Clinical and Neurobehavioral Changes With Weight Loss Drug Discontinuation and Reinitiation (CLIN-GLP1)

Clinical and Neurobehavioral Changes With GLP-1 (Glucagon-like Peptide-1) Discontinuation

The goal of this clinical study with research procedures is to learn how stopping and restarting tirzepatide (a medication that helps regulate blood sugar and appetite) affects brain activity, behavior, and health in adults ages 18-70 who are currently taking tirzepatide. Specifically, the study aims to examine how a short pause in tirzepatide affects hunger, mood, sleep, and daily functioning; how stopping and restarting tirzepatide alters brain chemistry and brain responses to food-related images; and how these changes relate to health measures such as quality of life and emotional well-being. There is no comparison group; instead, researchers will assess changes within each participant across three time points: while taking tirzepatide, after stopping it for 3-4 weeks, and after restarting it for 6-8 weeks. Participants will attend three in-person visits lasting approximately 3-4 hours each, during which they will complete interviews, questionnaires, and cognitive tasks; provide a urine sample (pregnancy screening for females); undergo a brain scan using magnetic resonance imaging (MRI) and MR spectroscopy (MRS); and receive a kit to provide a small stool sample. Participants will also complete two brief check-in phone calls between visits and the online BrainHealth Index between sessions, which includes surveys and cognitive tasks. All changes to tirzepatide use will occur under the supervision of a study physician to support participant safety and comfort, and the total study duration is approximately 13 weeks.

Study Overview

• Status: Not yet recruiting
• Conditions: Substance Use Disorders; Eating Behavior Changes; Drug Discontinuation; Tirzepatide
• Intervention / Treatment: Other: Discontinuation and Reinitiation of Tirzepatide

Detailed Description

This study specifically recruits individuals currently being prescribed for tirzepatide. The experimental design will consist of a brief discontinuation of the drug for roughly 3-4 weeks followed by a reinitiation of the medication. Prescription and administration of tirzepatide is done as part of normal patient care and is not a component of the study.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Samuel H Poelker-Wells, Master of Science; Phone Number: 972-883-3375; Email: sxp230129@utdallas.edu
• Study Contact Backup: Name: Aishwarya Veerkumar, Master of Public Health; Phone Number: 972-883-3304; Email: Aishwarya.Veerkumar@UTDallas.edu

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75235
      • Center for BrainHealth
      • Contact: Samuel M Poelker-Wells, Master of Science; Phone Number: 972-883-3375; Email: sxp230129@utdallas.edu
      • Contact: Linnea L Stahl, Master of Science; Email: Linnea.Stahl@UTDallas.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged 18-70 years.
• Currently on tirzepatide.
• Currently receiving care from University of Texas- Southwestern (UTSW) Weight Wellness Clinic.
• Cognitively capable of understanding and signing informed consent.
• Be proficient in English.

Exclusion Criteria:

• History of major neurological or psychiatric disorders, including substance use disorders that might confound brain imaging results (e.g., stroke, epilepsy, multiple sclerosis, schizophrenia, major depression requiring hospitalization).
• Diagnosis of Type 2 Diabetes.
• Current diagnosis of an eating disorder.
• Use of medications affecting weight other than tirzepatide.
• Pregnancy or breastfeeding.
• MR contraindications:
• Heart pacemaker, heart valve replacement, or aortic clips
• Metal fragments in the eyes, skin, or elsewhere in the body
• Brain clips or pieces of metal used in aneurysm surgery or intercranial bypass
• Venous umbrella
• Pieces of metal in the body resulting from work as a sheet-metal worker or welder
• Clips placed in an internal organ
• Prosthetic devices, such as middle ear, eye, joint, or penile implants
• Joint replacement
• Hearing aid that cannot be removed
• Neurostimulator
• Insulin pump
• Shunts or stents
• Metal mesh or coil implants
• Metal plate, pin, screws, or wires, or any other metal implants

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tirzepatide Discontinuation and Re-Initiation Arm; Participants in this single-group arm will complete three study visits that occur while they are taking tirzepatide, during a 3-4 week pause from the medication, and after they restart tirzepatide for 6-8 weeks. All medication changes are supervised by a study physician. At each visit, participants will complete interviews, questionnaires, cognitive tasks, magnetic resonance imaging (MRI) brain scans, and provide stool samples. They will also complete two short check-in phone calls and an online BrainHealth Index assessment between visits.

