The aim of this 2-stage, 3-site study is to investigate the effectiveness and safety of a combination of extended-release depot naltrexone plus extended-release bupropion as a potential pharmacotherapy for methamphetamine (MA) use disorder.

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.

Inclusion Criteria:

• Be 18 to 65 years of age;
• Be able to speak English sufficiently to understand the study procedures and provide written informed consent to participate in the study;
• Demonstrate understanding of study procedures by correctly answering all questions on the consent competency tool;
• Be interested in reducing or stopping methamphetamine use;
• Meet DSM-5 criteria for severe methamphetamine use disorder;
• Meet subjective and objective methamphetamine use criteria as defined by the protocol;
• Meet subjective and objective measures of being opioid-free prior to enrollment and medication induction per study medical clinician's determination (including passing a naloxone challenge);
• Agree to use study cellphone to record videos of take-home dosing for transfer to study team.
• If female of childbearing potential, agree to use acceptable birth control methods during participation in the study;

Exclusion Criteria:

• Have known allergy or sensitivity to study medications;
• Have a medical history or condition that would make study participation difficult or unsafe;
• Have an acute psychiatric disorder or condition that would make study participation difficult or unsafe;
• Liver function test results greater than 5 times the upper limit of normal or other exclusionary clinical lab test values;
• Recent or ongoing treatment with medications that, in the judgment of the study medical clinician, could interact adversely with study drugs or interfere with study participation;
• Have a current pattern of alcohol, benzodiazepine, or other sedative-hypnotic use, as determined by the study medical clinician, which would preclude safe participation;
• Pending action or situation that might prevent remaining in the area for the duration of the study or prevent participation in study activities
• Be currently pregnant or breastfeeding;