Daily Liraglutide for Nicotine Dependence

Tobacco use and obesity are the two leading causes of preventable deaths. A growing
literature indicates that common neurobiological substrates mediate drug addiction and
obesity. Therefore, it is not surprising that during smoking abstinence, highly palatable
food may serve as a substitute reinforcer ultimately leading to increased body weight gain.
Importantly, post-cessation weight gain (PCWG) can deter a quit attempt, precipitate smoking
relapse, and contribute to health issues related to excess body weight. The majority of
weight gain occurs within 3-6 months of quitting smoking and many individuals maintain this
increased weight 5 to 20 years post-cessation. Although there is substantial variability in
the amount of weight gained, individuals who successfully quit smoking gain an average of 4.2
kg, with estimates ranging from 2.5 kg to 8.6 kg, at 6-month follow-up. Weight gain after
smoking cessation contributes to increased risk of obesity, type II diabetes mellitus and
hypertension (18), as well as reducing the improvement in lung function conferred by smoking
cessation. Moreover, overweight or obese smokers comprise 70% of treatment-seeking smokers,
gain the most weight, and are the least accepting of PCWG. Thus, post-cessation weight gain
is a significant clinical problem. Unfortunately, current pharmacological interventions to
reduce post-cessation weight gain are not very effective.

While weight gain is often cited as a primary reason for smoking relapse, there is a
significant gap in our understanding of the biobehavioral mechanisms linking smoking
cessation and overeating. Recent evidence indicates that glucagon-like peptide-1 (GLP-1)
regulates the rewarding effects of nicotine. These effects are mediated, in part, by reduced
dopamine signaling in the nucleus accumbens, a key brain region known to regulate the
reinforcing effects of both drugs of abuse and palatable foods. Indeed, activation of GLP-1
receptors in the VTA, a brain region that sends dopaminergic projections to the nucleus
accumbens, reduces both drug intake and consumption of palatable food. Based on the ability
of GLP-1 receptor agonists to reduce drug and food intake, it is plausible that targeting
GLP-1 receptor signaling may be an effective strategy toward reducing withdrawal-induced
weight gain in abstinent smokers.

Investigators have recently developed a novel animal model of nicotine withdrawal-induced
hyperphagia and body weight gain in order to gain an improved understanding of the molecular
and behavioral mechanisms underlying increased food intake and body weight gain during
nicotine withdrawal. The pilot data provide strong empirical rationale for the proposed study
by establishing an animal model of withdrawal-induced hyperphagia and body weight gain
following voluntary nicotine self-administration. This withdrawal phenotype was evident only
in rats given ad libitum access to a highly palatable diet during withdrawal as parallel
studies using a normal chow diet did not produce hyperphagia or changes in body weight during
nicotine withdrawal (data not shown). Collectively,these results are consistent with human
laboratory studies indicating that nicotine withdrawal is associated with increased
consumption of highly palatable foods and body weight. The translational implications of
studying this behavioral phenotype are clear and significant and include: 1) informing
clinical approaches to treating weight gain during smoking abstinence, 2) identifying
potential biomarkers associated with nicotine addiction, and 3) addressing two significant
public health concerns.

GLP-1 receptor ligands are currently FDA-approved for the treatment of type II diabetes
mellitus and obesity. Re-purposing an existing FDA-approved treatment that has been
"de-risked" (i.e., previously shown to be safe) in numerous clinical trials removes a key
barrier for drug development and reduces the resources required to bring new drugs to market.

The promising preclinical data, combined with evidence that GLP-1 receptor agonists are
effective treatments for obesity, suggest that GLP-1 receptor ligands could be re-purposed
for attenuating nicotine withdrawal-induced bodyweight gain, thereby improving smoking
cessation rates. Specifically, this study will examine the effects of the GLP-1 receptor
agonist liraglutide on smoking behavior as well as food intake and body weight gain during
abstinence.

Inclusion Criteria:

Eligible subjects will be males and females:

1. 18 years of age or older who self-report smoking cigarettes (menthol and non-menthol)
at least 10 times per day, on average, for the past 6 months.

2. Interested in quitting smoking (defined as "intend to quit within one month").

3. Body mass index (BMI) greater than or equal to 27 kg/m2 with one weight-related
comorbidity (e.g. high blood pressure, high cholesterol, dyslipidemia) or greater than
or equal to 30 kg/m2 per the manufacturer label for weight management.

4. Women of childbearing potential (based on medical history) must consent to use a
medically accepted method of birth control (e.g., condoms and spermicide, oral
contraceptive, Depo-Provera injection, contraceptive patch, intrauterine device (IUD),
tubal ligation) or agree to abstain from sexual intercourse during the time they are
in the study.

5. Able to communicate (speak, read, and write) fluently in English.

6. Capable of giving written informed consent before any study-related activities, which
includes compliance with the requirements and restrictions listed in the combined
consent/HIPAA form.

