Stage 1 will include 20 individuals with severe stimulant use disorder (methamphetamine type) enrolled across three study sites. Following a maximum 30-day screening period to establish eligibility, participants will receive a monthly injection of extended-release depot naltrexone (XR-NTX; as Vivitrol®) plus once-daily bupropion extended-release tablets (BRP; as Wellbutrin XL®) for 8 weeks. Take-home oral study medication (BRP) will be dispensed weekly for dosing on non-clinic days. Participants will be asked to attend clinic twice weekly for observed BRP dosing, collection of urine samples, assessments, and medical management. Following the 8-week active medication phase, participants will complete a follow-up phase, including a medication taper and post-medication phase follow-up visit during Week 9. If Stage 1 data document success (see criteria below) in at least 3 "responder" study participants, Stage 2 will follow utilizing the same protocol as in Stage 1, to enroll an additional group of 29 participants. Using the same criteria of "responder" success, if the combined stages document success in at least 9 of 49 study participants, the combination medication will be considered to have shown sufficient potential to advance to a large-scale placebo-controlled trial.

This is a dose escalating, double-blind, placebo-controlled inpatient study in 16 cocaine-experienced volunteers. The subjects will receive atomoxetine 20 mg once daily (q.d.) for 2 days, 40 mg q.d. for 2 days, 80 mg q.d. for 5 days and 100 mg q.d. for 5 days orally or matched placebo. After beginning daily treatment with either atomoxetine or placebo, subjects will receive treatment cocaine infusions of 20 mg and 40 mg i.v. on the two last days of 80 mg and 100 mg atomoxetine dosage levels. Each cocaine infusion will be preceded or followed by saline i.v. infusion in random order; cocaine and saline infusions will be administered 60 minutes apart. The subjects will be discharged 4 days after the last infusion of cocaine (day 17). Subjects will be requested to return for follow-up 2 weeks after the day of discharge.

Project 1, Study 1 will evaluate the relationship between nicotine yield of very low nicotine content cigarettes and cigarettes smoked per day, nicotine exposure, discomfort/dysfunction, other health-related behaviors, nicotine/tobacco dependence, biomarkers of tobacco exposure, intention to quit, compensatory smoking, other tobacco use, cigarette characteristics, cognitive function, cardiovascular function, and perceived risk. We will also consider differences between conditions in compliance with product use.