For millions of people struggling with obesity, GLP-1 drugs like Wegovy and Zepbound have been a game-changer—helping users shed pounds by mimicking hormones that curb appetite and slow digestion. But while the results have been impressive, there’s a catch that’s hard to ignore: severe nausea and vomiting. According to NPR, these side effects have been so intense for some that they’ve abandoned treatment altogether. "They lose weight, which is a positive thing, but they experience such severe nausea and vomiting that patients stop treatment," explained Warren Yacawych of the University of Michigan at the 2025 Society for Neuroscience meeting in San Diego.
So, what’s being done to tackle this queasy conundrum? Scientists are racing to develop new versions of GLP-1 drugs that deliver the coveted weight-loss benefits without making users sick. The latest research, presented at the Society for Neuroscience gathering, offers a glimpse of hope—and some fascinating insights into how our brains process hunger, fullness, and even addiction.
GLP-1 drugs work by mimicking a hormone that not only reduces appetite but also slows the digestive process. But as Yacawych’s team discovered, these medications act on two key regions in the brain stem. The first, affectionately dubbed the "vomit center," is designed to detect toxins and trigger nausea and vomiting. The second monitors food intake and signals when we’re full. The challenge? Figuring out how to steer GLP-1 drugs away from the vomit center while still activating the fullness signal.
In experiments with mice, Yacawych and his colleagues managed to direct the drugs to the fullness area, sparing the animals the misery of nausea. But there was a hitch: the mice didn’t lose weight. It turns out that some cells in the vomit center, while not responsible for vomiting, are crucial to the weight-loss effect. "So it's very challenging," Yacawych admitted to NPR, "to be able to separate these side effects, like nausea, from GLP-1's intended effects, like weight loss."
But researchers aren’t giving up. A team led by Ernie Blevins at the University of Washington tried a new approach: pairing a low dose of GLP-1 drugs with oxytocin, a hormone known for its appetite-suppressing powers. When they administered this combo to obese rats, the animals lost weight—without the telltale signs of queasiness. It may not be a perfect solution yet, but it’s a step closer to a nausea-free weight-loss drug.
The story doesn’t end there. Another group, led by Ali D. Güler at the University of Virginia, has been exploring how GLP-1 drugs influence the brain’s reward system—the same circuitry involved in addiction. Their research revealed that delivering GLP-1 to this brain area in mice reduced their cravings for "rewarding food, like a burger," as Güler described to NPR. The mice continued to eat healthy foods, suggesting that future GLP-1 drugs could be tailored to curb unhealthy cravings while sparing users from nausea. Intriguingly, this finding also hints at a potential role for GLP-1 drugs in treating alcohol and substance use disorders, since people on these medications tend to drink less.
But nausea isn’t the only side effect scientists are hoping to sidestep. As Derek Daniels of the University at Buffalo pointed out to NPR, GLP-1 drugs can also reduce thirst—a risky proposition for those already losing fluids from vomiting or diarrhea. Daniels’ team stumbled upon this effect while studying Brattleboro rats, which have a genetic mutation that leaves them perpetually thirsty. When these rats were given GLP-1 drugs, their water consumption plummeted, leading the researchers to identify brain regions that control thirst independently from appetite. The hope is that future drugs can be engineered to avoid these "bad places," preserving thirst while still promoting weight loss.
While the quest for a side-effect-free GLP-1 drug continues, there’s more good news on the horizon for those seeking easier and more affordable options. A study published in The Lancet on November 21, 2025, detailed the development of orforglipron—a once-a-day oral GLP-1 agonist pill. Unlike current injectables, which are not only costly (up to £206 per dose in the UK, according to The Independent) but also require refrigeration and careful administration, orforglipron is predicted to be cheaper, more convenient, and easier to manufacture. The study tracked 1,444 obese participants in 10 countries over 16 months, all of whom received lifestyle advice alongside varying doses of the pill or a placebo.
The results were promising. Those taking the highest dose of orforglipron (36mg) lost an average of 9.6% of their body weight. Lower doses (12mg and 6mg) resulted in 7% and 5.1% weight loss, respectively, while the placebo group lost just 2.5%. In addition to weight loss, orforglipron helped reduce blood sugar levels. The most common adverse effects were "mild to moderate gastrointestinal events," a notable improvement over the severe nausea often seen with injectable GLP-1 drugs.
"Its effects in terms of weight loss or diabetes improvements are not as good as tirzepatide but it’s a tablet and that may make it more acceptable by patients who prefer not to inject," Alex Miras, professor of endocrinology at Ulster University, told The Independent. "As a tablet it is much easier and cheaper to be made by the manufacturer and I am hoping that this will be reflected in a favourable price." With orforglipron expected to hit the US market in early 2026 and expand globally soon after, accessibility could improve dramatically for those who have been priced out of current treatments.
Experts are optimistic about what this could mean for public health. Naveed Sattar, professor of cardiometabolic medicine at Glasgow University, told The Independent, "A new oral tablet for weight loss, which can be taken alongside other medications without the need for fasting, could provide a convenient option for people with mild to moderate obesity who want to prevent further weight gain." Dr. Deborah Horn, medical director at UTHealth Houston, went even further: "Because of the safety profile of orforglipron and the predicted much lower cost, it will open the door for many more individuals who need and deserve treatment for their obesity, with or without diabetes, to get care around the world." She hopes orforglipron will become the "metformin of obesity—a lower cost, broad coverage, low risk, highly effective medication for obesity and many of the inter-related diseases."
Meanwhile, the demand for GLP-1 drugs remains sky-high. According to a RAND report from August 2025, nearly 12% of Americans have tried these medications for weight loss, with about half experiencing nausea. With scientists closing in on drugs that can deliver results without the misery, and new oral options poised to expand access, the future of weight-loss medicine looks brighter—and a lot less queasy—than ever before.
As research continues and new treatments move closer to reality, those hoping for a side-effect-free solution to obesity may soon find relief not just on the scale, but in their day-to-day well-being as well.
