Funded for the last 4 years by a medication development center grant (U54DA038999), our research group at the Institute for Drug and Alcohol Studies (IDAS) at Virginia Commonwealth University has established the expertise and resources to execute early clinical trials of potential pharmacotherapies for substance use disorders including opioid and cocaine use disorders as well as comorbid opioid+cocaine use disorder. Under that funding, medication development studies were carried out using preclinical models, phase I inpatient studies, brain imaging studies, and behavioral laboratory phenotyping studies for novel compounds for opioid and cocaine use disorders. One of the novel compounds we have examined for opioid, cocaine, and comorbid opioid+cocaine use disorders is the 5-HT2CR agonist lorcaserin. This research was based on our preclinical data that lorcaserin significantly reduces opioid self-administration and opioid and cocaine cue elicited responding in rodents8. In response to RFA-DA-19-018, we propose to maintain and enhance the established medication development infrastructure at IDAS to support Phase I and Phase 2 clinical trials in collaboration with the Division of Therapeutics and Medical Consequences at NIDA. As a demonstration project of the ability of IDAS to conduct early phase clinical trials, we propose to assess safety, target engagement, and preliminary measures of efficacy, for lorcaserin in combination with buprenorphine for opioid use disorder. Specific Aims for Demonstration Project: Experiment 1 (0-18 months). Aim 1: Examine side effects and drug interactions between lorcaserin and buprenorphine-naloxone in participants with opioid use disorder who are in MAT with buprenorphine-naloxone. Aim 2: Examine effects of lorcaserin on subjective measures of drug craving compared to placebo in participants with opioid use disorder who are in MAT with buprenorphine-naloxone. Experiment 2 (Post Experiment I if approved by NIDA). Aim 1: Examine effect of lorcaserin on opioid cue related brain directional (effective) connectivity compared to placebo in participants with opioid use disorder who are in MAT with buprenorphine-naloxone. Aim 2: Examine effect of lorcaserin on impulsivity related effective connectivity compared to placebo in participants with opioid use disorder who are in MAT with buprenorphine-naloxone. Exploratory Aim: Examine noninvasively, using MRI spectroscopy, the effects of lorcaserin compared to placebo on brain GABA concentrations in opioid use disorder participants who are in MAT with buprenorphine- naloxone.