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Background: The response time speed-accuracy trade-off (SATO) is an established index of information processing ability, but rarely examined as a variable in association with treatment of substance use disorder (SUD).Aim: The purpose of this study was to test baseline information-processing ability differences between individuals who respond to treatment for cocaine use disorder v. those who do not.Methods: Eighty patients enrolled in a clinical trial for cocaine use disorder completed a baseline drug-specific eye-tracking (anti-saccade) assessment prior to treatment, which included trials with both cocaine-related and neutral stimuli. SATO functions were computed for treatment responders v. non-responders.Results: Unexpectedly, responders demonstrated statistically different SATO functions, showing poorer accuracy when executing faster response times. This difference was present on trials that presented cocaine stimuli only.Conclusions: SATO during performance of an eye-movement task may be useful for predicting differential response to substance use disorder treatment. However, in the present study, results were specific to cocaine cues rather than an overall SATO performance decrement. [ABSTRACT FROM AUTHOR]

Tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI) studies have consistently shown diminished white matter (WM) integrity for individuals with cocaine use disorder (CUD). The present study used seed-based d mapping (SDM) to determine the extent to which a systematic difference in the WM integrity of cocaine users may exist (as compared with that of healthy controls). Articles from 2006 (when TBSS was first developed) to present were reviewed, with eight selected for inclusion. Meta-analysis found lower fractional anisotropy (FA) in the genu of the corpus callosum for cocaine users, with a small-to-moderate peak effect size (Hedge's g = -0.331). Sensitivity analyses mostly supported the robustness of the obtained difference. Differences detected at exploratory thresholds for significance suggested insult to WM integrity extending beyond the corpus callosum. The present results compliment a previous region-of-interest (ROI)-based meta-analysis of DTI studies in individuals with CUD. These findings have significant implications for the potential role of neuroprotective agents in the treatment of CUD and merit additional iteration as more studies accrue in the literature. [ABSTRACT FROM AUTHOR]

Background: Medication development research for cocaine use disorder (CUD) has been a longstanding goal in addiction research, but has not resulted in an FDA-approved treatment. Rising cocaine use rates underscore the need for efficient adaptive designs. This study compared differences between two doses of the selective serotonin reuptake inhibitor (SSRI) citalopram (versus placebo) on duration of cocaine abstinence and applied adaptive decision rules to select the 'best efficacy' dose.Methods: A double-blind, placebo-controlled, randomized Bayesian drop-the-loser (DTL) trial with three arms compared placebo to citalopram 20 mg and 40 mg. Adults (N = 107) with CUD attended thrice-weekly clinic visits for 9 weeks. The primary outcome was longest duration of abstinence (LDA), based on continuous cocaine-negative urine drug screens (UDS). The secondary outcome was probability of cocaine-negative UDS during treatment. A planned interim analysis performed at approximately 50% of recruitment dropped the least-effective active medication. Bayesian inference was used for all analyses with a pre-specified posterior probability (PP) threshold PP ≥ 95% considered statistically reliable evidence RESULTS: Citalopram 40 mg satisfied interim efficacy criteria and was retained for the second half of the trial. For LDA, analyses indicated PP = 82% and PP = 65% of benefit for 40 mg and 20 mg, respectively (each relative to placebo). The odds of having cocaine-negative UDS decreased in all groups over 9 weeks but remained higher for 40 mg (PP = 97.4%) CONCLUSIONS: Neither dose met the 95% PP threshold for the primary outcome; however, 40 mg provided moderate-to-strong evidence for positive effects on LDA and cocaine-negative UDS. The 40 mg dose was declared the "winner" in this DTL trial. [ABSTRACT FROM AUTHOR]

Background: Chronic cocaine users show impairments in cognitive processes associated with dopamine (DA) circuitry. Medications aimed at bolstering cognitive functions via DA modulation might enhance treatment outcome.Methods: The trial used a double-blind, double-dummy, parallel-group design with four treatment arms comparing placebo (PLC) to levodopa/carbidopa 800 mg/200 mg alone (LR0), levodopa plus extended release (XR) ropinirole 2 mg (LR2) or XR ropinirole 4 mg (LR4). Adults (n = 110) with cocaine use disorder attended thrice weekly clinic visits for 10 weeks. Potential cognitive mediators assessed at week 5 consisted of measures of decision-making (Iowa Gambling Task, Risky Decision-Making Task), attention/impulsivity (Immediate Memory Task), motivation (Progressive Ratio task), and cognitive control (Cocaine Stoop task). The primary outcome measure was the treatment effectiveness score (TES) calculated as the number of cocaine-negative urines collected from weeks 6-10.Results: Bayesian mediation examined indirect and total effects of the relationships between each active treatment (compared to PLC) and TES. Total (direct) effects were supported for LR0 and LR2, but not for LR4. Indirect effects were tested for each mediator. Notably, 22.3 % and 35.4 % of the total effects of LR0 and LR2 on TES were mediated by changes in attention/impulsivity.Conclusions: The hypothesized mediation effect was strongest for levodopa plus 2 mg ropinirole, indicating that this DA medication combination predicted change (improvement) in attention/impulsivity, which in turn predicted change (reduction) in cocaine use. This finding provides modest support for cognitive enhancement as a target for medications to treat cocaine use disorder. [ABSTRACT FROM AUTHOR]

