDA) receptors. But while this theory was widely accepted, it had never been fully tested in living brain circuits. More importantly, it didn’t fully explain why nitrous oxide, which leaves the body very quickly, could produce lasting effects.
To investigate, the researchers from UChicago, UPenn, and WashU used advanced calcium imaging to observe brain activity in mice that inhaled nitrous oxide after being exposed to chronic stress — a common model for depression. Looking at the cingulate cortex, a brain region associated with emotional regulation and mood, they zeroed in on a specific group of neurons known as layer V (L5) pyramidal neurons.
Reactivating Stressed Neurons
“Particularly in stress-related depression, we usually see that these L5 neurons are underactive in both mice and humans,” Nagele said.
In the experimental mice, however, the researchers saw that nitrous oxide quickly and selectively activated L5 neurons, pulling them out of their state of stress-induced inactivity even after the gas left mice’s bodies. The previously-stressed mice almost immediately perked up and started doing more enjoyable activities like sipping sugar water.
“This ‘disinhibition’ effect’ — where the brain becomes less suppressed and more engaged — looks to be a crucial reason for the drug’s antidepressant benefits,” Nagele explained. “It helps reactivate neural circuits dulled by stress and depression without needing to form entirely new brain connections.”
The key turned out to be specialized potassium channels found in L5 neurons, called SK2 channels. Under normal conditions, these channels help shut down neuron activity, but nitrous oxide blocks the SK2 channels, preventing them from silencing the L5 cells. As a result, the neurons remain active and the surrounding brain circuit shifts into a more excitable, energized state.
A Broader Approach to Depression Treatment
“These results show us there might be more than one path to the desired outcome in depression treatment,” Nagele said. “NMDA receptors matter, but what we’re seeing with nitrous oxide suggests there’s another way to spark the brain’s circuitry back into action. It’s an exciting discovery because it widens our understanding of how we can tackle depression from multiple angles.
The researchers caution that while the findings are promising, more studies are needed to understand how long the neurological effects of laughing gas last and whether they contribute to deeper, more permanent recovery.
Paving the Way for Next-Gen Therapies
However, this fresh understanding of how fast-acting antidepressants might work — without relying solely on NMDA-receptor mechanisms — opens the door to future drug development. For example, rather than relying on an inhaled gas that must be clinically administered, scientists might one day design oral medications that mimic this mechanism.
“This study brings us one step closer to understanding how nitrous oxide can help patients who haven’t responded to anything else,” Nagele said. “If we can isolate the exact pathways involved, we could create new depression treatments that are more accessible and longer-lasting.”
Reference: “Nitrous oxide activates layer 5 prefrontal neurons via SK2 channel inhibition for antidepressant effect” by Joseph Cichon, Thomas T. Joseph, Xinguo Lu, Andrzej Z. Wasilczuk, Max B. Kelz, Steven J. Mennerick, Charles F. Zorumski and Peter Nagele, 3 April 2025, Nature Communications.
DOI: 10.1038/s41467-025-57951-y
The research was funded by the National Institutes of Health (R35GM151160-01) and the Brain & Behavior Research Foundation (K08GM139031, R01GM088156, R01GM151556, MH122379). Co-authors include Joseph Cichon, Thomas Joseph, Xinguo Lu, Andrzej Wasilczuk, Max Kelz, Steven Mennerick, Charles Zorumski and Peter Nagele.
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1 Comment
This will never be approved by the FDA because it would be too cheap and disrupt the depression pill industry. The FDA follows the money, not the science. RFK says they are guilty of aggressive suppression. These ‘discovery mills’ are encouraged because of the money made from them. This is all the same with cancer research and too cheap remedies never being brought to fruition.
Btw, I tried Wellburton antidepressant for back pain. Wow! What a surprised. It works fantastic for depression. Unbelievable.