Effects of Semaglutide on Nicotine Intake

Inclusion Criteria:

• Age 21-65

• Smoking 5+ cigarettes per day (on average) over the past year, with no period ofabstinence > 90 days

• Biochemical verification of smoking status, based on expired CO > 8 at baseline

• Willingness to take study medication and complete study procedures

• Willingness to complete lab sessions involving cigarette smoking

• Ability to communicate in English

Exclusion Criteria:

• Regular use of electronic nicotine delivery systems (ENDS/vaping), cigars, chewingtobacco or snuff, based on at least weekly use in the past 30 days

• Past 30-day use of nicotine replacement therapies/products

• Reporting past 30-day use of illicit drugs other than cannabis at baseline, orhaving a positive toxicology screen for illicit drugs other than cannabis atbaseline

• Current engagement in alcohol or smoking cessation treatments, or currently engagedin intentional efforts to quit cigarette use

• Past 30-day use of: Sincalide, Sulfonylureas, insulin and insulin products or othermedications that may interact with semaglutide, or weight control medications

• Prior use of semaglutide or other GLP-1 agonists

• Known or suspected hypersensitivity to study medication or related products

• Lifetime diagnosis of severe mental illness (including schizophrenia and bipolardisorder)

• Meeting criteria for current alcohol use disorder (AUD) or other substance usedisorder (with the exception of tobacco or mild cannabis use disorder)

• History of suicide attempt, or recent (past 30 day) suicidal ideation, orpsychiatric hospitalization in the last 6 months

• Current significant medical or neurological illness (based on self-report or medicalrecord) including severe hepatic impairment or cirrhosis, impaired renal function (eGFR <50ml/min), acute or chronic pancreatitis, gastroparesis, gallbladder diseaseor cholelithiasis, other severe gastrointestinal disease, heart failure, coronaryartery disease, stroke, seizure disorder, or other medical condition that poses arisk for the medication or alcohol administration components of the study (asdetermined by the MD)

• A personal or family history of medullary thyroid cancer or multiple endocrineneoplasia 2A or 2B

• Calcitonin greater than or equal to 50 ng/L

• Uncontrolled thyroid disease at screening

• History of major surgical procedures involving the stomach potentially affectingabsorption of trial product (e.g., subtotal and total gastrectomy, sleevegastrectomy, gastric bypass surgery)

• History of Type 1 or Type 2 diabetes, or HbA1c >6.5% measured at screening

• History of diabetic retinopathy, proliferative retinopathy, or maculopathy

• History of diabetic ketoacidosis

• History or presence of malignant neoplasms within the last 5 years (except basal andsquamous cell skin cancer and carcinoma in situ)

• Currently nursing, pregnant, anticipating pregnancy in the next 6 months, or notusing a highly effective contraceptive method as judged by the MD, and defined as:

1. combined (estrogen and progestogen containing) hormonal contraceptionassociated with inhibition of ovulation (oral, intravaginal, transdermal)

2. progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)

3. intrauterine device

4. intrauterine hormone-releasing system

5. bilateral tubal occlusion

6. vasectomized partner

7. sexual abstinence

• Elevation of serum lipase, amylase, direct (conjugated) bilirubin, or alkalinephosphatase (ALP), ALT, or AST) more than 3X the upper limit of normal on baselinebloodwork

• Baseline body mass index (BMI) <23kg/m^2

• Uncontrolled hypertension or systolic BP >180 mmHg and/or diastolic BP >105 mmHg,averaged from three measurements

• Plans for travel outside of the local area in the upcoming 12 weeks that wouldinterfere with lab visits during the study period (or other logistic factors thatwould make it difficult to commit to entire duration of study)