Brain scientists are seeking weight-loss drugs without the nausea

Millions of Americans have shed pounds with help from drugs like Wegovy and Zepbound.

But people who take these drugs often experience unpleasant side effects.

"They lose weight, which is a positive thing," says Warren Yacawych of the University of Michigan, "but they experience such severe nausea and vomiting that patients stop treatment."

So at this year's Society for Neuroscience meeting in San Diego, Yacawych and other researchers held a session to describe their efforts to understand and solve the side-effect problem.

The weight-loss products are called GLP-1 agonists. They work by mimicking a hormone that reduces appetite and slows digestion.

Yacawych and his colleagues wanted to know if they could tweak these drugs to suppress appetite without making people queasy.

The team focused on two areas in the brain stem where GLP-1 drugs have a big effect.

"The first is affectionately known as the brain stem's vomit center," Yacawych says. "It's naturally designed to detect any accidentally ingested toxin and coordinate the feeling of nausea and the vomit response."

The second area monitors food intake and tells people when they're full.

The team found a way to direct GLP-1 to the area involved in feeling full, while keeping the drug out of the vomit center.

When the researchers did this, the mice no longer felt sick. But they also didn't get thin — probably because there are specific cells in the vomit center that do not induce vomiting but are critical to weight loss.

"So it's very challenging," Yacawych says, "to be able to separate these side effects, like nausea, from GLP-1's intended effects, like weight loss."

A possible workaround came from a team led by Ernie Blevins of the University of Washington. They gave obese rats a low dose of a GLP-1 drug along with the hormone oxytocin, which is itself an appetite suppressant. That allowed the rats to lose weight without feeling sick.

Not just nausea

Another side effect of GLP-1 drugs is a decrease in thirst, which could be dangerous for people who are already losing lots of fluids from side effects like vomiting and diarrhea.

"If you're in that state of dehydration and you're not feeling thirsty to replace those fluids, that would be a problem," says Derek Daniels of the University at Buffalo.

To understand how GLP-1 drugs reduce thirst, Daniels and a team began studying the brains of rats. And they got lucky.

"We had a happy accident in the lab," Daniels says. "And the happy accident involved a rat called the Brattleboro rat."

Brattleboro rats are laboratory rodents with a genetic mutation that makes them thirsty nearly all the time. But the scientists discovered that these rats are also very sensitive to GLP-1 drugs, which drastically reduced their water consumption.

The team studied the rats' brains to see where GLP-1 was influencing thirst. That led them to several areas of the brain that appear to affect thirst but not appetite.

The discovery could help scientists preserve thirst by designing drugs that "target good places but not bad places," Daniels says.

Appetite and addiction

A team from the University of Virginia found that GLP-1 drugs are already targeting a brain area that plays a role in addiction as well as eating. It's a region involved in emotion and the reward system.

When the researchers delivered GLP-1 to this brain area in mice, it reduced their desire for "rewarding food, like a burger," says Ali D. Güler of the University of Virginia.

But the animals continued to eat healthy, nonrewarding foods, he says — a bit like people choosing a salad bar over dessert.

Identifying this brain area should help scientists find GLP-1 drugs that target the reward system while avoiding areas involved in appetite, Güler says. And that could lead to new treatments for alcoholism and other substance use disorders.

The finding also could explain the observation that people who take GLP-1 agonists tend to reduce their consumption of alcohol.