Treatment Of Cocaine Dependence Research Articles

The exploration of pioglitazone’s potential as a pharmacotherapy option for drug addiction

Pioglitazone is a selective agonist for peroxisome proliferatoractivated receptor gamma (PPARγ) that is currently used for the treatment of type 2 diabetes mellitus. However, recent evidence suggests that the PPARγ pathway may be a promising novel target for drug addiction therapy. There has been considerable evidence with preclinical models of addiction that support pioglitazone’s therapeutic potential for opioid, alcohol, methamphetamine, and cocaine dependence. Although the precise mechanisms remain unclear, these preclinical studies suggest that pioglitazone blocks the excitation of ventral tegmental area dopamine signaling, which is associated with the addictive properties of abused drugs. Recently, clinical studies have also emerged to investigate the role of pioglitazone for drug addiction in humans. Clinical evidence supports preclinical findings that pioglitazone may indeed be beneficial for the treatment of cocaine dependence. Other clinical evidence suggests that pioglitazone may also be effective for nicotine addiction. Further clinical research is needed to investigate pioglitazone’s effects in opioid, alcohol, and methamphetamine addiction. Pioglitazone also has a favourable and safe profile. These findings suggest that pioglitazone may be a novel treatment option for drug dependence in the future. Due to its status as a medication approved by the Food and Drug Administration, there is a potential for accelerated establishment of pioglitazone as an addiction treatment method.

A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial

Research has suggested that subanesthetic doses of ketamine may work to improve cocaine-related vulnerabilities and facilitate efforts at behavioral modification. The purpose of this trial was to test whether a single ketamine infusion improved treatment outcomes in cocaine-dependent adults engaged in mindfulness-based relapse prevention. Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay, during which they also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout). Overall, 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, compared with 10.7% in the midazolam group (intent-to-treat analysis). The ketamine group was 53% less likely (hazard ratio=0.47; 95% CI=0.24, 0.92) to relapse (dropout or use cocaine) compared with the midazolam group, and craving scores were 58.1% lower in the ketamine group throughout the trial (95% CI=18.6, 78.6); both differences were statistically significant. Infusions were well tolerated, and no participants were removed from the study as a result of adverse events. A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing risk of relapse. Further research is needed to replicate these promising results in a larger sample.

Determination of cocaine adulterants in human urine by dispersive liquid-liquid microextraction and high-performance liquid chromatography.

This study aimed to determine simultaneously five major street cocaine adulterants (caffeine, lidocaine, phenacetin, diltiazem, and hydroxyzine) in human urine by dispersive liquid-liquid microextraction (DLLME) and high-performance liquid chromatography. The chromatographic separation was obtained in gradient elution mode using methanol:water plus trifluoroacetic acid 0.15% (v/v) (pH = 1.9) at 1mLmin-1 as mobile phase, at 25°C, detection at 235nm, and analysis time of 20min. The effect of major DLLME operating parameters on extraction efficiency was explored using the multifactorial experimental design approach. The optimum extraction condition was set as 4mL human urine sample alkalized with 0.5M sodium phosphate buffer (pH 12), NaCl (15%, m/v), 300μL acetonitrile (dispersive solvent), and 800μL chloroform (extraction solvent). Linear response (r2 ≥ 0.99) was obtained in the range of 180-1500ngmL-1 with suitable selectivity, quantification limit (180ngmL-1), mean recoveries (33.43-76.63%), and showing relative standard deviation and error (within and between-day assays) ≤15%. The analytes were stable after a freeze-thaw cycle and a short-term room temperature stability test. This method was successfully applied in real samples of cocaine users, suggesting that our study may contribute to the appropriate treatment of cocaine dependence or with the cases of cocaine acute intoxication.