Exclusion Criteria:

Subjects who present with and/or self-report the following criteria will not be eligible to
participate in the study.

Smoking Behavior:

1. Current enrollment in a smoking cessation program, or use of other smoking cessation
medications (e.g. Chantix/varenicline, Zyban/bupropion, nicotine replacement
therapy/gum/patch, etc.) in the last month or plans to do either in the next 2 months.

2. Daily use of chewing tobacco, snuff and/or snus, or electronic cigarettes.

Alcohol/Drug Use:

1. Self-report current alcohol consumption that exceeds 25 standard drinks/week over the
past 6 months.

2. Current untreated and unstable diagnosis of severe substance use disorder (eligible if
past use and/or if receiving treatment and stable for at least 30 days). Current
untreated and unstable moderate substance use disorder requires Study Physician
approval.

3. Providing a breath alcohol concentration (BrAC) reading greater than 0.00.

4. A positive urine drug screen for marijuana, cocaine, amphetamines, methamphetamines,
benzodiazepines, PCP, methadone, barbiturates, ecstasy (MDMA), oxycodone, tricyclic
antidepressants, tetrahydrocannabinol (THC), and opiates (low level cut-off 300
ng/mL).

Medical:

1. Females who self-report current pregnancy, planning a pregnancy during the study,
currently breastfeeding/lactating, or not using adequate contraceptive measures. All
female participants will undergo a urine pregnancy test at Intake and at every study
visit.

2. Current diagnosis of unstable and untreated major depression, as determined by
self-report & MINI (eligible if stable for at least 30 days).

3. Current or past diagnosis of bipolar disorder or psychotic disorder, as determined by
self-report or MINI. Mood Disorder with Psychotic Features determined by MINI requires
PI approval eligibility.

4. Suicide risk on the C-SSRS indicated by active suicidal ideation (within past 30
days), any suicidal behavior/attempt within the past 2 years, or 2 or more lifetime
episodes of suicidal behavior/attempts.

5. Self-reported kidney and/or liver disease or transplant.

6. Heart/Cardiovascular disease (e.g., angina, coronary heart disease, stroke, etc.) in
the past 6 months.

7. Type-1 or type-2 diabetes (previously diagnosed or indicated by HbA1c level of 6.5% or
higher).

8. Uncontrolled hypertension (BP systolic greater than 159 and/or diastolic greater than
99)*.

9. Personal or family history of medullary thyroid carcinoma (MTC).

10. Personal or family history of Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

11. History of pancreatitis.

12. History of gallbladder disease.

13. A blood glucose level less than 70 mg/dl at the Intake Visit.

14. Prior history, or plans, of surgical intervention for weight loss.

15. Known or suspected allergy to liraglutide, excipients, or related products. *
Participants presenting with SBP greater than 159 mmHg and/or DBP greater than 99 mmHg
at the Intake visit will be instructed to sit quietly for 10 minutes. Then the
participant will have a second blood pressure reading taken after a 10 minute period.
If, after the second reading the SBP greater than 159 mmHg and the DBP greater than 99
mmHg, the individual will be instructed to sit comfortably for 10 minutes and then
have a third blood pressure reading. If, after the third reading the SBP greater than
159 mmHg and the DBP greater than 99 mmHg, the individual will be ineligible to
participate.

Medications:

1. Current use or recent discontinuation (within the past 14 days) of any of the
following medications:

1. Anti-anxiety or panic disorder medications (e.g., clonazepam, alprazolam).

2. Anti-psychotic medications (e.g., thorazine, Seroquel).

3. Mood-stabilizers (e.g., Lithium, Lamictal/lamotrigine, valproic acid,
Neurontin/gabapentin, Topamax/topiramate, Tegretol/carbamazepine).

4. Prescription stimulants (e.g., Provigil, Ritalin, Adderall).

2. Daily use of opiate-containing medications for chronic pain (Duragesic/fentanyl
patches, Percocet, Oxycontin). Smokers who report taking opiate-containing medications
on an "as-needed" basis will be instructed to refrain from use until their study
participation is over and that they will be tested to ensure they have complied with
this requirement.

3. Current or recent use (last 14 days) of weight loss medication, and/or use of
medications known to impact weight (e.g. corticosteroids).

General Exclusion:

1. Current, anticipated, or pending enrollment in another research program over the next
2-3 months that could potentially affect subject safety and/or the study data/design
as determined by the Principal Investigator and/or Study Physician.

2. Not planning to live in the area for the next 9 months.

3. Previous participation in this trial (i.e., previously randomized and started study
medication).

4. Any impairment (physical and/or neurological) including visual or other impairment
preventing ability to complete study tasks.

5. Inability to provide informed consent or complete any of the study tasks as determined
by the Principal Investigator.