TREATMENT-resistant depression could be eased with laughing gas – with scientists claiming it could “spark the brain back into action”.
The “exciting discovery” follows research into other unconventional ways to treat the condition – including and .
is a colourless gas commonly used as a painkiller in medicine and dentistry.
Mixed with oxygen, it's known as that's used to dull labour pains during childbirth.
Also known as NOS, is often used recreationally – making users feel relaxed and giggly when inhaled through balloons.
Regular and heavy use can cause a range of issues – from vitamin deficienciesto neurological damage – and in some cases can even be fatal.
Nitrous oxide was made a Class C drug in 2023, making possession and sale for recreational purposes .
But scientists have been tapping into its mood-boosting properties, in a effort to cure that resists other kinds of treatments.
According to American researchers, roughly one in three patients diagnosed with the condition suffer from treatment-resistant depression (TRD) – a form of the disorder that does not respond to first-line antidepressants.
Even when traditional work, they can sometimes take weeks to kick in.
Egged on by encouraging research into ketamine as a depression treatment, scientists looked into another fast-acting substance – laughing gas.
The study's first authorJoseph Cichon, an assistant professor of anaesthesiology and critical care at the University of Pennsylvania, said: “Nitrous oxide is the oldest anaesthetic 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.”;
While most people associate laughing gas with 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.
Previous clinical trials lead by Professor Peter Nagele from the University of found that a single inhalation session of 25 per cent nitrous oxide could rapidly relieve symptoms of treatment-resistant depression with few side effects, with the benefits lasting up to two weeks in some cases.
Prof Nagele said: “The results were striking. 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.”;
A new study – published in the journal Nature Communications – looked into how the gas works in the brain to trigger lasting improvements in mood, even though it exits the brain within minutes.
Prof Nagele said: “Figuring out how the observed antidepressant effects work at a neural and molecular level is an important step toward clinical acceptance and implementation.”
For years, scientists assumed the effects of 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 this theory was never tested in living brain circuits and 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 observed brain activity in mice that inhaled nitrous oxide after being exposed to chronic stress — a common model for depression.
Looking at the brain region associated with emotional regulation and mood, they zeroed in on a specific group of neurons known as layer V (L5) pyramidal neurons.
“Particularly in stress-related depression, we usually see that these L5 neurons are underactive in both mice and humans,”; Prof Nagele said.
But researchers saw that in the mice used in the study, the nitrous oxide quickly 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,”; Prof 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 specialised 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, energised state.
Prof Nagele said: “These results show us there might be more than one path to the desired outcome in depression treatment.
“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.”
While the findings are promising, researchers stressed that more studies are needed to understand how long the neurological effects of laughing gas last and whether they can help permanently cure depression.
And it goes without saying that nobody should be giving this treatment a go at home.
But scientists said their research opens the door to drug development, suggesting that pills that mimic the effects of inhaling laughing gas could be designed.
“This study brings us one step closer to understanding how nitrous oxide can help patients who haven’t responded to anything else,”; Prof Nagele said.
“If we can isolate the exact pathways involved, we could create new depression treatments that are more accessible and longer-lasting.”;
