Daily Liraglutide for Nicotine Dependence
Daily Liraglutide for Nicotine Dependence
This clinical research trial examines the effects of the GLP-1 receptor agonist liraglutide
 on smoking behavior, food intake, and weight gain. In this double-blind, placebo-controlled,
 parallel arm pilot study, overweight and obese smokers (N=40; 20 female and 20 male) will be
 randomized to 32 weeks of liraglutide or placebo and undergo 8 sessions of smoking cessation
 behavioral counseling. Outcomes are smoking abstinence and weight change.
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.

 7. If current or past diagnosis of bipolar disorder, eligible if:

 1. No psychotic features

 2. MADRS: total score less than 8 (past 4 weeks); suicidal item score less than 1
 (past 4 weeks)

 3. Y-MRS: total score less than 8 (past 4 weeks); irritability, speech content,
 disruptive or aggressive behavior items score less than 3 (past 4 weeks)

 4. No psychiatric hospitalization or Emergency Room visits for psychiatric issues in
 the past 6 months

 5. No aggressive or violent acts or behavior in the past 6 months

 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. A positive urine drug screen for cocaine, methamphetamines, PCP, barbiturates, and/or
 ecstasy (MDMA).

 1. Participants believed to have a false-positive result on the drug screen may
 continue with the study with investigator approval.

 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
 in-person 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 psychotic disorder, as determined by self-report or MINI.
 Mood Disorder with Psychotic Features determined by MINI requires PI approval for
 eligibility.

 4. Suicide risk on the C-SSRS indicated by active suicidal ideation (within past 30
 days), any suicidal attempt within the past 2 years, or 2 or more lifetime suicidal
 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. Hypersensitivity to liraglutide or any product components.

 16. Current diagnosis of hyperthyroidism or hypothyroidism (requires thyroid function test
 review by SP to determine eligibility)

 17. Recent weight loss (more than or equal to 5% body weight) in the past 3 months

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

 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.