Other: Discontinuation and Reinitiation of Tirzepatide; Participants will temporarily pause their tirzepatide medication for 3-4 weeks and then restart it for 6-8 weeks under the supervision of a study physician. The medication change is done only for research purposes to study how stopping and restarting tirzepatide affects brain activity, appetite, mood, and other health measures. During this period, participants will complete MRI scans, behavioral assessments, questionnaires, and provide stool samples across three study visits.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From On-Treatment to Discontinuation and Re-Initiation in Food Cue-Evoked BOLD Response in Reward and Salience Brain Regions	This outcome measures within-participant change in blood-oxygen-level-dependent (BOLD) signal during a food cue reactivity task, assessed using functional magnetic resonance imaging (fMRI). BOLD response will be quantified as the mean percent signal change in predefined reward- and salience-related regions of interest (including the ventral striatum and insula) during food image presentation relative to non-food control images. Higher BOLD values indicate greater neural responsivity to food cues.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Resting-State Functional Connectivity Within Salience and Executive Control Networks	This outcome measures within-participant change in resting-state functional connectivity, assessed using fMRI. Connectivity strength will be calculated using correlation coefficients between predefined brain regions within salience and executive control networks. Higher values indicate stronger functional connectivity.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Brain Glutamate Levels	This outcome measures within-participant change in neurochemical and dopaminergic markers associated with reward processing. Glutamate levels will be measured in the medial prefrontal cortex using magnetic resonance spectroscopy (MRS). Higher values indicate greater metabolite concentration or signal intensity.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in State Food Craving Severity	This outcome measure assesses within-participant change in momentary food craving severity. Food cravings will be measured using the Food Cravings Questionnaire-State (FCQ-S), a self-report instrument assessing current craving intensity. Scores range from 15 to 75, with higher scores indicating greater food craving severity.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Addictive-Like Eating Symptoms.	This outcome measure assesses within-participant change in addictive-like eating behaviors. Addictive-like eating symptoms will be assessed using the Yale Food Addiction Scale 2.0, a self-report measure of addictive-like eating based on diagnostic criteria. Symptom counts range from 0 to 11, with higher scores indicating greater severity of addictive-like eating behavior.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Intrusive Food-Related Thoughts.	This outcome measure assesses within-participant change in the frequency of intrusive food-related thoughts. Intrusive food-related cognitions will be assessed using the Food Noise Questionnaire, a self-report measure consisting of five items assessing persistent and intrusive thoughts about food. Total scores range from 0 to 20, with higher scores indicating greater food noise and more frequent intrusive food-related thoughts.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Psychological Responsiveness to Food Availability.	This outcome measure assesses within-participant change in psychological responsiveness to the food environment. Responsiveness to food availability will be assessed using the Power of Food Scale, a self-report questionnaire measuring the psychological impact of food availability independent of actual consumption. Scores are calculated as a mean item score ranging from 1 to 5, with higher scores indicating greater psychological impact of food availability.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Perceived Stress.	This outcome measure assesses within-participant change in perceived psychological stress. Perceived stress will be measured using the Perceived Stress Scale (PSS), a self-report questionnaire assessing the degree to which situations in one's life are appraised as stressful over the past month. Scores range from 0 to 40, with higher scores indicating greater perceived stress.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Quality of Life.	This outcome measure assesses within-participant change in quality of life. Quality of life will be assessed using the World Health Organization Quality of Life-BREF, a 26-item self-report questionnaire assessing perceived quality of life across physical health, psychological health, social relationships, and environmental domains. Total scores range from 26 to 130, with higher scores indicating better overall quality of life.