The primary objective of this study is to evaluate the efficacy of extended release naltrexone plus bupropion XL (XR-NTX/BUP-XL) compared to matched injectable and oral placebo (iPLB/oPLB) in reducing methamphetamine (MA) use in individuals with moderate or severe methamphetamine use disorder (MUD) seeking to stop or reduce MA use.

This is a double-blind, placebo-controlled, randomized clinical trial in which 360 individuals with moderate or severe MUD will be randomly assigned at a 1:1 ratio to receive either 1) extended release naltrexone (XR-NTX; as Vivitrol®) plus once daily oral extended release bupropion (BUP-XL) tablets (the XR-NTX/BUP-XL group) or 2) both the matching injection placebo (iPLB) and once daily oral placebo (oPLB) tablets (the iPLB/oPLB group). The study intervention consists of a 12-week treatment phase. It is hypothesized that the XR-NTX/BUP-XL arm will be associated with a greater number of "responders," defined as participants who provide at least 3 MA-negative urine drug screens (UDS) out of 4 samples obtained during the evaluation period (i.e., Weeks 11-12) of the 12-week long treatment phase, relative to the iPLB/oPLB arm. Secondary objectives include evaluating the effect of the extended release naltrexone plus bupropion XL (XR-NTX/BUP-XL) arm compared to the iPLB/oPLB arm on safety, other substance use outcomes, depression scores, quality of life, overall functioning, clinic attendance, and medication adherence.

Inclusion Criteria:

1. Is 18 to 65 years of age;
2. Meets DSM-5 criteria for moderate or severe MUD (4 or more criteria);
3. Is interested in reducing or stopping MA use;
4. Is able to speak English sufficiently to understand the study procedures and provide written informed consent to participate in the study;
5. Self-reports MA use on 18 or more days in the 30-day period prior to consent using the Timeline Followback (TLFB);
6. Provides at least 2 urine samples positive for MA out of up to 3 tests, which will occur at least 2 days apart within a 10-day period;
7. If assigned as female at birth and/or currently has a uterus, is not pregnant, agrees to use acceptable birth control methods, and have periodic urine pregnancy testing done during participation in the study unless documentation of hysterectomy provided;
8. Is not physically dependent on opioids and meets subjective and objective measures of being opioid-free prior to naltrexone injection per study medical clinician's determination, including, if clinically required, a negative naloxone challenge;
9. Is willing to comply with all study procedures and medication instructions;
10. Agrees to use a smartphone app (downloaded for free to own device or on a study provided smartphone device) to take daily videos of medication dosing.

Exclusion Criteria:

1. Has an acute medical or psychiatric disorder that would, in the judgment of the study medical clinician, make participation difficult or unsafe;
2. Has suicidal or homicidal ideation that requires immediate attention;
3. Has a history of epilepsy, seizure disorder, or head trauma with neurological sequelae (e.g., loss of consciousness that required hospitalization); current anorexia nervosa or bulimia; or any other conditions that increase seizure risk in the opinion of the study medical clinician;
4. Has evidence of second or third degree heart block, atrial fibrillation, atrial flutter, prolongation of the QTc, or any other finding on the screening ECG that, in the opinion of the study medical clinician, would preclude safe participation in the study;
5. Has Stage 2 hypertension as determined by the study medical clinician (e.g., greater than or equal to 160/100 in 2 out of 3 readings during screening);
6. Has any elevated bilirubin test value per laboratory criteria OR any other liver function test (LFT) value > 5 times the upper limit of normal per laboratory criteria;
7. Has a platelet count <100 x 10exp3/microliter;
8. Has a body habitus that precludes gluteal intramuscular injection of XR-NTX in accordance with the administration equipment (needle) and procedures;
9. Has a known allergy or sensitivity to bupropion, naloxone, naltrexone, PLG (polyactideco-glycolide), carboxymethylcellulose or any other component of the XR-NTX diluents;
10. Has been in a prior study of pharmacological or behavioral treatment for MUD within 6 months of study consent;
11. Has taken an investigational drug in another study within 30 days of study consent;
12. Has been prescribed and taken naltrexone or bupropion within 30 days of study consent;
13. Is concurrently enrolled in formal behavioral or pharmacological Substance Use Disorder (SUD) treatment services;
14. Is receiving ongoing treatment with tricyclic antidepressants, xanthines (i.e., theophylline and aminophylline), systemic corticosteroids, nelfinavir, efavirenz, chlorpromazine, MAOIs, central nervous system stimulants (e.g., Adderall, Ritalin, etc.), or any medication that, in the judgment of the study medical clinician, could interact adversely with study medications;
15. Has a current pattern of alcohol, benzodiazepine, or other sedative hypnotic use which would preclude safe participation in the study as determined by the study medical clinician;
16. Requires treatment with opioid-containing medications (e.g., opioid analgesics) during the study period;
17. Has a surgery planned or scheduled during the study period;
18. Is currently in jail, prison or any inpatient overnight facility as required by court of law or have pending legal action or other situation (e.g., unstable living arrangements) that could prevent participation in the study or in any study activities;
19. If assigned as female at birth and/or currently has a uterus, is currently pregnant, breastfeeding, or planning on conception.

Investigators don't plan to make individual participant data (IPD) available to other researchers.