FMRI Stroop and behavioral treatment for cocaine-dependence: Preliminary findings in methadone-maintained individuals

BackgroundAlthough behavioral treatment for cocaine use disorders is common, the use of cognitive neuroscience methods to investigate these treatments' mechanisms of action remains limited. Cognitive control (e.g., as measured by the Stroop task) has been proposed to be central to cocaine-use disorders, including treatment response. MethodsParticipants were methadone-maintained, cocaine-dependent individuals who were participating in a randomized clinical trial (RCT) of 8 weeks of treatment for cocaine-use disorder and randomized to outpatient treatment as usual (TAU) or computer-based cognitive-behavioral therapy (CBT4CBT) plus TAU. Participants completed fMRI Color-Word Stroop task at beginning-of-treatment (N = 19) and post-treatment (N = 10). Analyses assessed correlations between beginning-of-treatment Stroop effect with methadone dose or within-treatment cocaine abstinence, change in Stroop-effect at post- versus beginning-of-treatment, and correlations between ‘change in Stroop effect’ with methadone dose or within-treatment cocaine abstinence. ResultsHigher methadone dose was associated with higher beginning-of-treatment Stroop-related activity in the declive, culmen, and lingual gyrus. Stroop-related activity was reduced at post-treatment relative to beginning-of-treatment in the medial frontal gyrus/cingulate gyrus and thalamus/midbrain/culmen. Greater reduction in Stroop-related activity was associated with better within-treatment abstinence. ConclusionsDiminished Stroop-related activity following treatment may be consistent with improved efficiency of cognitive-control-related activity. Although preliminary, this study is the first to demonstrate a relationship between better treatment outcomes (lower cocaine use during treatment) and greater reduction in Stroop-related activity at post- versus beginning-of-treatment in cocaine users. These findings extend prior work.

Symptoms of anhedonia, not depression, predict the outcome of treatment of cocaine dependence

The purpose of this paper is to reanalyze data from two studies to determine if anhedonia specifically, rather than depression overall, predicts treatment outcome for patients with cocaine use disorders. Measures of baseline anhedonia symptoms were created using anhedonia items from the Beck Depression Inventory (BDI) to re-examine National Institute on Drug Abuse Cocaine Collaborative Treatment study data (Crits-Christoph et al., 1999) and the contingency management group from the McKay et al. (2010) trial. Baseline anhedonia was used to predict cocaine abstinence rates across the treatment period in both studies. Anhedonia was a significant predictor of cocaine abstinence, even when overall depression scores excluding anhedonia were included in the models. The development of treatments to target individuals with cocaine use disorder who have symptoms of anhedonia has the potential to improve overall outcomes for those with this disorder.

Is Ayahuasca an Option for the Treatment of Crack Cocaine Dependence?

ABSTRACTThe low efficacy of crack cocaine addiction treatment available in Brazil has led Brazilian users to find alternatives to reduce drug consumption or even to reach abstinence. One of them is the use of entheogenic substances, like ayahuasca, an infusion obtained from two native plant species from the Amazon. The present report aimed to understand how crack cocaine users recover from drug addiction by consuming ayahuasca tea in a religious context. This is a qualitative study with a purposeful sample of 40 crack cocaine users, based on in-depth, semi-structured interviews. Participants reported that ayahuasca allowed them to access a consciousness dimension which enabled them to solve problems and traumas and reduce crack cocaine consumption. The religious ceremony increased the user’s spirituality and the reception from the community gave them a sense of self-esteem, strengthening them in an emotional and social way. That positive experience has been incorporated into the daily routine of most participants. Findings indicate that ayahuasca, in a religious context, may have therapeutic value for crack cocaine dependence treatment.

The effect of N-acetylcysteine or bupropion on methamphetamine self-administration and methamphetamine–triggered reinstatement of female rats

N-acetylcysteine and bupropion are two promising candidate medications for treatment of substance use disorder. The effects of N-acetylcysteine or bupropion on methamphetamine self-administration of female rats are not well understood. To fill this gap, this study assessed the effects of N-acetylcysteine (0, 30, 60, or 120 mg/kg) and bupropion (0, 10, 30, and 60 mg/kg) on methamphetamine self-administration of female rats across the natural estrous cycle. Following a completed dose-response curve, responding for methamphetamine self-administration was extinguished and the effects of N-acetylcysteine or bupropion on methamphetamine-triggered reinstatement was evaluated in separate experiments. N-acetylcysteine did not decrease responding maintained by methamphetamine or methamphetamine-triggered reinstatement. Bupropion significantly decreased methamphetamine self-administration and methamphetamine-triggered reinstatement in female rats with highest dose (60 mg/kg) also significantly decreasing general chamber activity. In a companion experiment, testing the effect of bupropion on responding maintained by sucrose, we confirmed non-specificity of bupropion's effects as bupropion also decreased responding for sucrose. Considered together, our findings suggest that while N-acetylcysteine has considerable promise for treatment of cocaine dependence it may not generalize to other stimulants like methamphetamine. Furthermore, although bupropion has been shown to effectively decrease methamphetamine self-administration, and presently methamphetamine-triggered reinstatement, its locomotor and reward suppressing effects warrant further investigation including both sexes.