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Withdrawal-Related Psychological Symptoms.	This outcome measure assesses within-participant change in withdrawal-related psychological and behavioral distress during tirzepatide discontinuation. Withdrawal symptoms will be assessed using a Withdrawal Symptom Checklist, a self-report questionnaire assessing appetite and physiological symptoms, eating behavior and perceived control, restrictive dieting and compensatory behaviors, mood and emotional distress, and general physical and functional impairment associated with medication withdrawal. Items are rated on a 5-point scale ranging from 0 (not at all/never) to 4 (very severe/very often) and summed to create a total score. Total scores range from 0 to 128, with higher scores indicating greater withdrawal-related psychological and behavioral distress.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Sleep Quality as Measured by the Pittsburgh Sleep Quality Index	The Pittsburgh Sleep Quality Index (PSQI) is a 19-item self-report questionnaire assessing subjective sleep quality over the past month. Global scores range from 0 to 21, with higher scores indicating poorer sleep quality.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Addiction-Related Problem Severity	This outcome measure assesses within-participant change in addiction-related problem severity across multiple functional domains. Addiction-related severity will be assessed using the Addiction Severity Index, a standardized semi-structured interview administered by trained study personnel. The Addiction Severity Index evaluates seven domains: medical status, employment/support status, alcohol use, drug use, legal status, family/social functioning, and psychological status, based on both past 30-day functioning and lifetime history. Domain-specific composite scores range from 0 to 1, with higher scores indicating greater addiction-related problem severity.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Substance Use Frequency and Quantity.	This outcome measure assesses within-participant change in substance use behavior. Substance use frequency and quantity will be measured using the Timeline Follow-Back (TLFB) method, which captures the number of days and amount of alcohol, nicotine, and cannabis use over the past 30 days. Higher values indicate more frequent or greater substance use.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Risky and Impulsive Behavior.	This outcome measure assesses within-participant change in engagement in risky, impulsive, and self-destructive behaviors. Behaviors will be assessed using the Risky, Impulsive, and Self-Destructive Behavior Questionnaire, a 38-item self-report measure. Frequency responses are binned and summed to create a total score ranging from 0 to 152, with higher scores indicating greater engagement in risky, impulsive, and self-destructive behaviors.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Blood-Brain Permeability Levels	This outcome measures within-participant change in neurovascular properties of the blood-brain barrier. Blood-brain barrier permeability to water will be measured using phase-contrast arterial spin tagging (WEPCAST). Higher values indicate greater blood-brain barrier permeability.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Trait Food Craving Severity.	This outcome measure assesses within-participant change in habitual food craving frequency and intensity. Trait-level food cravings will be assessed using the Food Cravings Questionnaire-Trait, a self-report questionnaire. Scores range from 21 to 126, with higher scores indicating more frequent and intense food cravings.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Dietary Pattern Quality.	This outcome measure assesses within-participant change in dietary behaviors and overall eating patterns. Dietary patterns will be assessed using the Rapid Eating Assessment for Participants - Shortened Version, a self-report questionnaire evaluating habitual dietary behaviors. Total scores range from 13 to 39, with higher scores indicating healthier dietary patterns.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Perceived Loss of Control Over Eating.	This outcome measure assesses within-participant change in perceived loss of control over eating behavior. Perceived loss of control will be assessed using the Loss of Control Over Eating Scale-Short Form, a self-report questionnaire assessing the subjective experience of being unable to control eating. Total scores range from 7 to 35, with higher scores indicating greater perceived loss of control over eating.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Uncontrolled Eating Behavior.	This outcome measure assesses within-participant change in uncontrolled eating behavior. Uncontrolled eating will be assessed using the Uncontrolled Eating subscale of the Three-Factor Eating Questionnaire, a self-report measure of tendencies toward loss of control over eating. Subscale scores range from 3 to 36, with higher scores indicating poorer regulation of eating behavior.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Mood Disturbance.	This outcome measure assesses within-participant change in mood disturbance. Mood will be assessed using the Profile of Mood States-Short Form, a validated self-report questionnaire assessing multiple mood domains including tension, depression, anger, vigor, fatigue, and confusion. Mood disturbance will be quantified using the Total Mood Disturbance score, which ranges from -24 to 124, with higher scores indicating greater overall mood disturbance (reflecting higher negative mood and lower vigor).	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
