SUMMARY Cocaine use is endemic nationwide. According to a national survey, over 2.5% of the population of individuals 12 years and older reported crack or cocaine use in the past year, accounting for over 10,000 deaths related to cocaine overdose. Recent data suggests that the COVID-19 pandemic has exacerbated substance use in the United States. Only a small minority of cocaine users seek formal treatment for their addiction, and even in those who do, the relapse rate remains disturbingly high with some studies reporting rates as high as 90%, 12 months after treatment. Relapse in addicted individuals is presumed to precipitate from the re-exposure to cues that were previously associated with drug use. Over the course of chronic drug use, these cues are afforded enhanced attention (or attention-bias), which has shown to promote motivated arousal, culminating in compulsive drug-seeking or relapse. We have used the late positive potential (LPP), an EEG-derived marker of motivated arousal to show that, unlike commonly believed, arousal to drug cues (or cue-reactivity) increases (or incubates) during the first six months of abstinence. Such incubation of cue-reactivity is posited to confer disproportionately high relapse vulnerability in addicted individuals. Our recently acquired follow-up data show that addicted individuals are able to down-regulate drug cue-reactivity (as evident via a decrease in LPP amplitude) via cognitive reappraisal (an emotion-regulation technique) training, which then leads to a reduction in spontaneous attention-bias to drug cues (quantified using eye-tracking). Here, we propose to integrate the two pieces of evidence to test whether cognitive reappraisal training can reduce the incubation of drug cue-reactivity (Aim 1) and improve clinical outcomes (e.g., reduce craving and prolong cocaine abstinence duration; Aim 2) during the first 6 months of abstinence in individuals with cocaine use disorder (iCUD). We will further explore whether changes in attention-bias to drug cues and/or blunting of incubation of cue-reactivity tracks treatment response and predicts clinical outcomes at 6 months follow-up (exploratory aim). For this purpose, we propose to enroll 126 iCUD, half of whom will be randomized to undergo cognitive reappraisal training and the other half will instead complete a control task. In this longitudinal study, participants will complete these procedures at 1-week, 1-, 3-, and 5-months post abstinence initiation, and will then come back one month after (at 6 months post abstinence initiation) for the assessment of clinical outcomes. Thus, this novel study aims to bridge between the lab and the clinic by advancing basic mechanistic understanding of a novel evidence-based intervention to provide cognitive markers for tracking treatment response and predicting outcomes in addiction. Successful completion of this study would lay the foundation for further basic and clinical studies that will examine other putative me...