Effects of Semaglutide on Brain Dopamine Responses to Food Cues in Adults With Obesity and Food Addiction Tendencies

• Background and Rationale

GLP-1 receptor agonists, including semaglutide, are effective treatments for obesity. However, the brain mechanisms underlying their effects on appetite, food reward, and eating behavior remain incompletely understood. Food-related visual and olfactory cues may engage dopamine-mediated reward pathways during the pre-ingestive phase, and post-ingestive signals may further influence dopamine signaling after food intake.

This study will use [11C]raclopride positron emission tomography (PET) to assess dopamine-related binding measures in the human brain. The study will examine whether semaglutide changes dopamine-related brain responses during food cue and drink exposure and during the post-ingestive period.

• Study Protocol and Procedures

This is a prospective clinical trial using a 2-by-2 crossover design. Participants will receive once-weekly semaglutide treatment for 8 weeks and will undergo two [11C]raclopride PET scans. The scans will be performed under conditions with and without the effect of semaglutide, depending on group assignment.

Before each PET imaging session, participants will complete baseline assessments, including body measurements, psychological surveys, and computer-based cognitive tasks. [11C]raclopride will then be administered according to the PET protocol. Participants will undergo brain PET imaging while lying in the scanner.

During the imaging session, participants will complete a standardized chocolate milk drink task. This task includes a baseline period, exposure to chocolate milk images, smelling the chocolate milk drink, and the post-ingestive stage using the chocolate milk drink delivered through a tube. During the scan, participants will use a tablet to rate hunger, desire for the chocolate milk drink, and liking of the drink at set time points.

The same PET task procedures will be used across study conditions. This will allow researchers to compare dopamine-related PET measures, psychological survey results, and cognitive task results between conditions with and without the effect of semaglutide.

Inclusion criteria

• Participants aged between 19 and 50 years.
• Eligible for treatment with semaglutide, defined as either:
• Initial body mass index (BMI) of 30 kg/m2 or higher; or
• Initial BMI of 27 kg/m2 to less than 30 kg/m2 with at least one weight-related comorbidity, such as dysglycemia, hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease.
• Mild or greater food addiction tendency, defined as a Yale Food Addiction Scale (YFAS) score of 3 or higher.
• Able to understand the study tasks and provide appropriate responses.

Exclusion criteria

• Use of medications that may affect body weight or dopaminergic medications within the past 2 months.
• Known hypersensitivity to semaglutide.
• Pregnant, breastfeeding, or planning to become pregnant.
• Severe renal impairment, hepatic impairment, heart failure, acute pancreatitis, or thyroid disease.
• Any medical condition, disease, or medical history that, in the investigator's judgment, would make it difficult for the participant to complete the study or would interfere with interpretation of the study results.
• Allergy to ingredients in chocolate milk, including milk or soy, or to ingredients that may be present through cross-contamination, including egg, buckwheat, peanut, wheat, peach, tomato, walnut, pork, or beef.
• Participants with both no self-reported preference for chocolate milk and a chocolate milk preference score of less than 5 on a 10-point visual analog scale (VAS).