Tirzepatide s Dopaminergic Effects in Alcohol Use Disorders (AUD)

Tirzepatide s Dopaminergic Effects in Alcohol Use Disorders (AUD), a Phase 1b Study

Background:

Glucagon-like peptide 1 (GLP-1) agonist drugs are used to treat diabetes and aid weight loss. They may also help reduce cravings for drugs and alcohol. Researchers want to know if a GLP-1 drug (tirzepatide) can lessen the urge to drink in people with alcohol use disorder (AUD).

Objective:

To learn how the brains of people with AUD respond to a GLP-1 drug.

Eligibility:

People aged 21 to 65 years with AUD who are non-treatment seeking. They must be enrolled in protocol 14-AA-0181. Healthy volunteers are also needed.

Design:

This study consists of Part 1 and Part 2.

Part 1 (Imaging Procedures): Five healthy volunteers will undergo 2 to 3 combined positron emission tomography/magnetic resonance imaging (PET/MRI) scans, with an interval of 2 to 3 weeks between scans. For each scan, a radioactive substance (tracer) will be administered intravenously. Participants will undergo PET/MRI scanning to assess brain activity during resting state. Methylphenidate (Ritalin) will be administered during each scan. Each imaging session will last approximately 2 hours. Tirzepatide and placebo will not be administered in Part 1. Participants with alcohol use disorder (AUD) are not included in Part 1. The purpose of this part of the study is to assess test/retest reproducibility of the PET/MRI combined scan measures.

Part 2 (Randomization to Tirzepatide & Placebo): Participants will be randomized to receive either Tirzepatide or Placebo first. Healthy Volunteers and AUD participants will receive both treatments in a crossover design. Tirzepatide and placebo will be administered via subcutaneous injection (under the skin) once weekly for 2 to 3 weeks. This treatment period will be followed by 2 to 3 PET/MRI combined imaging scans described in the next paragraph. After a washout interval of approximately 2 to 3 weeks, participants will cross over to the alternate treatment (tirzepatide or placebo), administered once weekly for 2 to 3 weeks. This second treatment period will be followed by an additional 2 to 3 PET/MRI scans. Participants may receive up to 3 doses of tirzepatide and 3 doses of placebo.

Part 2 (Imaging Procedures): Healthy Volunteers and participants with an AUD will undergo PET/MRI scans at two time points: following tirzepatide administration and following placebo administration. For each scan a radioactive substance (tracer) will be administered intravenously. Brain activity will be measured during PET/MRI acquisition during resting state. Methylphenidate will be administered during 1 of the scans at each time point. Each imaging session will last approximately 2 hours. Participants will wear a device to track their activity for at least 1 week before each set of scans. They will have tests of their thinking, memory, and attention.

Study Overview

• Status: Recruiting
• Conditions: Alcohol Use Disorder (AUD)
• Intervention / Treatment: Drug: Tirzepatide; Drug: Placebo; Drug: [11C]NNC-112; Drug: [11C]raclopride plus drug

Detailed Description

Study Description:

Protocol has 2 parts:

Part 1 (n=5 healthy volunteers): Assess the reproducibility of striatal dopamine (DA) measures in response to iv methylphenidate (MP) using PET/MR combined scanning and the bolus infusion protocol in healthy controls.

Part 2 (n=88, 44 healthy volunteers and 44 AUD): Evaluate Tirzepatide s brain dopaminergic effects in controls and participants with alcohol use disorder (AUD) as compared to placebo (2 injections 1 week apart from each other) on MP induced brain DA increases and functional reactivity using PET/fMRI, on dopamine D1 and D2 receptors and reactivity to alcohol and food cues. We hypothesize that Tirzepatide compared to placebo will (1) increase striatal dopamine D2 receptors while decreasing D1 receptors, (2) attenuate DA increases to MP and functional reactivity and (3) blunt the response to alcohol and food cues to a greater extent in AUD than control participants.

Primary Objectives:

Part 1: Reproducibility of striatal DA measures

Part 2: Effects of Tirzepatide on: striatal dopamine D1R and D2R availability; striatal DA increase; brain reactivity to MP and to food and alcohol cues in AUD and in healthy controls.

Secondary Objectives:

Part 1: Subjective responses to MP

Part 2: Examine Tirzepatide s effects on subjective effects to MP, sleep, alcohol craving (AUD only), alcohol withdrawal symptoms (AUD only), food craving, locomotor activity, mood and weight.

Primary Endpoints:

Part 1: Striatal DA changes with MP tested in two separate occasions

Part 2: Striatal D1R and D2R availability; Striatal DA increases with MP; Brain functional reactivity to MP and to alcohol and food cues. Measures collected twice after placebo and after Tirzepatide

Secondary Endpoints:

Self-reports of drug effects

Sleep measures: actigraphy and self-reports.

Alcohol Craving (only AUD): Desire for Alcohol Questionnaire (DAQ).

Alcohol Withdrawal (only AUD): Clinical Institute Withdrawal Assessment (CIWA)

Food Craving: Food Cravings Questionnaire State (FCQ S) Locomotor activity: actigraphy

Mood: Profile of Mood States (POMS)

Exploratory Endpoints:

Part 2:

• Brain structure and function assessed by MRI (task and resting fMRI, structural MRI)
• Cognitive Test Performance
• Weight

• Study Type: Interventional
• Enrollment (Estimated): 176
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Nora D Volkow Adler, M.D.; Phone Number: (301) 443-6480; Email: nvolkow@nida.nih.gov
• Study Contact Backup: Name: Michele-Vera I Yonga, C.R.N.P.; Phone Number: (301) 273-4169; Email: michele-vera.yonga@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov

Participation Criteria

Eligibility Criteria

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

Description

• INCLUSION CRITERIA:

Healthy Volunteer Participants

To be eligible to participate in this study, an individual must meet the following criteria:

1. Enrollment in 14AA0181.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Male or female, ages 21-65 years old.
4. Ability to understand and willingness to sign a written informed consent document.
5. Have or had any prior experience with stimulant drugs including cocaine, methylphenidate, amphetamine or methamphetamine, or prescription stimulants (prescription or recreational use), whether or not they have had a past substance use disorder.

AUD Participants

To be eligible, individuals with AUD must meet the following criteria:

1. Enrollment in 14AA0181.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Male or female, ages 21-65 years old.
4. Ability to understand and willingness to sign a written informed consent document.
5. DSM 5 diagnosis of mild to moderate AUD.
6. Have or had any prior experience with stimulant drugs including cocaine, methylphenidate, amphetamine or methamphetamine, or prescription stimulants (prescription or recreational use), whether or not they have had a past substance use disorder.

7. Minimum 2-year history of heavy drinking (SAMSHA s criteria for heavy drinking: for men 5 or more drinks/day on at least 5 different days per month; and for women 4 or more

   drinks/day on at least 5 different days per month.

8. Non treatment seeking AUD participants.

EXCLUSION CRITERIA:

All Participants (Healthy Volunteers and AUD)

1. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head, fear of enclosed spaces, or other standard contraindication to MRI
2. Cannot lie comfortably flat on his/her back for up to 2 hours in the PET/MRI scanner.
3. BMI <23 or >35 (but no more than 500 lbs). The PET/MRI scanner bed is tested to a weight limit of 500 lbs.
4. Have had previous radiation exposure (from X-rays, PET scans, or other exposure) that, with the exposure from this study, would exceed NIH annual research limits as determined by medical history and physical exam.
5. Pregnant or breast-feeding: Females of childbearing potential, or with tubal ligation, or are post-menopausal and are age 55 or less will undergo a urine pregnancy test and it must be negative to continue participation. Urine pregnancy tests will be repeated on subsequent days of study (i.e., within 24 hours before study procedures). Females must not be currently breastfeeding.
6. Women using oral contraceptives (Part 2 of study). Women of childbearing age who are taking oral contraceptives will be required to switch to a non-oral hormonal contraceptive method (ie implants, injections, or IUDs) or add a barrier method (condoms) for the duration of the study and for 4 weeks after the last dose of study drug after explaining to them that Tirzepatide could make contraceptive less effective. We will not provide nonoral contraceptive medications to participants.
7. Severe head trauma with loss of consciousness > 60 minutes
8. Current severe mental illness (schizophrenia, bipolar disorder).
9. Montgomery-Asberg depression rating scale (MADRS) total score > 35 or suicidal thoughts item score > 3, indicating severe depression or moderate suicidality, respectively.
10. Thyroid cancer or family history of thyroid cancer or personal or family history of multiple endocrine neoplasia syndrome type-2 (MEN-2).
11. History for cerebral aneurysm.
12. Past or present history of chest pain and trouble breathing with activity.
13. History of Heart Disease, Hypertension or Cardiovascular disorders.
14. History of seizures, anxiety, panic attacks, psychosis or glaucoma which are contraindicated with receiving methylphenidate.
15. History of gallbladder disease, pancreatitis, gastroparesis, diabetic retinopathy, acute kidney injury (AKI), as these are contraindicated for Tirzepatide.
16. History of allergic reaction to methylphenidate, Tirzepatide or allergic reactions to dyes or preservatives.

17. Major medical problems that can permanently impact brain function (e.g., seizures, psychosis, stroke, Alzheimer s disease, Parkinson s disease, traumatic brain injury with

    loss of consciousness > 30 minutes, clinically significant arrhythmias except bradycardia, and HIV+).

18. Clinically significant laboratory findings that could impact brain function or study procedures (e.g., active infections, significant EKG results, hepatic or renal failure) will be

    exclusionary.

19. Current DSM-5 diagnosis of a psychiatric disorder that required daily psychoactive medications (antidepressant, antipsychotics, stimulants, opioids, benzodiazepines or barbiturates) in the past two months and that could impact brain function at the time of the study as determined by history and clinical exam.
20. History of moderate or severe SUD (other than nicotine or alcohol for AUD participants).
21. Current severe depression or moderate/severe suicidal ideation.
22. Daily current use (past 2 months) of the following drugs/medications are exclusionary: stimulant or stimulant-like drugs or medications (cocaine, methamphetamine, amphetamine, methylphenidate, modafinil); opioid drugs or medications; other GLP-1 or anti-diabetic drugs (e.g., insulin, sulfonylureas) medications, antianginal agents; antiarrhythmics; systemic corticosteroids; anticholinergics; anticoagulants; anticonvulsants; antidepressants with dopaminergic effects (bupropion, sertraline, and dopamine agonists like pramipexole and ropinirole); beta-blocker antihypertensives; antineoplastics; antipsychotics; anxiolytics (benzodiazepine or barbiturates); or lithium. Note that alcohol and cannabis use are not exclusionary but participants cannot be intoxicated on the day of study as evidence of alcohol in breathalyzer or cannabis in saliva. Caffeine and nicotine are permitted but participants will be asked to refrain from consuming caffeine or nicotine products (including cigarettes) two hours prior to the study. Antihistamines are also not exclusionary but should not be used on the day of study.

23. *Non-English speakers (must also be able to read and comprehend English

    • We are excluding non-English speakers since the study includes questionnaires that are validated for English and only some are available in Spanish. The fMRI paradigms also require that the subject be able to speak, read and comprehend English.

Note that subjects will not be excluded from enrollment onto this study if their urine test or breath alcohol level (BAL) is positive for alcohol/drugs on initial screening. The following guidelines will be followed for positive drug/alcohol screens on study procedure days involving imaging scans and neuropsychological testing for all participants:

