Cocaine Use Disorder (CocUD) incurs a high socioeconomic burden, yet no Food and Drug Administration (FDA)-approved pharmacotherapies are available for CocUD. We propose a proof of concept clinical trial of multiple dopamine (DA) receptor (D2/D3/D4/D5) agonist rotigotine (RTG) that could improve cocaine abstinence by increasing DA-dependent executive function (EF). EF is the set of cognitive abilities such as working memory, information updating and mental flexibility required for goal attainment. In patients with CocUD and poor EF, attention to and retention of psychoeducation information during cognitive behavioral therapy (CBT) could be impaired, and drug-predictive cues may capture attention away from sobriety goals more readily. Indeed, low EF has been linked to poor CocUD treatment outcomes. Such patients could benefit from DA-increasing medication to help maintain abstinence. In fact, prescription stimulants that release DA have been shown to reduce cocaine use, but are problematic because stimulants themselves have abuse potential. A multiple DA receptor agonist may be a safer alternative to improve DA function and EF. Although RTG is FDA-approved for Parkinson’s Disease treatment, RTG has been shown to improve cortical plasticity and EF in Alzheimer’s Disease. Moreover, the sustained-release RTG patches promote steady state drug levels. Therefore, we propose a clinical trial of six weeks of daily transdermal rotigotine (Neupro®) patches as an adjunct to CBT for cocaine use reduction in CocUD. Cocaine use outcomes will be compared between n = 30 (completed) participants randomized to six weeks of 4mg/d transdermal RTG, and n = 30 participants randomized to transdermal placebo. Per NIDA goals of identifying alternative quality of life-related endpoints beyond abstinence in clinical trials, we will also attain insights into RTG action by obtaining functional magnetic resonance imaging (fMRI) and neurocognition assessments pertinent to EF prior and following dosing as secondary endpoints. This will garner evidence as to whether RTG increases brain activation and overt behavioral signatures of EF. Such findings would provide critical mechanistic evidence that RTG induces its abstinence-promoting effect by way of improving EF and/or reducing impulsivity. Finally, in a step toward precision medicine for CocUD, we will determine how RTG benefits brain and behavior as a function of baseline EF. Several lines of evidence from previous trials of DA agents suggest that individuals with SUD and poor EF benefit most from DA enhancement, whereas participants with normal to supranormal EF at baseline derive lesser or no benefit from DA enhancement on substance abstinence. We will thus conduct a planned post-hoc analysis to detect differential change in EF and in EF- related brain connectivity and function following RTG as a function of whether the participant scored above vs below the median value of the RTG treatment arm in scores of a validated computerized cognitive battery that probes EF. A finding in this post-hoc analysis that RTG selectively benefited individuals with lower EF would augur a novel precision medicine approach in future clinical trials of other DA-promoting agents for CocUD.

Cocaine Use Disorder (CocUD) is a significant public health problem, yet no US Food and Drug Administration- approved pharmacotherapies are available for CocUD. Low executive brain function (EF) is thought to result from poor frontal cortex dopamine (DA) function, and has been linked to poor substance use disorder treatment outcomes. In persons in treatment for CocUD or who seek to reduce cocaine use, we will examine effects of six weeks of transdermal application of multiple DA receptor agonist rotigotine versus placebo as an adjunct to cognitive behavioral therapy to improve cocaine abstinence as well as to improve EF and brain activation.