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Cocaine use disorder (CUD) patients display heterogenous symptoms and unforeseeable responses to available treatment approaches, highlighting the need to identify objective, accessible biobehavioral signatures to predict clinical trial success in this population. In the present experiments, we employed a task-based behavioral and pharmacogenetic-fMRI approach to address this gap. Craving, an intense desire to take cocaine, can be evoked by exposure to cocaine-associated stimuli which can trigger relapse during attempted recovery. Attentional bias towards cocaine-associated words is linked to enhanced effective connectivity (EC) from the anterior cingulate cortex (ACC) to hippocampus in CUD participants, an observation which was replicated in a new cohort of participants in the present studies. Serotonin regulates attentional bias to cocaine and the serotonergic antagonist mirtazapine decreased activated EC associated with attentional bias, with greater effectiveness in those CUD participants carrying the wild-type 5-HT 2C R gene relative to a 5-HT 2C R single nucleotide polymorphism (rs6318). These data suggest that the wild-type 5-HT 2C R is necessary for the efficacy of mirtazapine to decrease activated EC in CUD participants and that mirtazapine may serve as an abstinence enhancer to mitigate brain substrates of craving in response to cocaine-associated stimuli in participants with this pharmacogenetic descriptor. These results are distinctive in outlining a richer "fingerprint" of the complex neurocircuitry, behavior and pharmacogenetics profile of CUD participants which may provide insight into success of future medications development projects., (© 2022. The Author(s).)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021. Published by Elsevier B.V.)

Past investigations utilizing diffusion tensor imaging (DTI) have demonstrated that cocaine use disorder (CUD) yields white matter changes, primarily in the corpus callosum. By applying Bayesian model averaging using multiple linear regression in DTI, we demonstrate there may exist relationships between the impaired white matter and glutamic acid decarboxylase (GAD) polymorphisms. This work explored the two-way and three-way interactions between GAD1a (SNP: rs1978340) and GAD1b (SNP: rs769390) polymorphisms and years of cocaine use (YCU). GAD1a was associated with more frontal white matter changes on its own but GAD1b was associated with more midbrain and cerebellar changes as well as a greater increase in white matter changes in the context of chronic cocaine use. The three-way interaction GAD1a|GAD1b|YCU appeared to be roughly an average of the polymorphism two-way interactions GAD1a|YCU and GAD1b|YCU. The three-way interaction demonstrated multiple regions including corpus callosum which featured fewer significant voxel changes, perhaps suggesting a small protective effect of having both polymorphisms on corpus callosum and cerebellar peduncle., Competing Interests: The authors have declared that no competing interests exist.

Cocaine use disorder (CUD) is a major public health challenge for which there are no pharmacotherapeutics approved by the United States Food and Drug Administration (FDA). The propensity to relapse in CUD involves several vulnerability factors including sensitivity to cues associated with cocaine-taking. Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission, particularly through the 5-HT 2A receptor (5-HT 2A R) and 5-HT 2C receptor (5-HT 2C R), is mechanistically linked to cocaine-seeking in preclinical models. In the present experiments, we employed self-administration assays in male rats to investigate whether acute and/or repeated administration of the FDA-approved selective 5-HT 2A R antagonist/inverse agonist pimavanserin, selective 5-HT 2C R agonist lorcaserin or their combination would alter cocaine intake and/or cocaine-seeking behavior. We found that acute administration of lorcaserin, but not pimavanserin, attenuated cocaine intake while pimavanserin plus lorcaserin did not impact cocaine self-administration. In contrast, 10-days of repeated administration of pimavanserin, lorcaserin, or pimavanserin plus lorcaserin during forced abstinence from cocaine self-administration, blunted cocaine-seeking, similar to the acute administration of each ligand. Taken together, these data reveal the efficacy of repeated treatment with pimavanserin plus lorcaserin to attenuate factors important to relapse-like behaviors in rodent models of CUD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Impulsivity and the attentional orienting response to cocaine-associated cues ( cue reactivity ) promote relapse in cocaine-use disorder (CUD). A time-dependent escalation of cue reactivity ( incubation ) occurs during extended, forced abstinence from cocaine self-administration in rats. The investigational serotonin (5-HT) 5-HT 2A receptor (5-HT 2A R) antagonist/inverse agonist M100907 suppresses impulsive action , or the inability to withhold premature responses, and cocaine-seeking behaviors. The present preclinical study was designed to establish the potential for repurposing the Food and Drug Administration-approved selective 5-HT 2A R antagonist/inverse agonist pimavanserin as a therapeutic agent to forestall relapse vulnerability in CUD. In male Sprague-Dawley rats, pimavanserin suppressed impulsive action ( premature responses ) measured in the 1-choice serial reaction time (1-CSRT) task, similarly to M100907. We also used the 1-CSRT task to establish baseline levels of impulsive action before cocaine self-administration and evaluation of cue reactivity (lever presses reinforced by the discrete cue complex previously paired with cocaine delivery). We observed an incubation of cocaine cue reactivity between day 1 and day 30 of forced abstinence from cocaine self-administration. Baseline levels of impulsive action predicted incubated levels of cocaine cue reactivity in late abstinence. We also found that baseline impulsive action predicted the effectiveness of pimavanserin to suppress incubated cue reactivity in late abstinence from cocaine self-administration at doses that were ineffective in early abstinence. These data suggest that integration of clinical measures of impulsive action may inform refined, personalized pharmacotherapeutic intervention for the treatment of relapse vulnerability in CUD., (U.S. Government work not protected by U.S. copyright.)

Cocaine continues to be one of the most widespread abused illicit drugs in the USA. Rapid methods are needed for the identification and quantitation of cocaine and its metabolites, benzoylecgonine (BE), ecgonine methyl ester (EME) and cocaethylene (CE), in biological specimens by clinical and forensic toxicology laboratories. Presented is a differential ion mobility spectrometry-tandem mass spectrometry (DMS-MS-MS) method for the analysis of cocaine and its major metabolites in human serum that requires minimal sample preparation and no column chromatography. A Shimadzu Nexera X2 ultra-high performance liquid chromatography system was used to infuse the samples into the DMS cell at a rate of 30 μL/min. Separation of cocaine and its metabolites were performed in a SelexION DMS component from Sciex coupled to a QTRAP 6500 with an IonDrive Turbo V source for TurbolonSpray® using acetonitrile as a chemical modifier. Analysis consisted of ramping the CoV from -35 V to -6 V while monitoring the multiple reaction monitoring (MRM) transitions of each analyte. The assay was evaluated for linearity, bias, precision, carryover, interferences and stability. Calibration curves ranged from 10 to 1,000 ng/mL with linear regression correlation coefficients (r2) of 0.9912 or greater for each analyte. The limit of quantitation was set at 10 ng/mL. Intra-day precision (%CV) ranged from 0% to 15% for cocaine, 1% to 19% for BE, 1% to 17% for EME and 0% to 18% for CE. Inter-day precision ranged from 9% to 14% for cocaine, 2% to 17% for BE, 5% to 11% for EME and 5% to 15% for CE. No carryover or interferences were detected. Bland-Altman analysis of previously analyzed specimens by UPLC-MS-MS showed variability of 30% or less. The method demonstrates the applicability of DMS-MS-MS for high throughout analysis of drugs and their metabolites in clinical and forensic toxicology laboratories.

