We are proposing BICX104, a subcutaneous, long-duration naltrexone implantable pellet, alone or in conjunction with bupropion for the treatment of Methamphetamine Use Disorder (MUD). Clinical studies have supported the potential use of naltrexone alone in the treatment of MUD, as well as naltrexone in combination with bupropion to significantly attenuate methamphetamine (METH) use. METH use is currently occurring in large numbers with an estimated 2 million people per year in the U.S. and a 43% increase in usage from 2015-2019. Efficacy studies show that compliance to NTX therapy is superior to placebo for maintaining abstinence to substance abuse, with some evidence that monthly injections are superior to oral doses. However, noncompliance severely limits NTX's clinical efficacy. The insertion of a sustained-release NTX depot pellet formulation such as BICX104 can both ensure compliance and provide therapeutic blood levels over long time periods. There are no approved medications for MUD, leaving patients, care givers, and society at risk to the epidemic of METH abuse and associated morbidity and death. The proposal investigates BICX104 alone and BICX104/BUP in comparison with a double placebo group (implant and tablet) to demonstrate safety, pharmacokinetics (PK), and efficacy in MUD. There is an FDA-approved IND in place and a completed Phase 1 study of BICX104 as of March 22, 2023 to enable the trials described in this proposal. Dr. Mallon has assembled an outstanding clinical research team paired with outstanding facilities that has a track record of success in this program. Aim 1: Determine the clinical safety profile of BICX104 in Methamphetamine Use Disorder patients in Phase 1b exploratory studies. Evaluate the safety of BICX104 in the patient population and the achievement of clinically relevant NTX plasma concentrations. Deliverables: Achieve minimum effective concentration (MEC) of >1 ng/ml NTX plasma concentrations for at least 10 weeks in all treatment groups. Demonstrate that at least one of the treatment arms is sufficiently well tolerated to enable Phase 2 clinical trial. Aim 2: Establish comparative efficacy of BICX104 and bupropion, alone and in combination in decreasing clinical markers of methamphetamine abuse in Methamphetamine Use Disorder patients. This Phase 2 trial tests efficacy in a sufficiently powered population of MUD patients. Success in this Phase 2 will inform the design of a definitive Phase 3 trial of efficacy that will enable drug approval. Deliverable: Safety and tolerability of at least one treatment arm. Clinically meaningful efficacy of at least one treatment compared to placebo. Milestone: Progression to Phase 3 efficacy trial to enable FDA approval.