The Effects of Exenatide, a GLP-1 Agonist, on Alcohol Self-Administration in Heavy Drinkers

This proposal is intended to answer the call for accelerating drug development by exploring
the potential of a glucagon-like peptide-1 (GLP-1) agonist, exenatide, as a candidate
medication for the treatment of Alcohol Use Disorder. There is now substantial preclinical
evidence that GLP-1 agonists can attenuate behaviors that model both the consumption and
seeking of several commonly abused substances including alcohol, cocaine, and nicotine. This
study is intended to accelerate medication development for Alcohol Use Disorder by testing a
commercially-available and well-tolerated agent at a fraction of the cost of new drug
discovery. None of the FDA-approved Alcohol Use Disorder medications or off-label Alcohol Use
Disorder medications target this GLP-1 pathway, making exenatide a promising compound for
Alcohol Use Disorder drug development.

The primary aim of this study is to test the effects of exenatide on alcohol
self-administration and craving among heavy drinkers. In this within-subjects crossover
design, 36 heavy drinkers will be randomized to exposure order (exenatide or sham injection)
prior to completing two alcohol self-administration trials. Subjects will receive a priming
drink of alcohol and will have access to 8 drinks over a 2-hour period. The investigators
anticipate that subjects will consume less alcohol following the administration of exenatide
compared to when they receive a sham injection. Significant exenatide-induced reductions in
drinking will be considered to be an indication that this drug may have value as an Alcohol
Use Disorder medication. This study may provide a rationale for phase II randomized
controlled trials testing exenatide with a treatment-seeking Alcohol Use Disorder population.
These results may also help to spur further clinical investigation of the effects of
exenatide and other available GLP-1 agonists on the factors implicated in the regulation of
alcohol consumption.

Inclusion Criteria:

1. 21-55 years of age

2. Able to verify age with a state or federal picture identification

3. Exceeds safe weekly drinking limits (14 drinks for women or 21 drinks for men per
week)

4. Reports at least one episode of binge drinking (>3 for women, >4 for men) an average
of once per week in the four weeks prior to baseline screening.

5. Meets Diagnostic Statistical Manual 5 criteria for mild alcohol use disorder or
greater severity.

Exclusion Criteria:

1. Seeking treatment for alcohol problems.

2. Clinical Institute Withdrawal Assessment at ≥10

3. Diagnosis of current major depression, bipolar disorder, schizophrenia,
bulimia/anorexia, dementia, or a substance use disorder other than alcohol, nicotine,
marijuana or caffeine

4. If female, pregnant, nursing, have plans to become pregnant

5. If female, does not agree to use an accepted form of birth control

6. Has a medical contraindication to the use of exenatide

7. Has medical or mental condition for which further alcohol exposure at the planned dose
range would be contraindicated

8. Current risk of suicidality.

9. Bosy Mass Index is less than 18 or greater than or equal to 30.

10. History of diabetes

11. Significantly elevated serum amylin levels

12. Impaired renal function (GFR <80 mL/min)

13. Pancreatitis, gastroparesis or other severe gastrointestinal disease

14. Has had gastric bypass surgery

15. Subject is currently taking warfarin

16. Has received alcohol counseling or other non-pharmacologic intervention to treat
Alcohol Use Disorder in the past 90 days.

17. Has taken medications that are used to treat Alcohol Use Disorder in the past 90 days.

18. Subjects with a history of thyroid cancer or other thyroid disease

19. Has urine toxicology results positive for cocaine, opioids, amphetamines,
buprenorphine, methadone, or methamphetamines

20. Prior history of anaphylaxis or angioedema with another GLP-1 receptor agonist