Cocaine dependence (CD) is associated with several cognitive deficits. Accumulating evidence, based on human and animal studies, has led to models for interpreting the neural basis of cognitive functions as interactions between functionally related brain regions. In this review, we focus on magnetic resonance imaging (MRI) studies using brain connectivity techniques as related to CD. The majority of these brain connectivity studies indicated that cocaine use is associated with altered brain connectivity between different structures, including cortical-striatal regions and default mode network. In cocaine users some of the altered brain connectivity measures are associated with behavioral performance, history of drug use, and treatment outcome. The implications of these brain connectivity findings to the treatment of CD and the pros and cons of the major brain connectivity techniques are discussed. Finally potential future directions in cocaine use disorder research using brain connectivity techniques are briefly described.

The effect of chronic cocaine exposure on multiple white matter structures in rodent brain was examined using diffusion tensor imaging (DTI), locomotor behavior, and end point histology. The animals received either cocaine at a dose of 100mg/kg (N=19), or saline (N=17) for 28 days through an implanted osmotic minipump. The animals underwent serial DTI scans, locomotor assessment, and end point histology for determining the expressions of myelin basic protein (MBP), neurofilament-heavy protein (NF-H), proteolipid protein (PLP), Nogo-A, aquaporin-4 (AQP-4), and growth associated protein-43 (GAP-43). Differences in the DTI measures were observed in the splenium (scc) and genu (gcc) of the corpus callosum (cc), fimbria (fi), and the internal capsule (ic). A significant increase in the activity in the fine motor movements and a significant decrease in the number of rearing events were observed in the cocaine-treated animals. Reduced MBP and Nogo-A and increased GAP-43 expressions were most consistently observed in these structures. A decrease in the NF-H expression was observed in fi and ic. The reduced expression of Nogo-A and the increased expression of GAP-43 may suggest destabilization of axonal connectivity and increased neurite growth with aberrant connections. Increased GAP-43 suggests drug-induced plasticity or a possible repair mechanism response. The findings indicated that multiple white matter tracts are affected following chronic cocaine exposure., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Key characteristics of cocaine dependence include attentional bias to cocaine cues and impaired inhibitory control. Studies suggest that serotonin modulates both cocaine cue reactivity and inhibitory control. We investigated effects of the selective serotonin reuptake inhibitor escitalopram on cocaine cue reactivity and inhibitory processes in cocaine-dependent subjects. In a double-blind placebo-controlled design, cocaine-dependent subjects received placebo (n=12) or escitalopram (n=11; 10 mg on days 1-3, 20 mg on days 4-24 and 10 mg on days 25-28) orally, once daily for 4 weeks. The cocaine Stroop and immediate memory task (IMT) were administered at baseline, days 1, 4, 11, 18 and 25 after placebo or escitalopram initiation. There were no significant between-group differences in baseline performance on the cocaine Stroop task or the IMT. On day 1 (acute phase), escitalopram produced a significantly greater decrease from baseline than placebo in attentional bias measured by cocaine Stroop task 5 hours post-dose. No significant changes from baseline in attentional bias were observed on subsequent test days (chronic phase). Inhibitory control as measured by IMT commission error rate was not significantly different between two groups in either the acute or chronic phase. Consistent with preclinical data, serotonin-modulating drugs like escitalopram may have acute effects on cocaine cue reactivity in human cocaine users.

Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT(2C) receptor (5-HT(2C)R) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT(2C)R agonist, WAY 163909, in cocaine and sucrose self-administration and reinstatement assays employing parallel experimental designs in free-fed rats. WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID(50) = 1.19 mg/kg) and sucrose (ID(50) = 0.7 mg/kg) as well as reinstatement (ID(50) = 0.5 mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues. The ID(50) of WAY 163909 predicted to decrease the reinforcing efficacy of cocaine or sucrose as well as reinstatement upon exposure to cocaine-associated cues was ∼5-12-fold lower than that predicted to suppress horizontal ambulation (ID(50) = 5.89 mg/kg) and ∼2-5-fold lower than that predicted to suppress vertical activity (ID(50) = 2.3 mg/kg). Thus, selective stimulation of the 5-HT(2C)R decreases the reinforcing efficacy of cocaine and sucrose in freely-fed rats, but differentially alters the incentive-salience value of cocaine- vs. sucrose-associated cues at doses that do not impair locomotor activity. Future research is needed to tease apart the precise contribution of 5-HT(2C)R neurocircuitry in reward and motivation and the learning and memory processes that carry the encoding for associations between environmental cues and consumption of rewarding stimuli. A more complete preclinical evaluation of these questions will ultimately allow educated proof-of-concept trials to test the efficacy of selective 5-HT(2C)R agonists as adjunctive therapy in chronic health maladies including obesity, eating disorders and drug addiction., (Copyright © 2011. Published by Elsevier Ltd.)

Background: Cocaine-dependent subjects show attentional bias to cocaine-related stimuli, increased impulsivity on questionnaires, and impaired inhibitory control (one component of impulsivity on behavioral tasks). However, the relationship between attentional bias, impulsivity, and inhibitory control in cocaine-dependent subjects is unknown., Objective: To investigate the relationship between attentional bias to cocaine-related stimuli, impulsivity, and inhibitory control in cocaine dependence., Methods: This study employed the cocaine Stroop task to measure attentional bias to cocaine-related stimuli, immediate memory task (IMT) to measure inhibitory control, and Barratt Impulsiveness Scale version 11 to measure impulsivity. Thirty-two controls and 37 cocaine-dependent subjects were recruited through newspaper advertisement., Results: Cocaine-dependent subjects had higher attentional bias to cocaine-related words, higher scores for Barratt Impulsiveness Scale, and higher commission error rate on the IMT than controls. The attentional bias was positively correlated with the commission error rate on the IMT in the cocaine-dependent subjects but not in control subjects., Conclusions: Cocaine-dependent subjects showed attentional bias to cocaine-related words, increased impulsivity, and poor inhibitory control compared with controls. The attentional bias was associated with inhibitory control in cocaine-dependent subjects but not in control subjects., Scientific Significance: Our findings suggest that cocaine-dependent subjects with poor inhibitory control may show higher attentional bias to cocaine-related words compared with controls and those with better inhibitory control., (Copyright © Informa Healthcare USA, Inc.)