• First examination of the orexin system in human psychostimulant users. • Results supported evidence for a signal of suvorexant in several target domains. • Orexin may be a favorable target for relapse-prevention in cocaine use disorder. Rationale. Current evidence and literature reviews provide a strong justification for examining the orexin receptor (OXR) system as a therapeutic target in substance use disorders, including cocaine and other psychostimulants. Objectives. In this preliminary, proof-of-concept examination of orexin modulation in humans with cocaine use disorder, we measured changes in domains tied to relapse: stress, sleep, cue reactivity, and inhibitory control. Additionally, mood symptoms (anxiety, depression), medication compliance, and side effects were assessed. Methods. Twenty non-treatment seeking subjects with cocaine use disorder (CUD) received either the OX 1 R / OX 2 R antagonist suvorexant PO or placebo at 10 PM daily for two weeks (10 mg week 1, 20 mg week 2). Using psychometrics, smart-watch actigraphy, a cold-pressor stress challenge, and eye-tracking technology, the following domains were examined: sleep, stress/anxiety, cue-reactivity (attentional bias, craving), and inhibitory control. Psychometric data were collected every M/W/F (7 time points). Laboratory data were collected weekly (3 time points). Results. Bayesian and frequentist generalized linear models were employed in parallel to examine the effects of suvorexant compared to placebo, with a Bayesian posterior probability threshold >80% as evidence of a signal for suvorexant. Notable results favoring suvorexant over placebo included fewer total anti-saccade errors, improved sleep actigraphy (sleep/awake periods), pre/post cold-pressor change in heart rate and salivary cortisol (all posterior probabilities >94%), and craving (posterior probability >87%). Conclusions. Initial but restricted evidence is provided supporting the orexin system as a modulator of relapse-related processes in cocaine use disorder. Baseline differences in the main outcome variables were not experimentally controlled and differences in craving were observed at baseline. This, in combination with a limited sample size, constrain the nature of the project. The results may serve to inform more comprehensive future research. [ABSTRACT FROM AUTHOR]

Inflammation is implicated in cocaine use and associated problems, including depression and cognitive impairment. We assessed 18 cytokines, cocaine use, cognition, and depression in individuals with Cocaine Use Disorder. Our general hypothesis was that higher pro-inflammatory cytokines would relate to more cocaine use, poorer cognition, and more depression, while higher anti-inflammatory cytokines would relate to less cocaine use, better cognition, and less depression. Data were collected from 85 individuals (76.5% male, 80% African American) aged 18–65. The ASI, Shipley-2, and BDI-II assessed frequency and duration of cocaine use, cognition, and depression. Cytokines were tested using Bio-Plex Pro™ assays. Elastic net regression identified which cytokines related to each measure, controlling for confounds. Lower IL-29 (B = −0.08, bootstrapped 95%CI = [−0.24,0.07]), scD163 (B = −0.11, bootstrapped 95%CI = [−0.27,0.04]), Eotaxin-1 CCL11 (B = −0.11, bootstrapped 95%CI = [−0.30,0.08]), and higher APRIL/TNFSF13 (B = 0.11, bootstrapped 95%CI = [−0.08,0.30]) related to more frequent cocaine use. Lower IL-29 (B = −0.24, bootstrapped 95% CI = [−2.26,1.79]) and IL-20 (B = −1.62, bootstrapped 95%CI = [−3.53,0.29]) related to longer duration of cocaine use. Higher Eotaxin-2 CCL24 (B = 2.79, bootstrapped 95%CI = [−0.59,6.17]) and TWEAK (B = 2.83, bootstrapped 95%CI = [−0.80,6.45]) related to better cognition. Finally, higher IL-20 (B = −1.83, bootstrapped 95%CI = [−3.70,0.04]) and Osteocalcin (B = −1.56, bootstrapped 95%CI = [−3.81,0.70]) related to lower depressive symptoms. However, none of these relationships survived bootstrapped analyses. Pro- and anti-inflammatory cytokines may relate to cocaine use, cognition, and depression, but inconsistent with our hypotheses, higher pro-inflammatory cytokines related to better functioning in several domains. Additionally, cytokines were selected at low frequencies and demonstrated weak relationships with outcomes. These preliminary findings suggest complex relationships between inflammation and cocaine use. [ABSTRACT FROM AUTHOR]

