Oral GLP-1 drugs may quiet the brain’s food craving circuit Oral relatives of Ozempic and other semaglutide drugs may curb cravings by turning down the brain’s reward response to pleasurable food. - Date: - July 25, 2026 - Source: - NIH/Office of the Director - Summary: - Newer oral drugs related to semaglutide medications such as Ozempic reduced pleasure-driven eating in mice by quieting a deep brain reward circuit. The finding could open new avenues for understanding food cravings and potentially treating substance use disorder.

- Share: Popular weight-loss and diabetes medications such as semaglutide and Ozempic belong to a broader group known as GLP-1 drugs. A study funded by the National Institutes of Health (NIH) has now identified a previously unrecognized way that some newer oral drugs in this class may affect the brain. In mice, the medications reduced hedonic feeding, which means eating for enjoyment rather than because the body needs energy.

The drugs appeared to do this by changing activity in a reward circuit located deep inside the brain. This newly mapped pathway is separate from the appetite-control systems previously linked to drugs such as semaglutide. Researchers say it may also offer clues about whether GLP-1 medications could eventually be used to address other problems involving reward and craving, including substance use disorder.

Oral Alternatives to Injectable GLP-1 Drugs The University of Virginia team studied small-molecule GLP-1 receptor agonists. These compounds differ from larger peptide medications such as semaglutide, which is used in well-known drugs including Ozempic, Wegovy, and Rybelsus. The researchers focused on orforglipron, a Food and Drug Administration (FDA)-approved oral medication, as well as the experimental small-molecule drug danuglipron.

Oral compounds of this kind can be taken as pills and may cost less to manufacture than injectable GLP-1 drugs. "As the accessibility of these medications continues to rise and patient uptake increases, it's crucial that we understand the neural mechanisms underlying the effects we're seeing," said Lorenzo Leggio, M.D., Ph.D., Clinical Director of NIH's National Institute on Drug Abuse (NIDA). How Semaglutide and Other GLP-1 Drugs Affect Hunger Scientists have already studied the effects of larger peptide GLP-1 drugs, such as semaglutide, extensively.

Research has shown that these medications reduce hunger-driven eating by acting on networks in the hypothalamus and hindbrain. Much less was known about what small-molecule oral GLP-1 drugs do after they enter the brain. To investigate, the researchers used gene-editing techniques to modify GLP-1 receptors in mice, making the receptors more similar to those found in humans.

A Surprising Signal Deep in the Brain The team gave the mice either orforglipron or danuglipron and then examined which parts of the brain became active. As expected, the drugs affected regions already associated with appetite regulation. However, they also activated the central amygdala, an area involved in desire and reward.

This region lies deeper in the brain than scientists had previously thought GLP-1 drugs could reach directly.