Recent studies demonstrated that diffusion tensor imaging (DTI) can provide information regarding white matter integrity of the corpus callosum (CC). In this study, DTI parameters were compared between cocaine dependent subjects (CDs) and non-drug using controls (NCs) in midsagittal CC. DTI images were acquired from 19 CDs and 18 age-matched NCs. The midsagittal CC was segmented into: genu, rostral body, anterior midbody, posterior midbody, isthmus, and splenium. Linear mixed models analyses showed that, relative to NCs, CDs had lower fractional anisotropy (FA), higher radial diffusivity (lambda(perpendicular)), and higher mean diffusivity (D(av)) in the isthmus; higher lambda(perpendicular) and D(av) in the rostral body; and lower FA in the splenium. After including mass of lifetime alcohol use in the mixed model analysis of covariance (ANCOVA) as a covariate, significant between group differences in lambda(perpendicular) in the rostral body and isthmus remained. These results suggest that alterations in lambda(perpendicular) in the rostral body and isthmus were mainly due to cocaine use, consistent with previous studies showing that cocaine may alter myelin integrity. Between group differences in FA in the isthmus and splenium, and D(av) in the rostral body and isthmus became non-significant after inclusion of alcohol use as a covariate. This is suggestive of alcohol influencing these values, or may be related to the decreased degrees of freedom for these effects. Consistent with clinical data of greater severity of drug use in smoked versus intranasal cocaine, subjects who smoked cocaine showed lower FA and higher lambda(perpendicular) compared to intranasal CDs.

Concurrent abuse of cocaine and heroin is a common problem. Methadone is effective for opioid dependence. The question arises as to whether combining agonist-like or antagonist-like medication for cocaine with methadone for opioid dependence might be efficacious. Two parallel studies were conducted. One examined sustained release d-amphetamine and the other risperidone for cocaine dependence, each in combination with methadone. In total, 240 subjects (120/study) were recruited, who were both cocaine and heroin dependent and not currently receiving medication. All provided consent. Both studies were carried out for 26 weeks, randomized, double-blind and placebo controlled. Study I compared sustained release d-amphetamine (escalating 15-30 or 30-60 mg) and placebo. Study II examined risperidone (2 or 4 mg) and placebo. All subjects underwent methadone induction and were stabilized at 1.1 mg/kg. Subjects attended clinic twice/week, provided urine samples, obtained medication take-home doses for intervening days, and completed self-report measures. Each had one behavioral therapy session/week. In Study I, reduction in cocaine use was significant for the 30/60 mg dose compared to the 15/30 mg and placebo. Opioid use was reduced in all groups with a trend toward greater reduction in the 30/60 mg d-amphetamine group. In Study II, methadone reduced illicit opioid use but cocaine use did not change in the risperidone or placebo groups. There were no adverse medication interactions in either study. The results provide support for the agonist-like (d-amphetamine) model in cocaine dependence treatment but not for antagonist-like (risperidone) treatment. They coincide with our previous reports of amphetamine or risperidone administered singly in cocaine-dependent individuals.

A properly implemented agonist treatment regimen should improve retention and reduce illicit drug use. Cocaine-dependent subjects (N = 128) were enrolled in a 12-week randomized, double-blind, placebo-controlled trial. In the multistage dosing design, subjects initially received placebo (PBO) or 15 to 30 mg of dextroamphetamine sulfate, sustained-release capsules. At week 5, the dose doubled to 30 mg or 60 mg for active groups. Subjects attended the clinic twice a week, provided urine samples, obtained medication, and had one behavioral therapy session a week. Retention was best for the 15- to 30-mg group, whereas the proportion of benzoylecgonine-positive urine screens was, from lowest to highest, 30 to 60 mg, 15 to 30 mg, and PBO at study end. Dosing must be refined. The results provide support for additional examination of the agonist model in psychostimulant-dependence treatment.

To study the relationship between cocaine abstinence symptoms, personality, and aggression, we used the Point Subtraction Aggression Paradigm (PSAP) to measure aggression in 18 subjects admitted for the treatment of cocaine dependence. Eight subjects met criteria for antisocial personality disorder (ASPD). There was a significant correlation between presence of ASPD and frequency of aggressive responding by stepwise multiple regression. When presence of ASPD was factored out of the correlations, there was no significant relationship between aggressive responding and cocaine craving, withdrawal symptoms, amount of cocaine used, or length of time since use. These preliminary results suggest that in cocaine dependent individuals seeking treatment, current aggression is most dependent on the individual's previous aggressive behavior.

1. 10 male cocaine dependent patients and 10 sex matched controls were administered several behavioral measures of aggression including the Buss-Durkee Hostility Inventory, and The Brown-Goodwin Life History of Aggression. 2. All subjects were also administered a buspirone neuroendocrine challenge as a measure of serotonin function. 3. The cocaine dependent subjects were significantly more aggressive than the controls. 4. There was a significant correlation between the growth hormone response to buspirone and behavioral measures of aggression in the cocaine dependent subjects, but not in the controls. 5. There was no difference in the overall growth hormone response between the controls and cocaine dependent subjects, possibly due to differences in metabolism of buspirone. 6. This study supports a role for serotonin in aggression in cocaine dependent subjects.

The drug overdose crisis has spawned serious health consequences, including the increased incidence of substance use disorders (SUDs), conditions manifested by escalating medical and psychological impairments. While medication management is a key adjunct in SUD treatment, this crisis has crystallized the need to develop additional therapeutics to facilitate extended recovery from SUDs. The “hunger hormone” ghrelin acts by binding to the growth hormone secretagogue receptor 1α (GHS1αR) to control homeostatic and hedonic aspects of food intake and has been implicated in the mechanisms underlying SUDs. Preclinical studies indicate that GHS1αR antagonists and inverse agonists suppress reward-related signaling associated with cocaine and opioids. In the present study, we found that the GHS1αR antagonist JMV2959 was efficacious to suppress both cue-reinforced cocaine and oxycodone drug-seeking, but not cocaine or oxycodone self-administration in male Sprague-Dawley rats. These data suggest a role of the ghrelin-GHS1αR axis in mediating overlapping reward-related aspects of cocaine and oxycodone and premises the possibility that a GHS1αR antagonist may be a valuable therapeutic strategy for relapse vulnerability in SUDs. [ABSTRACT FROM AUTHOR]

