The objectives of this application are to 1) compare short- and long-term harm reduction and abuse liability potential of a nicotine salt pod-based electronic cigarettes (EC) in adult (AA) exclusive EC, dual cig-EC, and exclusive cig users, 2) characterize factors that predict who switches fully, partially, or not at all, and 3) examine if harm reduction can be further enhanced by treating dual users with varenicline (VAR) to eliminate cigarette smoking.

Adult cigarette smokers (n=500) who are interested in switching to a nicotine salt-based electronic cigarette (EC) and are not established EC users will receive a 6-week supply of the EC and assistance with switching. After six weeks, those that are dual users (n=221) will receive an additional 12 weeks of the EC and be randomized in a 2:1 fashion to receive 12 weeks of varenicline (VAR) or placebo (PBO) and additional counseling to support a complete switch. Follow-up for all participants will continue through week 52. The primary outcome is change in the potent lung carcinogen, NNAL, between exclusive EC, dual cig-EC, and exclusive cig users at week 6.

Inclusion Criteria:

• ≥ 21 years of age
• Smoke >5 cigarettes per day
• Smoked cigarettes for > 6 months
• Verified smoker (CO > 5 ppm)
• Functioning telephone
• Interested in switching to EC
• Willing to take varenicline and complete all study visits

Exclusion Criteria:

• Interested in quitting smoking
• Use of smoking cessation pharmacotherapy in the month prior to enrollment
• Use of other tobacco products in past 30 days (i.e., cigarillos, cigars, hookah, smokeless tobacco, pipes)
• EC use on > 4 of the past 30 days
• Uncontrolled hypertension: BP > 180 (systolic) or > 105 (diastolic)
• Heart-related event in the past 30 days
• Medical contraindications to VAR: unstable cardiac condition (e.g., unstable angina or AMI) cardiac event, or stroke in the past 4 weeks; renal impairment; history of clinically significant allergic reactions; history of epilepsy or seizure disorder; hospitalized for psychiatric issue in past 30 days; active suicidal ideation
• Pregnant, contemplating getting pregnant, or breastfeeding
• Plans to move from Kansas City metro area during the treatment and follow-up phase
• Another household member enrolled in the study