PPAR‐gamma agonist pioglitazone modifies craving intensity and brain white matter integrity in patients with primary cocaine use disorder: a double‐blind randomized controlled pilot trial

Abstract

Background and aims Pioglitazone (PIO), a potent agonist of PPAR-gamma, is a promising candidate treatment for cocaine use disorder (CUD). We tested the effects of PIO on targeted mechanisms relevant to CUD: cocaine craving and brain white matter (WM) integrity. Feasibility, medication compliance, and tolerability were evaluated. Design Two-arm double-blind randomized controlled proof-of-concept pilot trial of PIO or placebo (PLC). Setting Single-site outpatient treatment research clinic in Houston, Texas, USA. Participants Thirty treatment-seeking adults with CUD. Mean [standard deviation (SD)] age was 47.8 (7.45), education was 12.7 (1.5), with 19.3 (7.8) years of reported cocaine use. Eighteen of the 30 participants (8=PIO; 10=PLC) completed diffusion tensor imaging (DTI) of WM integrity at pre/post-treatment. Intervention Study medication was dispensed at thrice weekly visits along with once weekly cognitive behavioral therapy for 12 weeks. Measurements Measures of target engagement mechanisms of interest included cocaine craving assessed by the Brief Substance Craving Scale (BSCS), the Obsessive Compulsive Drug Use Scale (OCDUS), a visual analog scale (VAS), and change in WM integrity. Feasibility measures included number completing treatment, medication compliance (riboflavin detection), and tolerability (side effects, serious adverse events). Findings Target engagement change in mechanisms of interest, defined as a ≥ 0.75 Bayesian posterior probability of an interaction existing favoring PIO over PLC, was demonstrated on measures of craving (BSCS, VAS) and WM integrity indexed by fractional anisotropy (FA) values. Outcomes indicated greater decrease in craving and greater increase in FA values in the PIO group. Feasibility was demonstrated by high completion rates among those starting treatment (21/26 = 80%) and medication compliance (≥ 80%). There were no reported serious adverse events for PIO. Conclusions Compared with placebo, patients receiving pioglitazone show a higher likelihood of reduced cocaine craving and improved brain white matter integrity as a function of time in treatment. Pioglitazone shows good feasibility as a treatment for cocaine use disorder.

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“…In contrast, antioxidants level is increased. Net effect of mentioned changes leads to amelioration of neuroinflammation [62]. Furthermore, by activating of peroxisome proliferator activator receptor-g it regulates lipid and glucose metabolism [52,53,63].…”

Measures of Possible Allostatic Load in Comorbid Cocaine and Alcohol Use Disorder: Brain White Matter Integrity, Telomere Length, and Anti-Saccade Performance

“…Participants for this project were recruited from the Greater Houston Metropolitan Area using local newspaper and radio advertisements. The data reported here constitute part of a larger clinical trial examining the effects 12-weeks of treatment with pioglitazone in participants with a primary cocaine use disorder (CUD) and a secondary alcohol use disorder (AUD), described in [31] (NCT02774343). For the present report, data were obtained from measures taken at baseline (Day 0), prior to initiation of the clinical trial, and included 22 CUD/AUD subjects who provided complete neuroimaging, eye tracking, and telomere data; two additional CUD/AUD subjects provided eye tracking and telomere data without DTI.…”

Functional signature of conversion in Mild Cognitive Impairment patients

“…These findings go along with evidence indicating that the loss of hippocampal GABAergic inter-neurons is closely associated with the appearance of enhanced signs of tau-pathology(Levenga et al 2013). These processes may accelerate an ongoing pattern of hippocampal hyperactivity, micro/ macro-structural damage, atrophy, and the progression of cognitive and behavioral disorders(Gilani et al 2014; Jones et al 2016;Schmitz et al 2017;Schobel et al 2013).…”