Background and Objectives: Preclinical studies show serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonists reduce cocaine-seeking and cocaine intake. This study examined safety of the 5-HT2CR agonist lorcaserin administered with cocaine in participants with cocaine use disorder (CocUD). Secondarily, subjective response to cocaine and choice of cocaine vs. money were examined. Methods: A double-blind, randomized, placebo-controlled trial of 25 inpatient non-treatment seeking participants with CocUD. Participants were randomized to either lorcaserin (n = 17) or placebo (n = 8). Primary outcome measures included cardiovascular measures and plasma cocaine levels. Secondary measures of subjective response to cocaine were assessed using a visual analog scale (VAS) and cocaine vs. money progressive ratio choice sessions. Results: Thirteen randomized participants were included in the final analysis. No serious or unexpected adverse events were related to lorcaserin. There were no significant interactions between cocaine and lorcaserin on cardiovascular measures, plasma cocaine, or subjective ratings. After multiple comparisons correction, cocaine significantly increased blood pressure, heart rate, and QTc. Lorcaserin significantly decreased VAS ratings of "feel irritable," "feel hungry," and "I am craving." For the cocaine vs. money choice procedure, there was a significant interaction between choice (cocaine vs. money) and lorcaserin. Participants treated with lorcaserin were more likely to choose cocaine. Discussion and Conclusions: This study showed safety of lorcaserin administered with cocaine but lack of efficacy to reduce the reinforcing effects of cocaine. Scientific Significance: This study is the first to show a disconnect between effects of 5-HT2CR agonists on craving and cocaine choice in human cocaine users. [ABSTRACT FROM AUTHOR]

Positive social connections are crucial for recovery from Substance Use Disorder (SUD). Of interest is understanding potential social information processing (SIP) mediators of this effect. To explore whether persons with different SUD show idiosyncratic biases toward social signals, we administered an emotional go-nogo task (EGNG) to 31 individuals with Cocaine Use Disorder (CoUD), 31 with Cannabis Use Disorder (CaUD), 79 with Opioid Use Disorder (OUD), and 58 controls. Participants were instructed to respond to emotional faces (Fear/Happy) but withhold responses to expressionless faces in two task blocks, with the reverse instruction in the other two blocks. Emotional faces as non-targets elicited more "false alarm" (FA) commission errors as a main effect. Groups did not differ in overall rates of hits (correct responses to target faces), but participants with CaUD and CoUD showed reduced rates of hits (relative to controls) when expressionless faces were targets. OUD participants had worse hit rates [and slower reaction times (RT)] when fearful faces (but not happy faces) were targets. CaUD participants were most affected by instruction effects (respond/"go" vs withhold response/"no-go" to emotional face) on discriminability statistic A. Participants were faster to respond to happy face targets than to expressionless faces. However, this pattern was reversed in fearful face blocks in OUD and CoUD participants. This experiment replicated previous findings of the greater salience of expressive face images, and extends this finding to SUD, where persons with CaUD may show even greater bias toward emotional faces. Conversely, OUD participants showed idiosyncratic behavior in response to fearful faces suggestive of increased attentional disruption by fear. These data suggest a mechanism by which positive social signals may contribute to recovery. [ABSTRACT FROM AUTHOR]

Chronic cocaine and alcohol use impart significant stress on biological and cognitive systems, resulting in changes consistent with an allostatic load model of neurocognitive impairment. The present study measured potential markers of allostatic load in individuals with comorbid cocaine/alcohol use disorders (CUD/AUD) and control subjects. Measures of brain white matter (WM), telomere length, and impulsivity/attentional bias were obtained. WM (CUD/AUD only) was indexed by diffusion tensor imaging metrics, including radial diffusivity (RD) and fractional anisotropy (FA). Telomere length was indexed by the telomere to single copy gene (T/S) ratio. Impulsivity and attentional bias to drug cues were measured via eye-tracking, and were also modeled using the Hierarchical Diffusion Drift Model (HDDM). Average whole-brain RD and FA were associated with years of cocaine use (R2 = 0.56 and 0.51, both p < .005) but not years of alcohol use. CUD/AUD subjects showed more anti-saccade errors (p < .01), greater attentional bias scores (p < .001), and higher HDDM drift rates on cocaine-cue trials (Bayesian probability CUD/AUD > control = p > 0.99). Telomere length was shorter in CUD/AUD, but the difference was not statistically significant. Within the CUD/AUD group, exploratory regression using an elastic-net model determined that more years of cocaine use, older age, larger HDDM drift rate differences and shorter telomere length were all predictive of WM as measured by RD (model R2 = 0.79). Collectively, the results provide modest support linking CUD/AUD to putative markers of allostatic load. [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]

Few studies have examined the effects of chronic cocaine use on the resting surface electrocardiogram (ECG) between exposures to cocaine. Researchers compared 12-lead ECGs from 97 treatment-seeking cocaine-dependent patients, with ECG parameters from 8,513 non-cocaine-using control patients from the Atherosclerosis Risk in Communities study. After matching and adjusting for relevant covariates, cocaine use demonstrated large and statistically reliable effects on early repolarization, bradycardia, severe bradycardia, and heart rate. Current cocaine dependence corresponds to an increased odds of demonstrating early repolarization by a factor of 4.92 and increased odds of bradycardia and severe bradycardia by factors 3.02 and 5.11, respectively. This study demonstrates the novel finding that long-lasting effects of cocaine use on both the cardiac conduction and the autonomic nervous system pose a risk of adverse cardiovascular events between episodes of cocaine use, and that bradycardia is a marker of chronic cocaine use. [ABSTRACT FROM AUTHOR]

Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors. [ABSTRACT FROM AUTHOR]

There has been significant progress in personalized drug development. In large part, this has taken place in the oncology field and been due to the ability of researchers/clinicians to discover and develop novel drug development tools (DDTs), such as biomarkers. In cancer treatment research, biomarkers have permitted a more accurate pathophysiological characterization of an individual patient, and have enabled practitioners to target mechanistically the right drug, to the right patient, at the right time. Similar to cancer, patients with substance use disorders (SUDs) present clinically with heterogeneous symptomatology and respond variably to therapeutic interventions. If comparable biomarkers could be identified and developed for SUDs, significant diagnostic and therapeutic advances could be made. In this review, we highlight current opportunities and difficulties pertaining to the identification and development of biomarkers for SUDs. We focus on cocaine dependence as an example. Putative diagnostic, pharmacodynamic (PD), and predictive biomarkers for cocaine dependence are discussed across a range of methodological approaches. A possible cocaine-dependent clinical outcome assessment (COA)-another type of defined DDT-is also discussed. At present, biomarkers for cocaine dependence are in their infancy. Much additional research will be needed to identify, validate, and qualify these putative tools prior to their potential use for medications development and/or application to clinical practice. However, with a large unmet medical need and an estimated market size of several hundred million dollars per year, if developed, biomarkers for cocaine dependence will hold tremendous value to both industry and public health. [ABSTRACT FROM AUTHOR]