This study explored anhedonia (lack of interest or pleasure in non-drug rewards) as a potentially modifiable individual difference associated with the effectiveness of Contingency Management (CM). It also tested the hypothesis that a dopaminergic drug, levodopa (L-DOPA), would improve the effectiveness of CM, particularly in individuals high in anhedonia. The study was a single-site, randomized, double-blind, parallel group, 12-week trial comparing L-DOPA with placebo, with both medication groups receiving voucher-based CM targeting cocaine-negative urines. Participants were N=85 treatment-seeking adults with CUD. Anhedonia was measured at baseline using a validated self-report measure and a progressive ratio behavioral measure. Treatment Effectiveness Score (TES) was defined as the total number of cocaine-negative urines submitted. Analyses based on Frequentist general linear models were not significant, but Bayesian analyses indicated a high probability (92.6%) that self-reported anhedonia was associated with poor treatment outcomes (lower TES). L-DOPA did not significantly improve outcomes, nor was the effect of L-DOPA moderated by anhedonia. While the study failed to replicate positive findings from previous studies of L-DOPA in combination with CM, it does provide preliminary evidence that anhedonia may be a modifiable individual difference associated with poorer CM outcomes. [ABSTRACT FROM AUTHOR]

This study tested an adaptive intervention for optimizing abstinence outcomes over phases of treatment for cocaine use disorder using a SMART design. Phase 1 assessed whether 4 weeks of contingency management (CM) improved response with the addition of Acceptance and Commitment Therapy (ACT). Phase 2 assessed pharmacological augmentation with modafinil (MOD) vs. placebo (PLA) for individuals not achieving abstinence during Phase 1. For Phase 1 of treatment, participants (N =118) were randomly allocated to ACT+CM or Drug Counseling (DC+CM), the comparison condition. At week 4, treatment response was defined as the submission of six consecutive cocaine-negative urine drug screens (UDS). Phase 1 non-responders were re-randomized to MOD or PLA as adjunct to their initial treatment. Phase 1 responders continued receiving their initial treatment. Primary outcomes included response rate and proportion of cocaine-negative UDS for Phase 1 and 2. Analyses used Bayesian inference with 80% pre-specified as the posterior probability (PP) threshold constituting moderate evidence that an effect exists. Phase 1 response was higher in the ACT+CM group (24.5%) compared to the DC+CM group (17.5%; PP = 84.5%). In Phase 2, the proportion of cocaine-negative UDS among Phase 1 responders did not differ by initial treatment (PP = 61.8%) but remained higher overall compared to Phase 1 non-responders (PPs > 99%). No evidence of an effect favoring augmentation with MOD was observed. Adding ACT to CM increased abstinence initiation. Initial responders were more likely to remain abstinent compared to initial non-responders, for whom modafinil was not an effective pharmacotherapy augmentation strategy. • Adaptive designs that tailor treatment based on patient response may be useful for cocaine use disorder. • A Sequential Multiple Assignment Randomized Trial (SMART) design is well suited for developing adaptive interventions. • Response rates for achieving initial abstinence were highest among participants receiving ACT + CM • Pharmacological augmentation with modafinil did not increase the probability of abstinence during Phase 2. • Stronger strategies are needed to achieve optimal outcomes after initial non-response. [ABSTRACT FROM AUTHOR]

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 out-patient treatment research clinic in Houston, TX, USA. Participants Thirty treatment-seeking adults, 18 to 60 years old, with CUD. Eighteen 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. [ABSTRACT FROM AUTHOR]

Cocaine use continues to be a significant public health problem with limited treatment options and no approved pharmacotherapies. Cognitive-behavioral therapy (CBT) remains the mainstay treatment for preventing relapse, however, people with chronic cocaine use display cognitive impairments that are associated with poor response to CBT. Emerging evidence in animal and human studies suggests that the peroxisome proliferator-activated receptor-gamma (PPAR- γ) agonist, pioglitazone, improves white matter integrity that is essential for cognitive function. This project will determine whether adjunctive use of pioglitazone enhances the effect of CBT in preventing relapse during the early phase of recovery from cocaine use disorder. This paper describes the design of a mechanism-focused phase 2 randomized clinical trial that aims first to evaluate the effects of pioglitazone on targeted mechanisms related to white matter integrity, cognitive function, and cocaine craving; and second, to evaluate the extent to which improvements on target mechanisms predict CBT response. Positive results will support pioglitazone as a potential cognitive enhancing agent to advance to later stage medication development research. [ABSTRACT FROM AUTHOR]