The purpose of this study is to see how well pioglitazone, when used with cognitive behavioral therapy, works at helping people who have recently stopped using cocaine to continue to not use cocaine.

Over one million American adults suffer from cocaine use disorder (CUD) with recent trends showing an increase in cocaine-related deaths since 2010. For the chronic cocaine user, significant changes in brain function and structure set the stage for relapse that, unfortunately, continues to be the most common outcome following treatment. For substance use disorders, cognitive-behavioral therapy (CBT) is arguably the most empirically supported and widely used relapse prevention approach. Considered to be a cognitive control therapy, CBT aims to improve 'top-down' executive control functions that are impaired in CUD and strongly connected to relapse. Converging evidence suggests that CBT promotes meaningful changes in brain regions associated with cognitive control. Still, many patients with cognitive impairments show suboptimal response to CBT, bolstering the call for research aimed at improving effects with integrative treatments.

The goal of this project is to enhance the relapse-prevention effects of CBT with adjunctive use of pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist. Unlike traditional medications that target classic neurotransmitter systems, PIO's activation of the PPAR pathway confers broad spectrum anti-inflammatory and neuroprotective effects against insult to brain white matter (WM). The functional significance of WM in CUD has been well established by evidence showing that: (1) chronic cocaine exposure alters WM structural integrity; (2) WM alterations compromise cognitive function in CUD; and (2) better WM integrity predicts better CUD treatment outcome. In a recent proof of concept trial it was found that PIO significantly improved brain WM integrity in a small sample of non-abstinent patients with CUD. Treatment with PIO was well-tolerated and associated with reduced cocaine craving relative to placebo. Collectively, these findings raise the exciting possibility that PIO may augment responding to CBT via improved neural structure and cognitive function.

A randomized double-blind clinical trial will be utilized to evaluate the efficacy of CBT with adjunctive PIO in recently abstinent patients during the early phase of recovery when craving is prominent, relapse risk is high, and intact cognitive control is required to actively maintain abstinence. Upon completion of a 5-day inpatient detoxification, 60 adults with CUD will complete titration to full dose of randomized medication, either PIO (45mg daily) or placebo, and begin 12 weeks of outpatient CBT treatment while continuing to receive study medication. Specific aims will examine the effects of PIO on targeted mechanisms of change (WM integrity, cognitive function, cocaine craving) and demonstrate evidence linking clinical efficacy (abstinence, functional health) with mechanism engagement. Expected results will establish PIO as an adjunctive treatment that can be integrated with CBT to reduce relapse risk following detoxification, thereby meeting NIDA's strategic priority of evaluating the use of medications to improve the efficacy of behavioral interventions (PA-18-055).

Inclusion Criteria:

• 18 to 65 years old
• meet DSM 5 diagnostic criteria for cocaine use disorder
• report recent cocaine use, verified by at least one positive urine drug screen for the cocaine metabolite, benzoylecgonine, during intake
• be judged by the medical staff to be psychiatrically stable and physically healthy
• for females, be using an effective form of birth control (e.g., barrier, IUD, or sterilization) and not be pregnant as determined by a serum pregnancy test at screening and negative urine pregnancy test at intake prior to first dose of investigational drug (test will be repeated weekly to ensure that female patients do not continue in the study if pregnant) or lactating
• be willing to be admitted to a 5-day inpatient detoxification program at The Right Step Houston
• be able to understand the consent form and provide written informed consent
• be able to provide the names of at least 2 persons who can consistently locate their whereabouts

Exclusion Criteria:

• have an acute medical or psychiatric disorder that would, in the judgment of the study physician, make participation difficult or unsafe
• have suicidal or homicidal ideation that requires immediate attention
• have another current (≥ moderate) substance use disorder aside from alcohol, nicotine, or marijuana
• have a medical condition contraindicating PIO pharmacotherapy (e.g., drug- or insulin-dependent diabetes, congestive heart failure, edema, clinical significant liver disease, hypoglycemia, history of bladder cancer) or be taking medications that would adversely interact with PIO (e.g., CYP2C8 inhibitors or inducers, antihyperglycemic medications)
• be concurrently enrolled in other addiction treatment services aside from smoking cessation
• if female, be currently pregnant, breastfeeding, or planning on conception
• have conditions of probation or parole requiring reports of drug use to officers of the court
• be unable to read, write, or speak English
• be homeless (live on the street)
• have medical contraindications to MRI/DTI scans (e.g., history of pacemaker, metal implants, or welding/metal work without protective eyewear)