The proposed project will include enrollment of 200 daily tobacco cigarette users, ages 22+, from the San Diego community. Participants will be assessed on the VR Nicotine Cue Exposure paradigm then randomized (stratified on age and sex) to receive varenicline (target dose 1mg twice daily) or placebo (n per group=100; total N=200). Following eight days of titration, participants will be assessed again on the VR Nicotine Cue Exposure paradigm. They will then be followed via mobile assessments for eight days on target dose of varenicline, and 30-days post assessment by phone, to assess short-term nicotine use behaviors.

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Persons, aged 22+
4. Ability to take oral medication and be willing to adhere to the dosing regimen
5. For participants able to become pregnant: use of highly effective contraception during study enrollment
6. Current daily tobacco use (use on 7 days per week, on average, ≥5 cigarettes per day, in the previous 3 months)
7. Tobacco use history ≥3 years
8. Endorsement of past week nicotine craving

Exclusion Criteria:

1. Contraindications/conditions with special precautions for varenicline treatment (i.e., history of serious hypersensitivity or skin reactions to varenicline, history of severe renal impairment, seizures, severe cardiovascular disease, chronic or severe nausea, Stevens-Johnson syndrome, erythema multiforme, pregnancy or nursing)
2. Medical or psychiatric history affecting brain development (i.e., history and/or treatment of neurologic disorders, severe head trauma with loss of consciousness >2 minutes, or current severe Diagnostic and Statistical Manual 5th edition (DSM-5) psychiatric disorders other than tobacco use disorders)
3. Current suicidal ideation or history of suicide attempt or self-mutilatory acts in the past 12 months
4. Other recreational drug use in the past 30 days (besides alcohol and cannabis) verified by oral and urine fluid toxicology
5. Visual/vestibular problems that may make task completion difficult (i.e., motion sickness, difficulty balancing, blindness)
6. Treatment seeking for tobacco use disorder/intent to quit within 30 days

Psychophysiology, mental health, and substance use de-identified data listed above sufficient in quality to validate and replicate the research findings described in the aims will be deposited to the National Addiction & HIV Data Archive Program (NAHDAP) repository. For specific variables where small sample sizes may allow for easy re-identification of research participants, only summarized data will be made available.

Data will become available 2025-2028

Standard procedures of the NAHDAP will be followed for determining the best level of access (public or restricted) based on review of disclosure risk by ICPSR.