Abstract: Functional magnetic resonance imaging (fMRI) studies of early abstinence cocaine users offer information about the state of the brain when most cocaine users seek treatment. This study examined the relationship between pretreatment brain function and subsequent treatment response in 19 treatment-seeking early abstinence cocaine-dependent (CD) subjects. These subjects and 14 non-drug-using control subjects underwent fMRI while performing a working memory task with three levels of difficulty. CD subjects were then randomized to treatment studies. Results showed CD subjects had significantly lower (random effects, corrected for multiple comparisons) brain activation in caudate, putamen, cingulate gyrus, middle and superior frontal gyri, inferior frontal gyrus pars triangularis and pars opercularis, precentral gyrus, and thalamus compared with non-drug-using controls. Within CD subjects, thalamic activation significantly correlated with treatment response. This study shows CD subjects in early abstinence have alterations of brain function in frontal, striatal, and thalamic brain regions known to be part of a circuit associated with motor control, reward, and cognition. Subjects with pretreatment thalamic deactivation showed the poorest treatment response, possibly related to thalamic involvement in mesocortical and mesolimbic dopamine projections. [Copyright &y& Elsevier]

This randomized, double-blind, placebo-controlled study compared the effects of high-dose (100 mg/d) naltrexone versus placebo in a sample of 87 randomized subjects with both cocaine and alcohol dependence. Medication conditions were crossed with two behavioral therapy platforms that examined whether adding contingency management (CM) that targeted cocaine abstinence would enhance naltrexone effects compared to cognitive behavioral therapy (CBT) without CM. Primary outcome measures for cocaine (urine screens) and alcohol use (timeline followback) were collected thrice-weekly during 12 weeks of treatment. Retention in treatment and medication compliance rates were low. Rates of cocaine use and drinks per day did not differ between treatment groups; however naltrexone did reduce frequency of heavy drinking days, as did CBT without CM. Notably, adding CM to CBT did not enhance treatment outcomes. These weak findings suggest that pharmacological and behavioral interventions that have shown efficacy in the treatment of a single drug dependence disorder may not provide the coverage needed when targeting dual drug dependence. [ABSTRACT FROM AUTHOR]

Previous studies have shown that cocaine users have higher levels of impulsivity and impaired decision making; however, few have examined these factors as predictors of treatment success. We obtained baseline neurocognitive measures from 75 cocaine-dependent individuals participating in a 12-week clinical trial targeting impulsivity with behavioral therapies and pharmacotherapy. Participants treated with citalopram had higher cocaine abstinence rates compared to placebo-treated participants. The aim of this secondary analysis study was to determine whether profiles of performance on neurocognitive measures administered at baseline discriminated among patients who achieved abstinence and those who did not. Participants completed the Immediate and Delayed Memory Task, Barratt Impulsiveness Scale-11, and Iowa Gambling Task. Profile analysis results showed different patterns of performance on these baseline measures as a function of outcome. Compared with non-abstinent participants, abstinent participants had higher scores on the Barratt Impulsiveness Scale-11 Non-Planning subscale and better performance on the Iowa Gambling Task. Profile differences for the two outcome groups did not vary as a function of treatment condition. Results suggest that cocaine-dependent patients entering treatment with higher impulsivity and less impaired decision-making abilities may respond favorably to targeted behavioral interventions. Neurocognitive profiles may be useful in understanding population heterogeneity and predicting differential outcomes in subgroups of cocaine abusers. [ABSTRACT FROM AUTHOR]

Aims: Difficulty identifying effective pharmacotherapies for cocaine dependence has led to suggestions that subgroup differences may account for some of the heterogeneity in treatment response. Well-attested methodological difficulties associated with these analyses recommend the use of Bayesian statistical reasoning for evaluation of salient interaction effects. Methods: A secondary data analysis of a previously published, double-blind, randomized controlled trial examines the interaction of decision-making, as measured by the Iowa Gambling Task, and citalopram in increasing longest sustained abstinence from cocaine use. Results: Bayesian analysis indicated that there was a 99% chance that improved decision-making enhances response to citalopram. Given the strong positive nature of this finding, a formal, quantitative Bayesian approach to evaluate the result from the perspective of a skeptic was applied. Conclusions: Bayesian statistical reasoning provides a formal means of weighing evidence for the presence of an interaction in scenarios where conventional, Frequentist analyses may be less informative. [Supplementary materials are available for this article. Go to the publisher's online edition of The American Journal of Drug and Alcohol Abuse for the following free supplemental resource: Appendix 1] [ABSTRACT FROM AUTHOR]

An assay in which groups perform at both similar and significantly different levels within the same test session may have experimental advantages both in understanding underlying behavioral-cognitive processes and in helping to resolve neuroimaging issues regarding functional significance vs. performance confounds. Here we report behavioral data from a response inhibition (Go/No-Go) task with two levels of No-Go difficulty (easy, hard). The sample included individuals with current cocaine dependence (N = 18) and controls (N = 15). Using signal detection methodology (d' and Beta), significant main effects were observed for group and trial type on d'. Post-hoc analyses revealed the cocaine-dependent individuals performed significantly worse than controls on difficult, but not easy, trials. Differences on d' but not Beta, and slower reaction times in cocaine subjects, suggest that response inhibition deficits were related to disruption in visual information processing rather than inhibition of motor activity. [ABSTRACT FROM AUTHOR]

Cocaine dependence continues to be a significant problem in the United States, without any approved pharmacotherapy. Promising findings from preclinical research on the effects of cocaine on serotonin lead to examination of selective serotonin reuptake inhibitors (SSRIs) as potential treatments for cocaine dependence with mixed results, possibly due to drug interactions or specifics of concomitant behavioral therapy. The purpose of this study was to examine whether the SSRI citalopram would reduce cocaine positive urines in a 12-week, double-blind placebo-controlled trial. Seventy-six cocaine dependent patients received either citalopram 20 mg per day or placebo along with cognitive behavioral therapy (CBT) and contingency management (CM). Citalopram treated subjects showed a significant reduction in cocaine-positive urines during treatment compared to placebo treated subjects. No differences were noted in retention between the two groups. Side effects reported for citalopram were mild, with none leading to discontinuation of study drug. Results of this study support further examination of citalopram in combination with behavioral therapy as a treatment for cocaine dependence. [ABSTRACT FROM AUTHOR]

