Currently, the abuse of heroin and prescription opioid medications is a pervasive social problem in the U.S. This Project will use a novel drug discovery algorithm to rapidly and systematically screen medications that show promise for treating opioid use disorder. The guiding principle is that a medication's effect on drug self- administration is the best laboratory procedure to date in predicting its clinical efficacy. We will test several different medication(s) in Project 3 for their ability to alter opioid-mediated responses including lorcaserin, doxazosin, nabilone in combination with cannabidiol, and zonisamide. If a medication shows a positive signal (i.e., a reduction in positive subjective responses and/or withdrawal and drug-taking behavior), it will be tested alone in a treatment trial in Project 4. If a medication shows a promising signal when tested alone (i.e., a reduction in positive subjective responses and/or withdrawal but no change in drug-taking behavior), it will be tested in combination with either buprenorphine/naloxone or sustained-release naltrexone in Project 3. Overall, this novel procedure in combination with our demonstrated productivity ensure that we will be able to complete the proposed studies, adapt our procedures if problems arise, publish our findings, and rapidly advance the development of pharmacotherapeutic strategies for opioid use disorder.