NIH Cognitive Toolbox: Flanker Inhibitory Control and Attention Test	This outcome measure tests inhibitory control and attentional filtering, relevant to recovery-related changes in top-down regulation. This task takes around 3 minutes. This task contains one practice block, and 1-2 testing blocks. The first testing block contains 25 trails. If the participant passes, then participant will complete a second block as well (25 trials). The scoring will be divided into Accuracy and Reaction Time. Accuracy is scored on a scale of 0 - 5, and if the Accuracy score is greater then or equal to 80%, then the Reaction Time score will be considered. (If less then 80%, then Reaction Time Score will not be used). Reaction Time is scored on a scale of 0 - 5. The Final Score is equal to the Accuracy + Reaction Time. Higher scores indicate greater ability to filter out distracting stimuli and greater ability to focus.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
NIH Cognitive Toolbox: Dimensional Change Card Sort Test	This outcome measure tests mental flexibility, relevant to adaptive reorganization and reduced rigid maladaptive responding. This task takes around 4 minutes. This task contains one practice block and 3 testing blocks. The first two testing blocks contain 5 trials each, and the final block contains 50 trials (10 non-dominant and 40 dominant). If the participant fails to pass the first 2 testing blocks (score of 4/5), the task is over. The scoring will be divided into Accuracy and Reaction Time. Only 40 trials are used to score Accuracy, and is scaled from 0 - 5. If the Accuracy score is greater then or equal to 80%, then the Reaction Time score will be considered. (If less then 80%, then Reaction Time Score will not be used). Reaction Time is scored on a scale of 0 - 5. The Final Score is equal to the Accuracy + Reaction Time. Higher Scores indicate higher cognitive flexibility and attention.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change from Baseline to Discontinuation in Food-Related Effort-Based Decision-Making	This outcome measures within-participant changes in willingness to select high-effort/high-reward options in relation to medication status, assessed using computational models. A hierarchical drift diffusion model will estimate parameters reflecting decision dynamics, while a subjective value model will generate participant-level estimates of reward sensitivity, probability sensitivity, and effort cost. Increased effort expenditure after GLP1-RA discontinuation may reflect rebound increases in incentive salience and reward sensitivity.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
NIH Cognitive Toolbox: Pattern Comparison Processing Speed Test	This outcome measure provides a brief index of general cognitive efficiency and helps contextualize executive findings. This task takes around 4 minutes, and includes one continuous testing block. The testing block consists of two visual patterns where the participant had to choose "same" or "not the same". The scores is based off the amount of correct responses in 90 seconds (max is 130), and will be scaled based off participants age. The Mean will be 100, with a standard deviation of 15. Participants with scores greater then 100 will indicate greater cognitive efficiency then of similar age group.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
NIH Emotion Toolbox: Negative Effect	This outcome measure captures emotional distress that may covary with neural markers of recovery, including anger, sadness, and fear. The 7 tasks included in this measure are: Anger, Anger/Hostility, Anger/Physical Aggression, Apathy, Fear/Anxiety, Fear/Somatic Arousal, and Sadness/Depression. Each task takes 2 minutes to complete and contains self reported emotional measures. Participants answer a series of questions, using a scale ranging from 1 ("Never") to 5 ("Always"). Scores are then combined and converted into a "T-score", with a mean of 50 and a standard deviation of 10. Higher T-scores indicate greater emotional distress.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
