Current enrollment or plans to enroll in another smoking cessation program during the study time frame, including plans to use other smoking cessation medications (i.e., over the counter [OTC] or prescription medication for smoking cessation) or smoking cessation treatments

Serious or unstable medical or psychiatric disorder within the past 3 months, as determined by the study physician

Being pregnant, engaging in breast-feeding, or being of childbearing potential and engaging in sexual activity that could lead to pregnancy and is not protected by a medically acceptable, effective method of birth control while enrolled in the study, as determined by self-report. Medically acceptable contraceptives include: (1) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (2) barrier methods (such as a condom or diaphragm) used with a spermicide, or (3) an intrauterine device (IUD). Contraceptive measures sold for emergency use after unprotected sex are not acceptable methods for routine use

Current use of certain medications:

• Smoking cessation meds (last 7 days; e.g., bupropion, NRT, varenicline). Episodic use of NRT in the last 7 days may be considered if the participant agrees to only use study medication once randomized
• Certain medications may be exclusionary and others are precautionary, to be evaluated on a case-by-case basis by study physician (See Exclusionary/Precautionary Medication List, Appendix 5)
• Daily use of opioids for 30 days or more on phone screen or at screening is exclusionary, however as needed (PRN) use is allowed (i.e., 3 out of 7 days per week or less or if more frequent use in less than a month's duration)

History of hypersensitivity or allergic reaction to varenicline, NRT, or any component of these formulations as determined by the medical team

Self-report of a history or current diagnosis of schizophrenia or bipolar disorder unless cleared by study physician

Current substance use disorder (Drug Abuse Screening Test [DAST] score > 3 or use >0 in the past year and refuses to refrain from use for the duration of the study; Alcohol Use Disorders Identification Test [USAUDIT] score > 24)

Individuals who report depressive symptoms in the moderately severe or severe range on the Patient Health Questionnaire - Mood Module (PHQ-9) (scores of 15 or above); or who report current suicidal ideation on the PHQ-9

Individuals who report anxiety symptoms in the severe range on the Generalized Anxiety Disorder Scale (GAD-7) (scores of 15 or above); or meet criteria for panic syndrome on the PHQ Panic module

Psychiatric hospitalization within 1 year of screening date

Any otherwise not specified medical or psychiatric condition, illness, disorder, or concomitant medication that could compromise participant safety or treatment, as determined by the principal investigator and/or study physician

Participant considered by the investigator as unsuitable candidate for full participation in both the treatment and follow-up phases of the study