Tirzepatide may only temporarily suppress brain activity associated with 'food noise'

A rare glimpse into the brain activity of obese and out-of-control patients who took Tirzepatide, sold as Munjaro and Zepbound, reveals that the drug suppresses signaling in the brain's “reward center” thought to be associated with the noise of eating, but only temporarily.

According to research, this drug glucagonBeta-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists were originally developed for the management of type 2 diabetes and have the potential to treat a wide range of conditions related to impulse control, including bulimia. However, while there may be interesting clues to help patients with unwanted urges, GLP-1 and GIP inhibitors may not be optimally designed to adequately treat them, and further research is needed, a case study reveals. A doctoral dissertation from the Perelman School of Medicine at the University of Pennsylvania was published today. natural medicine.

“This study provides important insight into how these drugs work in the brain and will guide us as we explore new indications,” said lead author Casey H. Halpern, MD, professor of neurosurgery and chair of the Division of Stereotactic and Functional Neurosurgery. “Until we better understand their effects on the brain, it is premature to call GLP-1 and GIP inhibitors silver bullets for diseases other than type 2 diabetes and obesity.”

Common debilitating symptoms

Losing control over eating is a very common problem, affecting millions of obese patients and patients with various eating disorders. Bulimia nervosa (BED) is considered the most common eating disorder in the United States, affecting at least 3 million people. People with bulimia have a sense of loss of control over their eating and continue to eat beyond their normal sense of fullness.

Eating behaviors, including overeating, are controlled by brain circuits involving the hypothalamus and the reward center nucleus accumbens (NAc). Specifically, the NAc regulates motivational systems in the brain, guiding decision-making regarding pleasure-seeking and impulse control. Previous studies have shown that NAc signaling and circuits in the brain are dysregulated in people with concurrent obesity and BED.

Even without a diagnosis of BED, up to 60% of obese patients report experiencing “food noises” or constantly thinking about food, leading to distress and dysregulated eating behaviors such as uncontrolled eating and overeating. “Food sounds” are also very common in the treatment of diseases such as bulimia nervosa and anorexia nervosa. It is particularly important to note that an association between the presence of bulimia and suicide risk has been established in obese patients and patients in whom these eating disorders are associated with common impulsive traits and associated emotion dysregulation.

“Developing new ways to treat these patients is paramount,” Halpern said. “While many people taking GLP-1 and GIP inhibitors report reduced food noise, these drugs are not approved by the FDA to treat food obsessions or related impulsivity. In fact, their effects on human brain activity are only beginning to be studied.”

A new approach to managing dining noise

The 60-year-old woman, identified in the new report as “Participant 3,” was diagnosed with severe, treatment-resistant obesity and was bothered by the noise of her meals. She often had obsessive thoughts about food, which led her to order takeout and continue snacking even when she wanted to resist. She reported eating large amounts of food until she was uncomfortably full and being particularly preoccupied with both sweet and salty foods, including prepackaged cupcakes, fast food roast beef sandwiches, and French fries. Participant 3 also had type 2 diabetes and was prescribed the GLP-1 inhibitor dulaglutide, which did not affect his weight or interest in eating.

Participant 3 unsuccessfully attempted to manage his obesity using every possible medical avenue, from bariatric surgery to pharmacotherapy, behavioral therapy, and pharmacotherapy for dysregulated eating behaviors and weight loss. When these available treatments failed, she entered Halpern's clinical trial. The clinical trial involved brain surgery to implant electrodes to create an interface with the brain, with the eventual goal of stopping cravings before they start.

The relationship between the brain and overeating

Halpern's previous research revealed distinctive electrical activity in the NAc that occurs just before someone becomes obsessed with food and experiences the urge to binge, but does not occur when they are simply hungry before a normal meal. A pilot study previously led by Halpern et al. demonstrated that high-frequency electrical stimulation of the NAc whenever craving-related signals occur can prevent binge eating behavior.

The current trial, involving four participants, will implant intracranial electroencephalography (iEEG) electrodes into the brains of obese patients who have lost control over their eating, similar to devices used to study and treat drug-resistant epilepsy and Parkinson's disease. In this case, the device records electrical activity in the NAc when a participant encounters a food that would normally trigger a binge eating episode.

After establishing a baseline for each participant, Halpern's team programs the electrodes to deliver high-frequency electrical stimulation to the NAc whenever a craving-related signal occurs. During this 6-month interval, early participants reported a sharp decrease in their feelings of loss of control and the frequency of their binge-eating episodes.

Unique endeavors lead to even more unique research opportunities

Participant 3's doctor prescribed tirzepatide to help manage her type 2 diabetes before surgery because the first GLP-1 inhibitor did not work for her. Because diabetes can be a risk factor for post-surgery infections, her dosage was slowly increased to maximum levels before and after surgery to implant the electrodes. This gave the researchers a unique opportunity to observe in real time how tirzepatide affects brain signals related to eating behavior.

“Brain surgery to implant electrodes is invasive, so it's very rare to study human brain activity in this way,” Halpern said. “Study prompts further research. When this participant enrolled in the trial, he was already taking tirzepatide before the stimulus was delivered, so we had a unique opportunity to make fundamental observations about how the drug changes brain signals.”

Short-term suppression, long-term questions

After the electrodes were implanted and Participant 3 reached the full dose of tirzepatide, she reported no preoccupation with eating and associated NAc activity was silent. However, after 5 months, NAc activity was detected, consistent with what would be expected in an obese patient, and there were also reports of severe food obsessions, suggesting that the effect of tirzepatide on this patient's behavioral disturbances was temporary and that the “food noise” was being broken through.

In contrast, trial participants who did not take tirzepatide had expectedly elevated NAc activity and more frequent food cravings, consistent with earlier findings from the Halpern Institute. Participant 3's remarkable tranquility in NAc signaling and focus on food suggests that tirzepatide is involved in the temporary silencing of food noise.

“GLP-1 and GIP inhibitors are amazing drugs that have been developed to help manage blood sugar levels. people with type 2 diabetes and weight loss in obesity,” said study investigator Kelly Allison, Ph.D. psychiatry Director of the Center for Weight and Eating Disorders. “This study shows that it may help manage food obsessions and overeating, but not in its current form.”

“Although this study only features data from one patient taking tirzepatide, it provides compelling data about how GLP-1 and GIP inhibitors alter electrical signals in the brain,” said co-first author Won-Kyung Choi, a doctoral candidate in Halpern's lab. “These insights should stimulate further research to develop safe, long-term treatments tailored to the impulsivity characteristics of obesity and related eating disorders.”

This research was supported by the National Institutes of Health (7UH3NS103446-03, 1R01MH124760-01A1, R25MH119043 and T32NS091008).