NIH Emotion Toolbox: Perceived Stress	This outcome measure indexes stress regulation, a clinically meaningful process linked to relapse vulnerability and functional recovery. This task takes 2 minutes and consists of self reported measures. Participants answer a series of questions using a scale ranging from 1 ("Never") to 5 ("Always"). Scores are then combined and converted into a "T-score", with a mean of 50 and a standard deviation of 10. Higher T-scores indicate greater perceived stress and reduced emotional regulation and coping.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
NIH Emotion Toolbox: Meaning and Purpose	This outcome measure captures positive psychological change and broader recovery-related adaptation. This task takes approximately 2 minutes, and uses a computer-adaptive test (CAT). Participants answer a series of questions using a scale ranging from 1 ("Never") to 5 ("Always"). Scores are then combined and converted into a "T-score", with a mean of 50 and a standard deviation of 10. Higher T-scores indicate greater sense of meaning and purpose, as well as greater feelings of optimism and hopefulness.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Gut-Derived Neurotransmitter Levels.	This outcome measure assesses within-participant change in gut-derived neurotransmitter levels associated with tirzepatide discontinuation and re-initiation. Neurotransmitter levels will be measured from stool samples collected at each study timepoint and analyzed for gut-derived neurotransmitters relevant to brain-gut signaling. Changes in values reflect alterations in gut-derived neurotransmitter levels.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Gut Microbiome and Inflammatory Marker Profiles	This outcome measure assesses within-participant change in gut microbiome composition and gut-related inflammatory markers. Exploratory analyses will be conducted on stool samples to evaluate changes in microbial profiles and inflammatory markers associated with tirzepatide discontinuation and re-initiation. Higher or lower values reflect changes depending on the specific marker assessed.	Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change in Multidimensional Brain Health as Measured by the BrainHealth Index	This outcome measure assesses within-participant change in overall brain health using the BrainHealth Index (BHI), a multidimensional composite derived from standardized self-report questionnaires and objective cognitive performance measures developed at the Center for BrainHealth. The BHI integrates measures across three domains: cognitive function/clarity (e.g., attention, learning and memory, reasoning, processing speed, and sleep quality), emotional balance (e.g., mood, stress, anxiety, happiness), and social connectedness (e.g., compassion, social support, resilience, engagement in meaningful activities, and life satisfaction). Component measures are standardized and combined using predefined BrainHealth Index aggregation procedures to generate a single composite score, with higher scores indicating better overall brain health.	Between baseline and discontinuation (about 2 weeks after baseline), and between discontinuation and re-initiation (about 4 weeks after start of reinitiation)
Occurrence and Severity of Withdrawal-Related Symptoms During Medication Discontinuation	This outcome measure assesses within-participant change in withdrawal-related symptom severity during tirzepatide discontinuation. Withdrawal symptoms will be assessed using the Glucagon-like Peptide-1 (GLP-1) Withdrawal Symptom Checklist Brief Version, a self-report questionnaire assessing appetite and physiological symptoms, eating behavior and loss of control, restrictive dieting and compensatory behaviors, psychological/mood distress, and general physical and functional symptoms over the past 7 days. Items are rated on a 5-point scale ranging from 0 (not at all/never) to 4 (very severe/very often). A total symptom severity score is calculated as the mean of items 1-5, yielding a minimum score of 0 and a maximum of 4, with higher scores indicating greater withdrawal-related symptom severity. An additional item assessing overall subjective burden is collected separately for descriptive purposes on a scale of 0 to 4 with higher scores indicating higher burden.	Between baseline and discontinuation (about 2 weeks after baseline), and between discontinuation and re-initiation (about 4 weeks after start of re-initiation)

Collaborators and Investigators

• Sponsor: The University of Texas at Dallas
• Collaborators: University of Texas Southwestern Medical Center
• Investigators: Principal Investigator: Francesca Filbey, Doctor of Philosophy, The University of Texas at Dallas

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: January 8, 2026
• First Submitted That Met QC Criteria: January 29, 2026
• First Posted (Actual): February 4, 2026

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Substance Use Disorders; Drug Discontinuation; Tirzepatide; Eating Behavior Changes
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders
• Other Study ID Numbers: IRB-26-3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes