Tirzepatide s Dopaminergic Effects in Alcohol Use Disorders (AUD)

NCT07559500 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10002447002447-AA
• Study Type: interventional
• Target: 176
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Alcohol Use Disorder (AUD)

Keywords

Tirzepatide; Dopamine; Alcohol Use Disorder (AUD); Normal Physiology; GLP-1

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Part 1: Subjective responses to MP

  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 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.

Study Arms (5)

[11C]NNC-112 - Part 2

PLACEBO COMPARATOR

\[11C\]NNC-112 PET/MR or PET/CT scan obtained without any drug intervention to measure dopamine D1 receptors.

Drug: Tirzepatide; Drug: Placebo; Drug: [11C]NNC-112

[11C]raclopride plus drug - Part 1

ACTIVE COMPARATOR

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

[11C]raclopride plus drug - Part 2

ACTIVE COMPARATOR

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: Placebo; Drug: [11C]raclopride plus drug

Placebo - Part 2

PLACEBO COMPARATOR

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

Tirzepatide - Part 2

ACTIVE COMPARATOR

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

Interventions

Tirzepatide DRUG

Drug approved for diabetes administered SQ. Subject is blind to drug.

Tirzepatide - Part 2; [11C]NNC-112 - Part 2; [11C]raclopride plus drug - Part 2

Placebo DRUG

Placebo will be normal saline administered SQ. Subject is blind to drug.

Placebo - Part 2; [11C]NNC-112 - Part 2; [11C]raclopride plus drug - Part 2

[11C]NNC-112 DRUG

\[11C\]NNC-112 PET/MR or PET/CT scan obtained without any drug intervention to measure dopamine D1 receptors.

[11C]NNC-112 - Part 2

[11C]raclopride plus drug 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.

[11C]raclopride plus drug - Part 1; [11C]raclopride plus drug - Part 2

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy Volunteer Participants
• To be eligible to participate in this study, an individual must meet the following criteria:
• Enrollment in 14AA0181.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Male or female, ages 21-65 years old.
• Ability to understand and willingness to sign a written informed consent document.
• 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:
• Enrollment in 14AA0181.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Male or female, ages 21-65 years old.
• Ability to understand and willingness to sign a written informed consent document.
• DSM 5 diagnosis of mild to moderate AUD.
• 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.

You may not qualify if:

• All Participants (Healthy Volunteers and AUD)
• 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
• Cannot lie comfortably flat on his/her back for up to 2 hours in the PET/MRI scanner.
• BMI \<23 or \>35 (but no more than 500 lbs). The PET/MRI scanner bed is tested to a weight limit of 500 lbs.
• 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.
• 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.
• 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.
• Severe head trauma with loss of consciousness \> 60 minutes
• Current severe mental illness (schizophrenia, bipolar disorder).
• Montgomery-Asberg depression rating scale (MADRS) total score \> 35 or suicidal thoughts item score \> 3, indicating severe depression or moderate suicidality, respectively.
• Thyroid cancer or family history of thyroid cancer or personal or family history of multiple endocrine neoplasia syndrome type-2 (MEN-2).
• History for cerebral aneurysm.
• Past or present history of chest pain and trouble breathing with activity.
• History of Heart Disease, Hypertension or Cardiovascular disorders.
• History of seizures, anxiety, panic attacks, psychosis or glaucoma which are contraindicated with receiving methylphenidate.

Sponsors & Collaborators

• National Institute on Alcohol Abuse and Alcoholism (NIAAA): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Alcoholism

Interventions

Tirzepatide; Pharmaceutical Preparations

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Proteins; Amino Acids, Peptides, and Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide

Study Officials

• Nora D Volkow Adler, M.D.

  National Institute on Alcohol Abuse and Alcoholism (NIAAA)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michele-Vera I Yonga, C.R.N.P.

CONTACT

(301) 273-4169; michele-vera.yonga@nih.gov

Nora D Volkow Adler, M.D.

CONTACT

(301) 443-6480; nvolkow@nida.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2026
• First Posted: April 30, 2026
• Study Start: May 20, 2026
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): December 31, 2031
• Last Updated: July 28, 2026

Record last verified: 2026-07-22

Locations

US (1)