Previous studies report reduced amplitude of the P300 event-related potential in cocaine-dependent individuals. Cocaine dependence is also associated with increased impulsivity, possibly due to deficits in cognitive function that are associated with reduced P300 amplitude. In the current study, the relationship between cocaine dependence, impulsivity, and P300 amplitude were examined. An auditory oddball event-related potential task along with self-report (Barratt Impulsiveness Scale version 11) and behavioral laboratory (Immediate and Delayed Memory Task) measures of impulsivity were assessed in healthy controls (n = 14) and subjects who met DSM-IV criteria for current cocaine dependence (n = 17). P300 amplitude was reduced and self-reported and behavioral laboratory impulsivity scores were elevated among the cocaine-dependent group compared to controls. There was a positive correlation between the questionnaire and behavioral laboratory measures of impulsivity, and a negative correlation between impulsivity measures and P300 amplitude. The correlation between self-reported impulsivity scores and P300 amplitude remained after taking into account the number of childhood conduct disorder symptoms. This study supports the hypothesis that the basic neurophysiology responsible for the P300 amplitude in cocaine-dependent individuals is associated with impulsivity independent of a history of childhood conduct disorder symptoms. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Several previous studies show a relationship between impulsivity and substance abuse; however, it is unclear whether the increased impulsivity seen in substance dependent groups is specifically related to substance abuse, or if it is due to concomitant antisocial personality disorder (ASPD) or aggression. The issue of whether impulsivity is specifically related to substance abuse is important since it has a bearing on risk factors for development of substance abuse. To determine whether cocaine dependent subjects show increased impulsivity independent of ASPD, the Barratt impulsiveness scale (BIS-11), a delayed reward laboratory measure of impulsivity, and the life history of aggression scale were administered to 49 cocaine dependent subjects and 25 controls. Results showed that cocaine dependent subjects with ASPD were more impulsive and aggressive than controls, but cocaine dependent subjects without ASPD were also more impulsive compared to controls. Controlling for aggression history, cocaine dependent subjects without ASPD continued to have elevated impulsivity as measured by the BIS-11, but not the delayed reward task. This study supports the hypothesis that the increased impulsivity as measured by the BIS-11 in cocaine dependent individuals is not exclusively due to concomitant increases in aggression or ASPD. [Copyright &y& Elsevier]

Abstract: Rationale: The role of dopamine in cocaine abuse has been long recognized. Cocaine use can profoundly alter dopaminergic functioning through depletion of this monoamine and changes in receptor functioning. Based on these facts, levodopa (L-dopa) pharmacotherapy may be helpful in reducing or abolishing cocaine use. Objective: The current studies sought to evaluate the safety, tolerability and efficacy of L-dopa as a treatment for cocaine dependence. Methods: In Study 1, 67 cocaine-dependent subjects were randomized in a 5-week, double-blind, placebo-controlled safety trial. Subjects received either placebo, or 400mg L-dopa plus 100mg of the peripheral decarboxylase inhibitor, carbidopa, in a sustained-release preparation (Sinemet CR®). In Study 2, 122 cocaine-dependent subjects were enrolled in a 9-week, randomized, double-blind, placebo-controlled trial to compare placebo to 400/100mg and 800/200mg L-dopa/carbidopa treatments. Placebo or L-dopa were administered twice daily in both studies. Results: L-dopa was well tolerated with similar retention and medication adherence rates compared to placebo. Only two side effects occurred more often in L-dopa-treated patients: nausea and dizziness. L-dopa lowered diastolic blood pressure in a dose-dependent fashion. In these trials, L-dopa had no effect on cocaine use, cocaine craving, or mood. Conclusion: These two studies demonstrate the safety and tolerability of L-dopa pharmacotherapy in cocaine-dependent patients. No evidence for greater efficacy of L-dopa compared to placebo was observed. The possibility of enhancing treatment effects by combining L-dopa with other behavioral or pharmacological interventions is discussed. [Copyright &y& Elsevier]

Background: Converging lines of evidence from diffusion tensor imaging (DTI) studies reveal significant alterations in white matter (WM) microstructure in the prefrontal cortex of chronic stimulant users compared to controls, suggesting compromised axonal microstructure and/or myelin.Methods: A meta-analysis of DTI-based WM integrity was conducted for white matter regions across the corpus callosum and association fibers. Articles were sourced and selected using PRISMA guidelines for systematic review and meta-analysis. Inclusion and exclusion criteria were determined by the authors in order to best capture WM integrity among individuals with primary stimulant use in comparison to healthy control subjects.Results: Eleven studies that focused on region-of-interest (ROI)-based analysis of WM integrity were extracted from an initial pool of 113 independent studies. Analysis across ROIs indicated significantly lower fractional anisotropy (FA) values in stimulant use groups compared to controls with a small to moderate overall effect (Hedges' g = -0.37, 95% CI [-0.54, -0.20]). Eigenvalues were also analyzed, revealing a significant effect for radial diffusivity (RD; Hedges' g = 0.24, 95% CI [0.01, 0.47]) but not axial diffusivity (AD; Hedges' g = 0.05, 95% CI [-0.20, 0.29]) or mean diffusivity (MD; Hedges' g = 0.20, 95% CI [-0.01, 0.41]). Subgroup analyses based on specific ROIs, primary substance use, poly-substance use, and imaging technology were also explored.Conclusion: Results of the present study suggest a consistent effect of compromised WM integrity for individuals with stimulant use disorders. Furthermore, no significant differences were found between cocaine and methamphetamine-based groups. [ABSTRACT FROM AUTHOR]

Background: Previous diffusion tensor imaging (DTI) studies have consistently shown that subjects with cocaine use disorder (CocUD) had altered white matter microstructure in the corpus callosum. It is believed that these alterations are due to preexisting factors, chronic cocaine use, or both. However, there is no published longitudinal DTI study on human cocaine users yet which could shed light on the relationship between cocaine use and DTI findings.Methods: This study used a longitudinal design and DTI to test if the white matter microstructure shows quicker alteration in CocUD subjects than controls. DTI data were acquired from eleven CocUD subjects who participated a treatment study and eleven non-drug-using controls at baseline (Scan 1) and after ten weeks (Scan 2). The baseline fractional anisotropy (FA), a general measure of white matter microstucture, and the change in FA (ΔFA, equals Scan 1 FA minus Scan 2 FA) were both compared between groups.Results: The two groups did not show a difference in FA at baseline. The CocUD subjects had significantly greater ΔFA than the controls in the left splenium of the corpus callosum. In CocUD subjects, greater ΔFA in this region was associated with shorter lifetime cocaine use and greater number of positive cocaine urine samples collected during the treatment.Conclusion: The finding in the left splenium is consistent with previous animal studies and provide indirect evidence about the effects of chronic cocaine use on white matter alterations. The subject sample size is small, therefore the results should be treated as preliminary. [ABSTRACT FROM AUTHOR]

Neuroimaging and genetic studies provide distinct and complementary information about the structural and biological aspects of a disease. Integrating the two sources of data facilitates the investigation of the links between genetic variability and brain mechanisms among different individuals for various medical disorders. This article presents a general statistical framework for integrative Bayesian analysis of neuroimaging-genetic (iBANG) data, which is motivated by a neuroimaging-genetic study in cocaine dependence. Statistical inference necessitated the integration of spatially dependent voxel-level measurements with various patient-level genetic and demographic characteristics under an appropriate probability model to account for the multiple inherent sources of variation. Our framework uses Bayesian model averaging to integrate genetic information into the analysis of voxel-wise neuroimaging data, accounting for spatial correlations in the voxels. Using multiplicity controls based on the false discovery rate, we delineate voxels associated with genetic and demographic features that may impact diffusion as measured by fractional anisotropy (FA) obtained from DTI images. We demonstrate the benefits of accounting for model uncertainties in both model fit and prediction. Our results suggest that cocaine consumption is associated with FA reduction in most white matter regions of interest in the brain. Additionally, gene polymorphisms associated with GABAergic, serotonergic and dopaminergic neurotransmitters and receptors were associated with FA. [ABSTRACT FROM AUTHOR]

