Laughing gas may be far more effective for some than antidepressants.
- Standard antidepressant medications don't work for many people who need them.
- With ketamine showing potential as an antidepressant, researchers investigate another anesthetic: nitrous oxide, commonly called "laughing gas."
- Researchers observe that just a light mixture of nitrous oxide for an hour alleviates depression symptoms for two weeks.
The usual antidepressants don't work for everyone. That's what makes a new study of the antidepressant properties of nitrous oxide so intriguing. It looks like just a single low dose of what your dentist may call "laughing gas" can help alleviate symptoms of depression for weeks afterward.
The study, from researchers at University of Chicago and Washington University-St. Louis, is published in the journal Science Translational Medicine.
Resistance to anti-depression medications
Nitrous oxide: two atoms of nitrogen, one of oxygenCredit: Big Think
According to the senior author of the study, Charles Conway, "A significant percentage — we think around 15 percent — of people who suffer from depression don't respond to standard antidepressant treatment."
"These 'treatment-resistant depression' patients," Conway says, "often suffer for years, even decades, with life-debilitating depression. We don't really know why standard treatments don't work for them, though we suspect that they may have different brain network disruptions than non-resistant depressed patients. Identifying novel treatments, such as nitrous oxide, that target alternative pathways is critical to treating these individuals."
"There is a huge unmet need," says lead author Peter Nagele. "There are millions of depressed patients who don't have good treatment options, especially those who are dealing with suicidality."
If ketamine can help, can nitrous oxide?
Credit: sudok1 / Adobe Stock
The researchers wondered if some of the anti-depression properties seen in ketamine might also apply to nitrous oxide. Nagele explains, "Like nitrous oxide, ketamine is an anesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression."
The researchers conducted a one-hour session — they describe it as a "proof-of-principle" trial — in which 20 individuals with depression were administered an air mixture with 50 percent nitrous oxide. Twenty-four hours later, the researchers found a significant reduction in the participants' symptoms of depression versus a control group.
However, the individuals also suffered the unpleasant side effects that laughing gas often causes in dental patients: headache, nausea, and vomiting.
Smaller dose, longer effect
Credit: sudok1 / Adobe Stock
"We wondered if our past concentration of 50 percent had been too high," recalls Nagele. "Maybe by lowering the dose, we could find the 'Goldilocks spot' that would maximize clinical benefit and minimize negative side effects."
In a new trial, 20 people with depression were given a lighter nitrous oxide mix, just 25 percent, and the individuals tested reported a 75 percent reduction in side effects compared to the a control group given an air/oxygen placebo. This time, the researchers also tracked the effect of nitrous oxide on symptoms of depression for a far longer period, two weeks instead of just 24 hours.
"The reduction in side effects was unexpected and quite drastic," reports Nagele, "but even more excitingly, the effects after a single administration lasted for a whole two weeks. This has never been shown before. It's a very cool finding."
Nagele also notes that, despite its popular renown as laughing gas, even a light 25 percent mix of nitrous actually causes people to nod off. "They're not getting high or euphoric; they get sedated."
Delivering help to people with depression
Nagele cautions, "These have just been pilot studies. But we need acceptance by the larger medical community for this to become a treatment that's actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we'll have to show the community how to deliver this treatment safely and effectively. I think there will be a lot of interest in getting this into clinical practice."
After all, Nagele adds, "If we develop effective, rapid treatments that can really help someone navigate their suicidal thinking and come out on the other side — that's a very gratifying line of research."
Studies and trials point to the potential of a rave drug becoming the newest antidepressant medication in decades.
A powerful anesthetic, used as an animal tranquilizer and an illicit club drug, has been receiving growing attention for its potential to treat depression. A number of studies point to the possibility that ketamine (known in the club scene as “special K”) can become the next big thing in anti-depressant medications.
While it’s not approved by the FDA for treating depression, numerous clinics have sprung up to treat patients “off-label”, with low doses of the drug, while drug manufacturers are ramping up research and development.
Yale professor of psychiatry Dr. Sanacora, who has used ketamine to treat hundreds of patients suffering from severe depression, said in a recent interview with NPR that he feels an obligation to use the drug.
"If you have patients that are likely to seriously injure themselves or kill themselves within a short period of time, and they've tried the standard treatments, how do you not offer this treatment?" said Sanacora.
He also says a survey of U.S. and Canada clinics showed that “over 3,000” patients have already been treated.
How effective can ketamine be? It has been shown to relieve the kind of depression that no other drugs can affect. It's lifted even suicidal depression in just hours. With studies into ketamine going on for over a decade, a recent statement from the American Psychiatric Association says there is “compelling evidence” that it works, although its effects have been described as “transient.”
There is definitely more research to be done, especially considering the absence of large-scale trials.
“We don't know how much or how often it should be given for it to be effective or safe,” said psychiatry and neuroscience Professor James Murrough, in a review of ketamine published in Nature Reviews Drug Discovery.
Murrough is concerned that we don’t know the long-term effects of taking the drug. It also tends to wear off, necessitating more to be taken. Another big issue — how to avoid the often-unpleasant “high” from the drug, leaving only its therapeutic qualities. Professor Sanacora shares those concerns:
“In a nutshell, I feel confident telling patients who have had little help from previous treatments that ketamine provides meaningful relief from some of their worst symptoms for at least a few days or even weeks,’’ said Dr. Sanacora. “But I can’t tell them with any degree of certainty how long the benefit can be sustained or how safe it is to repeatedly administer the medication over periods of months or years. "
But even with reasonable cautions, ketamine’s promise is very much real, as it can lead to a totally new kind of medication.
"There's warranted caution that's balanced with an optimism that says we've never had a new medication for depression since the era of Prozac," says Murrough.
While most current antidepressants target the neurotransmitters serotonin and noradrenaline, ketamine works on glutamate. Before ketamine was studied, the role of this pathway in depression was not known.
Will we see a ketamine drug soon?
A 2016 study on mice found that the compound hydroxynorketamine may be responsible for ketamine’s success in treating depression. The scientists involved are going to human trials next.
A compound formed from ketamine called esketamine is now in the final testing stage before being considered by the FDA. Other ketamine-like drugs are also in development.
When used in clubs, ketamine is usually injected or snorted to create strong feelings of detachment. The more it’s taken, leading down what’s called a “K hole,” the more feelings of disassociation it will cause. For that reason, it can also be dangerous, with potential to cause temporary amnesia, confusion, increased heart rate, aggression and impaired motor function. There have also been cases of ketamine overdosing leading to date rape (due its paralyzing effects) or even death. In other words - don’t try this at home and wait for the science to catch up.
Check out this Big Think interview with neurobiologist and psychiatric Dennis Charney, who explains how ketamine works differently than other antidepressants: