ABSTRACT The growing prevalence of stimulant use disorder (StUD) in the US is a major public health concern. As of 2020, 3.2M people had StUD in the US, which exceeds the 2.7M people with opioid use disorder (OUD), and there were ~57K stimulant-related overdose deaths in 2021. In fact, stimulants are considered the “4th wave” of the overdose crisis. In 2020, NIDA Director Nora Volkow, MD stated that “although deaths from opioids continue to command the public’s attention, an alarming increase in deaths involving the stimulant drugs methamphetamine and cocaine are a stark illustration that we no longer face just an opioid crisis”. Despite substantial R&D efforts, there is no FDA-approved pharmacotherapy for the treatment of StUD – in contrast to OUD where medication-assisted treatment (MAT) is the standard of care – and there is an urgent need for such. This UG3/UH3 proposal aims to develop SBS-518 as a first-in-class treatment for StUD. SBS- 518 is a dual sigma receptor antagonist and dopamine active transport (DAT) inhibitor. We have demonstrated that SBS-518 decreases stimulant self-administration in rats, without being rewarding itself. These data support the development of SBS-518 as a novel, first-in-class treatment for StUD. In the UG3, we will conduct a targeted lead optimization to select our lead compound (SBS- 518x) and quickly move into development. We will conduct nonGMP API and drug product development, nonGLP toxicology studies, and submit for a pre-IND meeting with FDA to align on the IND-enabling program. By the end of the UG3, we will have our identified our clinical candidate and conducted preliminary CMC and tox work. In the UH3, we will conduct the IND- enabling CMC and toxicology work, submit an IND and conduct a Phase 1 clinical trial. In summary, we propose to develop a novel agent for StUD and bring it through a first in human clinical trial.