Cocaine-dependent (CD) subjects show attentional bias toward cocaine-related cues, and this form of cue-reactivity may be predictive of craving and relapse. Attentional bias has previously been assessed by models that present drug-relevant stimuli and measure physiological and behavioral reactivity (often reaction time). Studies of several CNS diseases outside of substance use disorders consistently report anti-saccade deficits, suggesting a compromise in the interplay between higher-order cortical processes in voluntary eye control (i.e., anti-saccades) and reflexive saccades driven more by involuntary midbrain perceptual input (i.e., pro-saccades). Here, we describe a novel attentional-bias task developed by using measurements of saccadic eye movements in the presence of cocaine-specific stimuli, combining previously unique research domains to capitalize on their respective experimental and conceptual strengths. CD subjects ( N = 46) and healthy controls ( N = 41) were tested on blocks of pro-saccade and anti-saccade trials featuring cocaine and neutral stimuli (pictures). Analyses of eye-movement data indicated (1) greater overall anti-saccade errors in the CD group; (2) greater attentional bias in CD subjects as measured by anti-saccade errors to cocaine-specific (relative to neutral) stimuli; and (3) no differences in pro-saccade error rates. Attentional bias was correlated with scores on the obsessive–compulsive cocaine scale. The results demonstrate increased saliency and differential attentional to cocaine cues by the CD group. The assay provides a sensitive index of saccadic (visual inhibitory) control, a specific index of attentional bias to drug-relevant cues, and preliminary insight into the visual circuitry that may contribute to drug-specific cue reactivity. [ABSTRACT FROM AUTHOR]

In the present study, we tested the hypothesis that the potent and selective dopamine-β-hydroxylase (DβH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160 mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40 mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to nepicastat (n = 13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0 mg), 80 mg of nepicastat or 160 mg of nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder. [ABSTRACT FROM AUTHOR]

Background Diffusion tensor imaging (DTI) is a useful technique for non-invasively investigating the microstructural organization of white matter (WM), and the most consistent DTI finding regarding cocaine-related WM alterations is in the corpus callosum (CC). WM injury has also been observed in subjects with traumatic brain injury (TBI), including in the CC. Methods We used DTI to test if the WM microstructure is relatively more impaired in cocaine-dependent subjects who had suffered a mild TBI (mTBI). Fractional anisotropy (FA), which reflects the degree of alignment of cellular structures within fiber tracts and their structural integrity, was compared across cocaine-dependent subjects with mTBI (COCTBI group, n = 9), matched cocaine-dependent subjects without TBI (COC group, n = 12), and matched healthy controls (CTL group, n = 12). Results The COCTBI group had significantly lower FA in the genu, body, and splenium of CC, than the CTL group whenever the education was controlled or not. The COC group had significantly lower FA in the left and right anterior corona radiata than the CTL group only when the education was controlled. There was no significant difference in FA between the COC and COCTBI groups. Conclusion Cocaine dependence (or mTBI) related WM impairments in the CC were not detectable in this small subject sample. The significant finding in the CC suggests that the concurrence of cocaine dependence and mTBI might result in more severe damage to the CC, which could even be detected in small sample size. [ABSTRACT FROM AUTHOR]

• We administered the attentional network task to controls and to persons with cocaine use disorder (CoUD), cannabis use disorder (CaUD), opioid use disorder (OUD). • After controlling for group differences in sex representation and age, both OUD and CaUD participants showed blunted alerting effects compared to controls. • After controlling for sex representation and age, both CaUD and CoUD participants showed greater conflict effects of target-incongruent stimuli than controls. • No substance use disorder (SUD) group showed prolonged stop-signal reaction time compared to controls. • These data indicate differences in components of attentional function between persons with SUD as a function of the substance of choice. Attentional function in substance use disorder (SUD) is not well understood. To probe attentional function in SUD as a function of primary substance of abuse, we administered the attentional network task (ANT) to 44 individuals with Cocaine Use Disorder (CoUD), 49 individuals with Cannabis Use Disorder (CaUD), 86 individuals with Opioid Use Disorder (OUD), and 107 controls with no SUD, along with the stop-signal task (SST). The ANT quantifies the effects of (temporal) alerting cues and (spatial) orienting cues to reduce reaction time (RT) to targets, as well as probing how conflicting (target-incongruent) stimuli slow RT. The SST quantifies individuals' ability to inhibit already-initiated motor responses. After controlling for sex representation and age, OUD and CaUD participants showed blunted alerting effects compared to controls, whereas CaUD and CoUD participants showed greater stimulus conflict (flanker) effects. Finally, CoUD participants showed a trend toward increased orienting ability. In SST performance, no SUD group showed a prolonged stop-signal reaction compared to controls. However, the OUD group (and CoUD group at trend level) showed prolonged "go" RT to targets and reduced hit rates. These data indicate differences in attentional function in persons with SUD as a function of the primary substance use. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cocaine pharmacotherapy trials are often confounded by considerable variability in baseline cocaine-use levels, obscuring possible medication efficacy. Testing the feasibility of using a prerandomization, abstinence-induction protocol, we screened three candidate medications to explore treatment response in patients who did, or did not, achieve abstinence during an extended baseline phase. Method: Eligible treatment-seeking, cocaine-dependent subjects entered a 4-week baseline period (Phase I) with high-value abstinence contingent vouchers and two motivational interviewing sessions, followed by a 12-week medication trial (Phase II) with random assignment stratified on Phase I abstinence status to (1) modafinil (400mg/d), (2) levodopa/carbidopa (800/200mg/d), (3) naltrexone (50mg/d), or (4) placebo. Treatment consisted of thrice-weekly clinic visits for urine benzoylecgonine testing and weekly cognitive behavioral therapy with contingency management targeting medication compliance. Results: Of the 118 subjects enrolled, 81 (80%) completed Phase I, with 33 (41%) achieving abstinence, defined a priori as 6 consecutive cocaine-negative urines. Tests of the interaction of each medication (active versus placebo) by baseline status (abstinent versus nonabstinent) permitted moderator effect analysis. Overall, baseline abstinence predicted better outcome. Cocaine-use outcomes for levodopa and naltrexone treatment differed as a function of Phase I abstinence status, with both medications producing benefit in nonabstinent but not baseline-abstinent subjects. There was no evidence of a moderator effect for modafinil. Conclusions: The two-phase screening trial demonstrated that subgrouping of patients with respect to baseline abstinence status is feasible and clinically useful for exploring cocaine cessation and relapse-prevention effects of candidate medications. [Copyright &y& Elsevier]

