Trial of Naltrexone/Bupropion for the Treatment of Methamphetamine Use Disorder

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.

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 \