Methamphetamine (meth) use is very common among MSM, particularly MSM living with HIV. Meth use among HIV-negative and HIV-positive MSM is up to 13 and 34 times more prevalent than in the general U.S. adult population, respectively. Meth use is independently associated with HIV-related sexual risk behaviors among MSM and can function as a barrier to ART and pre-exposure prophylaxis (PrEP) adherence. Thus, effective interventions to reduce meth use may also function as an important HIV prevention and care intervention by reducing substance-related HIV risk behavior, and optimizing ART and PrEP adherence. MSM comprise two-thirds of the new infections in the United States. Despite this continued domestic HIV epidemic and the high prevalence of meth use among MSM, few interventions have proven effective in this population. There are no FDA-approved pharmacotherapies for methamphetamine use, a major gap in the treatment field. We seek to address this gap by evaluating the efficacy of intermittent oral naltrexone enhanced with an ecological momentary intervention (ION+EMI) for meth use treatment. Naltrexone, a µ-opioid receptor antagonist, is a promising agent for meth-using MSM. Meth is rapidly metabolized to amphetamine in the bloodstream and naltrexone has shown efficacy in reducing relapse to amphetamine use. Additionally, emerging evidence suggests that ecological momentary interventions (EMI) that respond to in-the-moment contexts can lead to positive health behaviors, such as increasing medication dosing. A pilot study of intermittent naltrexone conducted by our group found that meth-using MSM who used at least 1 day per week had significantly greater reductions in meth-using days and sexual risk behaviors when treated with as-needed naltrexone, compared to placebo. In the pilot, participants reported taking study drug 64% of the days that they craved meth or anticipated meth use. To build on the results of this study, we propose to evaluate intermittent naltrexone to treat meth use in an efficacy trial enhanced by an EMI that responds to participant’s levels craving or anticipated meth use to provide in-the-moment medication reminders during periods when participants would most benefit from naltrexone. This proposal, entitled “The ION+EMI Study: Intermittent Oral Naltrexone enhanced with an Ecological Momentary Intervention for Methamphetamine-using MSM” is a double-blind, placebo-controlled phase 2b trial in which 54 meth-using MSM will be randomly assigned (2:1) to receive 12 weeks of as-needed intermittent oral naltrexone 50 mg enhanced with an EMA-informed EMI platform, or as-needed placebo with EMI. Primary outcomes will be assessed upon trial completion as measured by proportion of meth-positive urine samples (Aim 1); sexual risk behavior data, accounting for PrEP and viral load status, through monthly surveys via ACASI (Aim 2); and PrEP or ART adherence by drug levels or viral load test (Aim 3).