Extended-release naltrexone (XR-NTX, VIVITROL) is an FDA-approved medication with efficacy in treating alcohol dependence and prevention of relapse to opioid dependence. It has shown promise in reducing relapse to amphetamine use among amphetamine-dependent, yet currently amphetamine-abstinent heterosexuals. The investigators will expand upon this promising work to determine whether monthly intramuscular injections of naltrexone will reduce methamphetamine (meth) use among actively using, meth-dependent men who have sex with men (MSM) in this double-blind randomized controlled trial of extended-release naltrexone versus placebo. The investigators will focus on MSM because of the disproportionate and intertwining epidemics of meth use and HIV in this population.

The investigators will enroll 100 sexually active, meth-dependent MSM who will be randomized 1:1 to receive monthly injections of extended-release naltrexone (n=50) or placebo (n=50) for 12 weeks at weeks 0, 4, and 8. Study participants will be seen weekly at our site at the HIV Prevention Section of the San Francisco Department of Public Health, where they will provide urine for drug testing and participate in substance use counseling. All participants will receive HIV risk-reduction counseling. Behavior will be assessed using standardized measures via audio computer-assisted self-interview (ACASI).

Inclusion criteria:

1. born male; or born female and does not identify as female
2. reports having anal sex with men in the prior six months while under the influence of meth;
3. diagnosed with meth dependence as determined by SCID;
4. interested in stopping or reducing meth use;
5. at least one meth-positive urine during screening and run-in period;
6. no current acute illnesses requiring prolonged medical care;
7. no chronic illnesses that are likely to progress clinically during trial participation;
8. able and willing to provide informed consent and adhere to visit schedule;
9. age 18-65 years;
10. baseline CBC, total protein, albumin, glucose, alkaline phosphatase, creatinine, BUN, total bilirubin, and electrolytes without clinically significant abnormalities as determined by investigator in conjunction with symptoms, physical exam, and medical history.

Exclusion criteria:

1. any psychiatric condition (e.g. current depression with suicidal ideation or schizophrenia) that would preclude safe participation in the protocol;
2. known intolerance and/or hypersensitivity to naltrexone, carboxymethylcellulose, or polylactide-co-polymers (PLG) or any other components of the diluents;
3. current use of or dependence on any opioids; a known medical condition which currently requires or is likely to require opioid analgesics; or positive opioid urine screening tests
4. diagnosed with current alcohol dependence as determined by the SCID;
5. current CD4 count < 200 cells/mm3;
6. moderate or severe liver disease (AST and/or ALT > 5 times upper limit of normal);
7. moderately or severely impaired renal function (eGFR < 50 mL/min);
8. thrombocytopenia or other coagulation disorder
9. currently participating in another research study;
10. pending legal proceedings with high risk for incarceration during the time of planned study participation;
11. any condition that, in the principal investigator's judgment, interferes with safe study participation or adherence to study procedures.