Abstract: Neuroimaging data suggest that impaired performance on response inhibition and information processing tests in cocaine-dependent subjects is related to prefrontal and frontal cortical dysfunction and that dysfunction in these brain areas may underlie some aspects of cocaine addiction. In subjects with attention-deficit hyperactivity disorder and other psychiatric disorders, the Intra-Individual Reaction Time Variability (IIRTV) has been associated with frontal cortical dysfunction. In the present study, we evaluated IIRTV parameters in cocaine-dependent subjects vs. controls using a cocaine Stroop task. Fifty control and 123 cocaine-dependent subjects compiled from three studies completed a cocaine Stroop task. Standard deviation (SD) and coefficient of variation (CV) for reaction times (RT) were calculated for both trials with neutral and trials with cocaine-related words. The parameters mu, sigma, and tau were calculated using an ex-Gaussian analysis employed to characterize variability in RTs. The ex-Gaussian analysis divides the RTs into normal (mu, sigma) and exponential (tau) components. Using robust regression analysis, cocaine-dependent subjects showed greater SD, CV and Tau on trials with cocaine-related words compared to controls (p<0.05). However, in trials with neutral words, there was no evidence of group differences in any IIRTV parameters (p>0.05). The Wilcoxon matched-pairs signed-rank test showed that for cocaine-dependent subjects, both SD and tau were larger in trials with cocaine-related words than in trials with neutral words (p<0.05). The observation that only cocaine-related words increased IIRTV in cocaine-dependent subjects suggests that cocaine-related stimuli might disrupt information processing subserved by prefrontal and frontal cortical circuits. [Copyright &y& Elsevier]

Abstract: Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT2C receptor (5-HT2CR) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT2CR agonist, WAY 163909, in cocaine and sucrose self-administration and reinstatement assays employing parallel experimental designs in free-fed rats. WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID50 = 1.19 mg/kg) and sucrose (ID50 = 0.7 mg/kg) as well as reinstatement (ID50 = 0.5 mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues. The ID50 of WAY 163909 predicted to decrease the reinforcing efficacy of cocaine or sucrose as well as reinstatement upon exposure to cocaine-associated cues was ∼5–12-fold lower than that predicted to suppress horizontal ambulation (ID50 = 5.89 mg/kg) and ∼2–5-fold lower than that predicted to suppress vertical activity (ID50 = 2.3 mg/kg). Thus, selective stimulation of the 5-HT2CR decreases the reinforcing efficacy of cocaine and sucrose in freely-fed rats, but differentially alters the incentive-salience value of cocaine- vs. sucrose-associated cues at doses that do not impair locomotor activity. Future research is needed to tease apart the precise contribution of 5-HT2CR neurocircuitry in reward and motivation and the learning and memory processes that carry the encoding for associations between environmental cues and consumption of rewarding stimuli. A more complete preclinical evaluation of these questions will ultimately allow educated proof-of-concept trials to test the efficacy of selective 5-HT2CR agonists as adjunctive therapy in chronic health maladies including obesity, eating disorders and drug addiction. This article is part of a Special Issue entitled ‘Serotonin’. [Copyright &y& Elsevier]

Abstract: Magnetic resonance imaging (MRI) was performed in cocaine-dependent subjects to determine the structural changes in brain compared to non-drug using controls. Cocaine-dependent subjects and controls were carefully screened to rule out brain pathology of undetermined origin. Magnetic resonance images were analyzed using tensor-based morphometry (TBM) and voxel-based morphometry (VBM) without and with modulation to adjust for volume changes during normalization. For TBM analysis, unbiased atlases were generated using two different inverse consistent and diffeomorphic nonlinear registration techniques. Two different control groups were used for generating unbiased atlases. Independent of the nonlinear registration technique and normal cohorts used for creating the unbiased atlases, our analysis failed to detect any statistically significant effect of cocaine on brain volumes. These results show that cocaine-dependent subjects do not show differences in regional brain volumes compared to non-drug using controls. [ABSTRACT FROM AUTHOR]

Abstract: Studies in cocaine-dependent human subjects have shown differences in white matter on diffusion tensor imaging (DTI) compared with non-drug-using controls. It is not known whether the differences in fractional anisotropy (FA) seen on DTI in white matter regions of cocaine-dependent humans result from a pre-existing predilection for drug use or purely from cocaine abuse. To study the effect of cocaine on brain white matter, DTI was performed on 24 rats after continuous infusion of cocaine or saline for 4 weeks, followed by brain histology. Voxel-based morphometry analysis showed an 18% FA decrease in the splenium of the corpus callosum (CC) in cocaine-treated animals relative to saline controls. On histology, significant increase in neurofilament expression (125%) and decrease in myelin basic protein (40%) were observed in the same region in cocaine-treated animals. This study supports the hypothesis that chronic cocaine use alters white matter integrity in human CC. Unlike humans, where the FA in the genu differed between cocaine users and non-users, the splenium was affected in rats. These differences between rodent and human findings could be due to several factors that include differences in the brain structure and function between species and/or the dose, timing, and duration of cocaine administration. [Copyright &y& Elsevier]

• This study investigated drug-related attentional bias in opioid use disorder. • Dynamic causal modeling was used to assess underlying neural circuits. • Opioid cues caused increase in anterior cingulate cortex (ACC) to hippocampus effective connectivity. • Greater increase of this connectivity was associated with greater attentional bias. • The findings were consistent across opioid use disorder and cocaine use disorder. Individuals with opioid use disorder (OUD) often relapse when exposed to opioid-related cues. Previous functional magnetic resonance imaging (fMRI) studies have identified neuronal corticolimbic changes related to drug cue reactivity in OUD. However, the corresponding manner in which brain regions interact is still unclear. Effective (directional) connectivity was analyzed using dynamic causal modeling of fMRI data acquired from 27 OUD participants (13 with OUD and 14 with OUD and cocaine use disorder [OUD+CUD]), while performing an opioid-word Stroop task. Participants were shown opioid and neutral words presented in different colors and were instructed to indicate word color but ignore word meaning. The effects of opioid words relative to neutral words on effective connectivity and on behavioral reaction time were defined as modulatory change and attentional bias, respectively. For all the 27 participants, left anterior cingulate cortex (ACC) to right hippocampus effective connectivity exhibited the largest modulatory change, which was positively correlated with attentional bias. The findings for the ACC to hippocampus EC were consistent across OUD and CUD found in a previous study. [ABSTRACT FROM AUTHOR]