Project Summary Alterations in glutamate neurotransmission are recognized as an important target of pharmacotherapy for cocaine use disorders (CUDs). Our preliminary investigations with ketamine, a glutamate modulator with potent prefrontal effects, suggest sub-anesthetic infusions may work to facilitate behavioral modification by addressing critical CUD- related vulnerabilities. Alongside being safely administered to active cocaine users, we have found that sub-anesthetic ketamine, 24 hours post-infusion, significantly increases motivation to stop cocaine use by 60%, decreases cue-induced craving by a similar magnitude, and reduces the choice for cocaine now vs. money later by 67% when compared to an active control. A pilot efficacy trial also indicates that a single infusion of ketamine facilitates mindfulness-based relapse prevention (MBRP) and promotes abstinence (53% ketamine vs. 11% midazolam). Expanding on these promising but preliminary findings, this trial aims to evaluate whether ketamine promotes abstinence by facilitating behavioral modification in a treatment model approximating a general clinical setting. We will evaluate the effect of up to two outpatient sub-anesthetic doses of ketamine (0.11 mg/kg over 2 minutes, followed by 0.60 mg/kg over 50 minutes) on CUDs in 110 non-depressed individuals engaged in motivation enhancement therapy followed by MBRP. We predict that, compared to the control midazolam, ketamine will significantly promote 3 weeks of end-of-study abstinence in this 7-week trial. Secondary aims pertain to the effects of ketamine on other drug use outcomes, such as reduction in number of cocaine use days; and the evaluation of behavioral and biological mediators of ketamine efficacy, such as serum brain-derived neurotrophic factor (BDNF) levels and measures of behavioral non-reactivity. If successful, this project stands to contribute significantly to the treatment of CUDs, for which there are no clearly effective pharmacotherapies at present, and has the potential to lead the field in new directions of combined medication-behavioral treatment development. Future studies might test other medications using the design introduced in this proposal, as well as focus on clarifying the mechanisms by which ketamine addresses CUDs.