Weight-loss drugs like Wegovy and Zepbound have helped millions of Americans shed pounds, yet many users struggle with significant side effects. Nausea, vomiting, and decreased thirst can make treatment difficult to maintain. Researchers are now investigating how to refine these drugs, targeting appetite reduction while minimizing unpleasant effects.
How GLP-1 Drugs Work
GLP-1 agonists mimic a hormone that reduces appetite and slows digestion. They are highly effective at helping people lose weight, but the side effects are a major obstacle. Warren Yacawych of the University of Michigan explains, “They lose weight, which is a positive thing, but they experience such severe nausea and vomiting that patients stop treatment.”
At the Society for Neuroscience meeting in San Diego, Yacawych and his colleagues discussed efforts to separate the beneficial effects of these drugs from the negative ones.
Gut-Brain Connection
Instagram | @medscape | GLP-1 drugs cause effective weight loss, but severe nausea often stops treatment.
Scientists have identified two types of neurons in the abdomen that play a role in digestion. These neurons play a crucial role in the gut-brain connection, influencing appetite, satiety, and nausea.
1. One area in the brain stem, sometimes called the “vomit center,” detects potential toxins and triggers nausea or vomiting.
2. Another area monitors food intake and signals fullness to the brain.
Yacawych’s team experimented with directing GLP-1 drugs specifically to the fullness-regulating area while avoiding the vomit center. In mice, this prevented nausea but did not trigger weight loss.
This suggests that some cells within the vomit center are essential for GLP-1’s weight-loss effects, making it challenging to eliminate side effects without compromising efficacy.
Exploring Combination Approaches
A separate approach comes from Ernie Blevins at the University of Washington. His team administered a low dose of GLP-1 drugs along with oxytocin, another hormone that suppresses appetite.
This combination allowed obese rats to lose weight without experiencing nausea, offering a potential path forward for human treatments.
Additional Side Effects
GLP-1 drugs can also reduce thirst, which poses risks for people already experiencing dehydration due to vomiting or diarrhea. Derek Daniels from the University at Buffalo notes, “If you’re in that state of dehydration and you’re not feeling thirsty to replace those fluids, that would be a problem.”
Freepik | GLP-1 drugs reduce thirst, risking dehydration in patients with vomiting or diarrhea.
While studying rats, Daniels’ team discovered that Brattleboro rats—a type with a mutation causing constant thirst—were highly sensitive to GLP-1 drugs, which sharply reduced their water intake. Mapping the brain regions affected by GLP-1 could allow future drugs to reduce appetite while preserving thirst signals.
Appetite, Reward, and Addiction
Research from the University of Virginia revealed that GLP-1 drugs also interact with brain regions associated with reward and emotion. Ali D. Güler explains, “When GLP-1 was delivered to this brain area in mice, it reduced their desire for rewarding food, like a burger, but they continued to eat healthy, nonrewarding foods.”
This discovery may also explain why some people taking GLP-1 agonists reduce alcohol consumption. Targeting these brain regions could lead to new treatments for overeating, alcohol use, and other substance-related disorders, separating appetite suppression from unwanted nausea.
Challenges and Future Directions
Efforts to develop GLP-1 drugs that reduce appetite without triggering nausea, vomiting, or dehydration are ongoing. By identifying the specific brain regions responsible for each effect and exploring targeted drug delivery or combinations with hormones such as oxytocin, scientists aim to create safer and more tolerable weight-loss therapies.
Understanding how neurons control appetite, nausea, and thirst could make future treatments more effective and easier for patients to maintain, improving long-term health outcomes.