A unique opportunity to observe deep brain activity in a person with obesity and loss of control eating provided new insight into how tirzepatide, sold as Mounjaro and Zepbound, interacts with the brain. Recordings showed that the medication reduced activity in the brain’s reward center, a region linked to food noise and compulsive cravings, although this reduction did not last.
Researchers noted that tirzepatide is a glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist originally created for Type 2 diabetes. Early findings suggest it may also help with conditions related to impulse control, including binge eating disorder. However, the new report from the Perelman School of Medicine at the University of Pennsylvania cautions that current GLP-1 and GIP inhibitors may not be fully optimized for treating these behaviors and warrant more investigation. The case study appears in Nature Medicine.
“This study offers major insights into how these drugs may work inside the brain and will guide us as we explore new indications,” said senior author Casey H. Halpern, MD, a professor of Neurosurgery and head of the Division of Stereotactic and Functional Neurosurgery. “Until we better understand their action on the brain, it’s far too soon to call GLP-1 and GIP inhibitors miracle drugs for more conditions beyond type 2 diabetes and obesity.”
Understanding Loss of Control Eating and Food Noise
Loss of control eating is widespread, affecting many people with obesity as well as multiple eating disorders. Binge eating disorder (BED) is considered the most common eating disorder in the United States, impacting more than 3 million individuals. People with BED often feel unable to stop eating and continue long after they feel full.
Critical brain regions involved in regulating eating behavior include the hypothalamus and the nucleus accumbens (NAc), which serves as a key reward center. The NAc helps govern motivation, pleasure-seeking behaviors, and impulse control. Studies have shown that in people with obesity and BED, signaling within the NAc and related circuits becomes disrupted.
Even without a diagnosis of BED, up to 60 percent of individuals with obesity experience persistent “food noise,” a constant stream of thoughts about food that can lead to distress and maladaptive patterns such as bingeing or loss of control eating. Food noise is also common in bulimia nervosa and anorexia nervosa. Research has linked binge eating with an increased risk of suicide among people with obesity and eating disorders, likely tied to impulsive traits and emotional dysregulation.
“Developing new ways to treat these patients is of the utmost importance,” said Halpern. “While many individuals taking GLP-1 and GIP inhibitors report a reduction in food noise, these medications are not FDA-approved to treat food preoccupation and its related impulsivity. In fact, their impact on human brain activity has only begun to be studied.”
A Patient’s Struggle With Severe Obesity and Food Noise
A 60-year-old woman referred to as “Participant 3” in the study was living with severe, treatment-resistant obesity and persistent food noise. She described constant, intrusive thoughts about food that frequently led her to order takeout or snack throughout the day, even when she tried to stop. She often ate until she felt uncomfortably full and was especially drawn to sugary and salty foods such as packaged cupcakes, fast-food roast beef sandwiches, and French fries. She also had Type-2 diabetes and had previously been prescribed dulaglutide, a GLP-1 inhibitor, but it did not reduce her weight or her obsessive focus on food.
After attempting numerous treatments including bariatric surgery, medications, behavioral therapy, and other interventions for disordered eating, she joined Halpern’s clinical trial. The study involved brain surgery to implant electrodes designed to eventually detect and interrupt cravings before they escalated into binge episodes.
How Brain Signals Reveal the Onset of Cravings
Halpern’s earlier research identified a distinct pattern of electrical activity in the NAc that appears right before a person begins to fixate on food and feels the urge to binge. This activity does not appear when a person is simply hungry before a typical meal. A previous pilot trial led by Halpern showed that delivering high-frequency electrical stimulation to the NAc exactly when these craving signals emerged could stop binge eating behavior.
In the current study of four participants, intracranial electroencephalography (iEEG) electrodes were implanted in individuals with obesity and loss of control eating. Similar to systems used for epilepsy and Parkinson’s disease, the device recorded activity in the NAc as participants encountered foods known to trigger their binge episodes.
After establishing each person’s baseline responses, the research team programmed the electrodes to deliver high-frequency stimulation when craving-related signals were detected. Over six months, participants reported large reductions in loss of control sensations and fewer binge episodes.
Tirzepatide Offers a Rare Research Window
Before surgery, Participant 3 was prescribed tirzepatide to manage her Type-2 diabetes after the first GLP-1 inhibitor did not help her. Her dose was gradually increased to the maximum before and after electrode implantation, since diabetes increases infection risks following surgery. This created an unusual opportunity for researchers to observe how tirzepatide affects brain signals tied to cravings in real time.
“Brain surgery to implant the electrodes is invasive, and thus it is extremely rare to study human brain activity in this way,” said Halpern. “Research fuels more research; This participant was already taking tirzepatide when she enrolled in the trial, but before any stimulation was delivered, giving us a unique opportunity to make foundational observations about how the drug alters brain signals.”
Tirzepatide’s Effects Fade Over Time
Once Participant 3 reached her full tirzepatide dose and had the electrodes implanted, she reported no food preoccupation, and her NAc activity reflected this silence. After roughly five months, however, the previously quiet NAc activity reappeared, along with intense food noise. This shift suggested that tirzepatide’s effect on her loss of control eating was temporary and that the underlying patterns of food preoccupation had resurfaced.
Other participants in the trial who were not taking tirzepatide consistently showed heightened NAc activity and frequent food preoccupation, which aligned with earlier observations from Halpern’s group. The dramatic reduction in signaling seen only in Participant 3 strongly indicated that tirzepatide temporarily suppressed this activity.
“GLP-1 and GIP inhibitors are amazing medications at doing what they were developed for — managing blood sugar in people with type 2 diabetes and weight loss in obesity,” said study investigator Kelly Allison, PhD, a professor of Psychiatry and Director of the Center for Weight and Eating Disorders. “This research shows us that they might be useful to manage food preoccupation and binge eating, but not in their current form.”
“Although this study only featured the data from one person taking tirzepatide, it provides compelling data about how GLP-1 and GIP inhibitors alter electrical signals in the brain,” said co-first author Wonkyung Choi, a PhD candidate in Halpern’s lab. “These insights should inspire further research into developing a treatment better tailored to the impulsivity traits of obesity and related eating disorders that is safe and long-lasting.”
This research was supported by the National Institutes of Health (7UH3NS103446-03, 1R01MH124760-01A1, R25MH119043 and T32NS091008).