• If a subject s breath alcohol (>0.08%) screen test is positive on days involving imaging (PET/MRI) and NP testing, the procedures will be postponed and rescheduled. We will allow for up to 3 rescheduled study days resulting from positive breath alcohol screens. If subject continues to show up intoxicated they will be withdrawn.
• If urine drug screen is positive for THC-COOH a saliva drug screen will be performed and subject may proceed with study day testing procedures if saliva results for THC are negative. If we are unable to perform the saliva drug screen for any reason, the study day procedures will be postponed. If the urine/saliva drug test is positive on the third rescheduled visit, the participant will be withdrawn from the study. Saliva THC is not required for determining eligibility.
• If a participants urine drug screen test is positive for cocaine, heroin or methamphetamine after 3 days of rescheduling they will be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: [11C]NNC-112 - Part 2; [11C]NNC-112 PET/MR or PET/CT scan obtained without any drug intervention to measure dopamine D1 receptors.	Drug: Tirzepatide; Drug approved for diabetes administered SQ. Subject is blind to drug.; Drug: Placebo; Placebo will be normal saline administered SQ. Subject is blind to drug.; Drug: [11C]NNC-112; [11C]NNC-112 PET/MR or PET/CT scan obtained without any drug intervention to measure dopamine D1 receptors.
Active Comparator: [11C]raclopride plus drug - Part 1; Radiotracer injection of [11C]raclopride during combined PET/MR scan to measure striatal dopamine release (Methylphenidate 0.25 mg/kg injected 45 minutes post radiotracer injection). Subject is not blind to this drug during scan.	Drug: [11C]raclopride plus drug; Radiotracer injection of [11C]raclopride during combined PET/MR scan to measure striatal dopamine release (Methylphenidate 0.25 mg/kg injected 45 minutes post radiotracer injection). Subject is not blind to this drug during scan.
Active Comparator: [11C]raclopride plus drug - Part 2; Radiotracer injection of [11C]raclopride during combined PET/MR scan to measure striatal dopamine release (Methylphenidate 0.25 mg/kg injected 45 minutes post radiotracer injection). Subject is not blind to this drug during scan.	Drug: Tirzepatide; Drug approved for diabetes administered SQ. Subject is blind to drug.; Drug: Placebo; Placebo will be normal saline administered SQ. Subject is blind to drug.; Drug: [11C]raclopride plus drug; Radiotracer injection of [11C]raclopride during combined PET/MR scan to measure striatal dopamine release (Methylphenidate 0.25 mg/kg injected 45 minutes post radiotracer injection). Subject is not blind to this drug during scan.
Placebo Comparator: Placebo - Part 2; 1st Dose: placebo will be administered to the abdomen.2nd Dose: placebo will be administered to the abdomen. 3rd Dose (if needed): placebo will be administered to the abdomen.Subject is blinded to drug.	Drug: Placebo; Placebo will be normal saline administered SQ. Subject is blind to drug.
Active Comparator: Tirzepatide - Part 2; 1st Dose: Tirpezatide (2.5 mg dose) will be administered to the abdomen.2nd Dose: Tirzepatide (5 mg dose) will be administered to the abdomen. 3rd Dose (if needed): Tirzepatide (5 mg dose) will be administered to the abdomen.Subject is blinded to drug.	Drug: Tirzepatide; Drug approved for diabetes administered SQ. Subject is blind to drug.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1 (n=5 healthy volunteers): We will assess the reproducibility of striatal dopamine (DA) measures in response to iv methylphenidate (MP) using PET/MR combined scanning and the bolus infusion protocol in healthy controls.	We will measure dopamine in the brain. Dopamine is a chemical messenger that carries signals between brain cells. It plays a role in human behavior. It is also believed to play a role in addiction. In this study, we will use a combined scanner for PET and MRI to measure dopamine with the stimulant drug methylphenidate. Each scan will be done by getting a small amount of a radiotracer through an IV catheter. During each of the two PET/MRI scan sessions each subject will receive IV methylphenidate. We will look at the effects of methylphenidate on brain dopamine. We will also look at brain responses, mood and thinking. The results of each subject's scans will be compared to each other. We will also compare the results to other participants to see if we get similar information.	We aim to have each subject (n=5) complete all study procedures within 60 days.
Part 2 (n=88, 44 healthy volunteers and 44 AUD) : Effects of Tirzepatide on striatal dopamine D1R and D2R availability; striatal DA increase; brain reactivity to MP and to food and alcohol cues in AUD and in healthy controls.	We will measure dopamine levels in the brain. Dopamine is a chemical messenger that carries signals between brain cells. It plays a role in human behavior. It is also believed to play a role in addiction. In this study, we will use a combined scanner for PET and MRI to measure dopamine with the stimulant drug methylphenidate. We will look at the effects of methylphenidate on brain dopamine. To do this we will obtain imaging scans after the subject receives Tirzepatide and a Placebo. We will also look at brain responses, mood and thinking. Results from the same scans on two separate days will be compared to each other. We will also compare the results to other participants to see if we get similar information.	We aim to have each subject complete study procedures within 90 days, but this could take longer. AUD participants will undergo a Follow Up phone call about 1 month after imaging scans are complete.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Subjective responses to MP	The purpose of this research study is to measure dopamine in the brain. Dopamine is a chemical messenger that carries signals between brain cells. It plays a role in human behavior. It is also believed to play a role in addiction. In this study, we will use a combined scanner for PET and MRI to measure dopamine with the stimulant drug methylphenidate. Each scan will be done by getting a small amount of a radiotracer through an IV catheter. During each of the two PET/MRI scan sessions each subject will receive IV methylphenidate. We will look at the effects of methylphenidate on brain dopamine. We will also look at brain responses, mood and thinking. The results of each subject's scans will be compared to each other. We will also compare the results to other participants to see if we get similar information.	We aim to have each subject (n=5) complete all study procedures within 60 days.
Part 2: Examine Tirzepatide s effects on subjective effects to MP,sleep, alcohol craving (AUD only), alcohol withdrawal symptoms (AUD only), food craving, locomotor activity, mood and weight.	We will measure dopamine levels in the brain. Dopamine is a chemical messenger that carries signals between brain cells. It plays a role in human behavior. It is also believed to play a role in addiction. In this study, we will use a combined scanner for PET and MRI to measure dopamine with the stimulant drug methylphenidate. We will look at the effects of methylphenidate on brain dopamine. To do this we will obtain imaging scans after the subject receives Tirzepatide and a Placebo. We will also look at brain responses, mood and thinking. Results from the same scans on two separate days will be compared to each other. We will also compare the results to other participants to see if we get similar information.	We aim to have each subject complete study procedures within 90 days, but this could take longer. AUD participants will undergo a Follow Up phone call about 1 month after imaging scans are complete.

Collaborators and Investigators

• Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: Nora D Volkow Adler, M.D., National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2026
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: April 29, 2026
• First Submitted That Met QC Criteria: April 29, 2026
• First Posted (Actual): April 30, 2026

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: May 18, 2026

More Information

Terms related to this study

• Keywords: GLP-1; Dopamine; Normal Physiology; Tirzepatide; Alcohol Use Disorder (AUD)
• Additional Relevant MeSH Terms: Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Alcoholism; Amino Acids, Peptides, and Proteins; Proteins; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide; Tirzepatide; Pharmaceutical Preparations
• Other Study ID Numbers: 10002447; 002447-AA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: For Parts 1 & 2, we will do individual subject analysis as well as group analysis. In Part 2 of this study, each subject will serve as their own control too.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No