The Unexplored Effects of Weight-Loss Drugs on the Brain

In the past few years, Ozempic has become totemic with weight loss. About one in eight adults reportedly takes this popular diabetes and weight loss drug, chemically known as semaglutide, at some point.¹ Semaglutide is a glucagon-like peptide-1 (GLP-1) mimic that stimulates insulin production and slows down emptying of the stomach, making one feel fuller for longer.² Researchers have studied this molecule for over 20 years and understand how it regulates metabolism well. But scientists are now finding out that the drug has other wide ranging, and less described, effects on the brain. In new studies presented at the Society for Neuroscience conference in October 2024, scientists reported that semaglutide can mitigate cognitive deficits associated with Alzheimer’s disease, reduce acute and chronic pain, and alter exercise motivation in rodent models.

“The brain is the organ that controls what you eat, how you eat and how much energy you expend,” said Karolina Skibicka, a neuroscientist at the Pennsylvania State University who is an expert on GLP-1 and was not part of the studies. It makes sense then that a drug that modulates the appetite will influence the brain. But it turns out that semaglutide also plugs into physiological processes that are far removed from metabolism.

Previously, researchers have shown that GLP-1 mimics can alter the reward value associated with food, alcohol, cocaine, and nicotine.^3–6 They administered GLP-1 or its analogs to rodents and saw that their motivation to obtain these substances reduced.Ralph DiLeone, a neuroscientist at Yale University, was interested in understanding whether this effect translated to exercise motivation, especially since mice are naturally drawn to exercise and view it as a reward. “If you give these mice wheels, they run anywhere between 10–12 kilometers every single night,” DiLeone said. He showed that giving semaglutide to mice reduced their motivation to run, irrespective of how much they ate. A reduction in running time was equivalent to a lack of interest in exercising.

The brain also perceives reward in other ways, such as eating food. This can play a key role in alleviating pain, a phenomenon called ingestion analgesia. “In my experience, after eating, you feel a little bit better, when you’re sick,” said Yong Ho Kim, a pain researcher at Gachon University. Considering that GLP-1 levels increase after a meal, Kim investigated if and how this peptide could modulate pain caused by a variety of factors. A key receptor that signals pain is the transient receptor potential vanilloid 1 (TRPV1) channel. In chronic pain, not only do the levels of TRPV1 on pain sensing neurons go up, but the receptors also become hypersensitive to stimuli. Kim showed that treating mice with semaglutide reduced their sensitivity to painful stimulus like heat, as compared to control mice. He also reported that semaglutide alleviated pain in both acute and chronic pain models.

Another therapeutic avenue for semaglutide is in combating neurodegenerative diseases. Chronically high levels of blood glucose can cause inflammation and death of neurons, brain aging, cognitive impairment, and even dementia. Researchers have shown that GLP-1 can act as a link between metabolic and brain disorders.⁷ In a recent study, Emile Andriambeloson, a neuroscientist at Neurofit, showed that semaglutide can improve memory deficits in mouse models of late-stage Alzheimer’s disease. The accumulation of misfolded amyloid-β proteins and the consequent inflammation in the brain leads to Alzheimer’s disease. Andriambeloson and his team saw that administering semaglutide to mice that had these protein plaques or inflammation for one week significantly ameliorated their memory and cognition deficits, as compared to placebo-treated mice. Inflammation also causes neurons to die, a hallmark of Alzheimer’s disease. The team noted that semaglutide protected these neurons and prevented their death.

These new findings set the foundation to explore the wide net GLP-1 casts in the body. “We definitely don’t know everything,” said Skibicka. “There are populations of [GLP-1] receptors that we haven’t asked what they do. They might be doing something surprising.” As to what we know about how GLP-1 is orchestrating these diverse behaviors, according to DiLeone, there might be common underlying pathways, but it is likely that there are also unique elements driving these effects. This opens possibilities to target them specifically at a behavioral and therapeutic level.