Understanding Factors That Influence Electronic Cigarette Nicotine Delivery Through PET Imaging of Beta-2 Nicotinic Acetylcholine Receptors

C.2 Subject Inclusion and Assessments Overall study design: Non-EC-naïve smokers or e-cigarette users (n=20) will abstain from tobacco smoking/nicotine products for 5 days prior to each PET scan. In a randomized order (counterbalanced), after baseline quantification of receptor availability, subjects will be scanned while using an EC: (1) "JUUL" 5%, a common commercially available unmodified nicotine salt EC, and (2) JUUL 3%, a lower nicotine strength product. A third optional scan where subjects smoke a cigarette may be conducted but is not required. During scanning, subjects will undergo arterial blood nicotine level measurements following EC use and measures of nicotine withdrawal, craving, and drug effects will be measured. 5-7 days of smoking abstinence will be required prior to each PET scan to ensure no residual nicotine occupies receptors. Subjects will go back to smoking as usual after first scan for 2-3 weeks prior to subsequent smoking abstinence/PET scanning. Subjects will be provided with smoking cessation resources upon request.

C.2.b Subjects: Twenty non-EC-naïve tobacco dependent smokers or e-cigarette users will be recruited for the study. All research subjects will be recruited under guidelines of the Yale University Institutional Review Board (Human Investigation Committee). Smokers will be recruited from the community via IRB-approved advertising. After completing informed consent, subjects will have a psychiatric, physical and neurological examination, laboratory tests and an electrocardiogram (EKG) (see C.2.c Clinical Assessments below). This is considered the screening phase. Subjects will be excluded for major medical, neurological or psychiatric illness, abnormal laboratory tests, or contraindication to PET or MR imaging. A urine drug screen and pregnancy test are performed at screening and prior to each imaging session and participants are excluded for a positive test. Detailed inclusion/exclusion criteria can be found in Protection of Human Subjects section. All women will be required to have a negative urine pregnancy test and all subjects are required to have a negative urine drug toxicology test prior to radiotracer administration.

C.2.c Clinical Assessments: A standardized battery will be administered to all subjects at intake including Health Questionnaire, the SCID, assessments of demographics, measures of tobacco use, alcohol and drug use, family history of smoking, mood (PROMIS short forms for depression, anxiety, and anger), Center for Epidemiologic Studies Depression Scale), anxiety (State Trait Anxiety Inventory), impulsivity (Brief - Barratt Impulsivity Scale, smoking dependence (PROMIS nicotine dependence scale), smoking craving (Tiffany QSU) and withdrawal (Minnesota Nicotine Withdrawal Scale). Mood and smoking assessments will be repeated on each scan day before and after challenge. Product liking, craving and the Drug Effects Questionnaire (DEQ) will be assessed on a subjective scale (0-100, low-high) immediately following product use. The DEQ will measure acute effects consisting of seven items: drug strength, high, feeling stimulated, good effects, bad effects, wanting more drugs, and drug liking.

Baseline and after each PET scan/e-cig challenge:

• Health Questionnaire
• PROMIS Dyspnea Severity Item Pool
• PROMIS Dyspnea Characteristics
• PROMIS Fatigue Short Form
• Functional Assessment of Chronic Illness Therapy (FACIT) Cough item
• The health questionnaire titled 'assessment of health problems' (and provided as an attachment via a comment in IRES) will be added to the protocol and will be completed at intake and before each exposure. Note that potential subjects with chronic symptoms that would interfere with monitoring of vaping complications, will not be enrolled.