Nicotine Replacement Therapy, Counseling, Varenicline, and Bupropion for Smoking Cessation, the PISCES I Trial

Inclusion Criteria: * Smoking 5 or more cigarettes, little cigars and/or cigarillos per day, on average, within the past 30 days preceding the screening visit and expired carbon monoxide (CO) ≥ 6 ppm and/or a urine Nic Check test \> 0 (or a reading of positive if an alternate nicotine test used) * Interested in treatment that might change smoking behavior or help them quit smoking * Able to follow verbal and written instructions in English and complete all aspects of the study * Provide informed consent and agree to all assessments and study procedures * Have an address and telephone number where they may be reached * Subjects must report current stable residence in the state of Texas and must not have plans to move out of state in the next 6 months. Stable residence is a domicile in which an individual can operate as if it were his or her own homestead and does not include shelters, halfway houses, treatment centers, or group homes * Be the only participant in their household currently receiving treatment on this protocol * Agree to be treated via telehealth (live audio-video conference and phone) and to be contacted via text and/or email * Willing to refrain from the use of other nicotine/tobacco products for the duration of the study Exclusion Criteria: * 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