Comparing pharmacological treatments for cocaine dependence: Incorporation of methods for enhancing generalizability in meta‐analytic studies

Few head-to-head comparisons of cocaine dependence medications exist, and combining data from different randomized controlled trials (RCTs) is fraught with methodological challenges including limited generalizability of the RCT findings. This study applied a novel meta-analytic approach to data of cocaine dependence medications. Data from 4 placebo-controlled RCTs (Reserpine, Modafinil, Buspirone, and Ondansetron) were obtained from the National Institute of Drug Abuse Clinical Trials Network (n=456). The RCT samples were weighted to resemble treatment-seeking patients (Treatment Episodes Data Set-Admissions) and individuals with cocaine dependence in general population (National Survey on Drug Use and Health). We synthesized the generalized outcomes with pairwise meta-analysis using individual-level data and compared the generalized outcomes across the 4 RCTs with network meta-analysis using study-level data. Weighting the data by the National Survey on Drug Use and Health generalizability weight made the overall population effect on retention significantly larger than the RCT sample effect. However, there was no significant difference between the population effect and the RCT sample effect on abstinence. Weighting changed the ranking of the effectiveness across treatments. Applying generalizability weights to meta-analytic studies is feasible and potentially provides a useful tool in assessing comparative effectiveness of treatments for substance use disorders in target populations.

Comparison Between the Efficiency of Pharmacotherapy and Cognitive Behavioral Therapy in Reducing Cocaine Addiction and Relapse Prevention

Objectives: To examine the therapeutic efficacy and effectiveness of cognitive behavior therapy and pharmacotherapy in the treatment of Major Cocaine Dependence. Method: A 41 outpatients males, selected for the study, diagnosed as they suffering from Cocaine Dependence according to the DSM-5, with mean age 34.58 ± 5.11. The sample was divided into three experimental groups, first group (A) (N= 14 cocaine dependents) treated by cognitive behavior therapy and pharmacotherapy in combination. The second group (B) (N=13 cocaine dependents) treated by cognitive behavior therapy alone. The third group (C) (N=14 cocaine dependents) treated by pharmacotherapy alone. The CBT second group had been exposed to 20 regular sessions of a full CBT program. All groups were assessed by Beck Depression Inventory (BDI), Automatic Thoughts Checklist, Irrational Thoughts Questionnaire, Negative Health Beliefs Questionnaire, Beck Craving Beliefs Questionnaire (CBQ), Beck Relapse Prediction Scale (RPS), and the Social Efficacy Treatment Checklist (SETC) designed by the researcher. All groups were assigned to four measurements, one for the baseline before any treatment interventions, one for the post-treatment evaluation, and two for evaluating the groups in tow times of follow-up within a short time and long time. Non-parametric statistics were used to analyze the data collected by SPSS. Results: There is no significant intra-group differences were found in terms of baseline assessment. There was no significant discrepancy between the first and the second group except in the term of reducing cocaine craving, as it was clearer in the first group in comparison with other groups. There was a clear significant discrepancy between the first and third group, for all the study variables and it’s phases of assessment especially follow up. There was a clear degree of differences among the second and the third group, through the different phases of post-assessment, which refers to the great efficacy and effectiveness of Cognitive Behavioural Therapy in Treating Cocaine Dependence. There was a difference among the three groups in reducing the different variables of the study for the first group. Cognitive Behaviour Therapy (CBT) was proved to be more effective than pharmacotherapy in the treatment of Cocaine Dependence. The combination of CBT and pharmacotherapy was more effective than each other alone in the treatment of Cocaine Dependence and Relapse Prevention. All the results had been discussed in terms of information processing model and discussed in terms of cognitive-behavioral models of dependencies and relapse prevention. Conclusions: Available evidence suggests that cognitive–behavioral therapy is an effective intervention method for psychological aspects of automatic thoughts, depression, negative health beliefs, craving, and relapse prevention, although its efficacy in reducing cocaine dependence.

Synergistic interactions between mirtazapine and prazosin prevent the induction and expression of behavioral sensitization to cocaine in rats

Cocaine abuse and dependence are a global public health problem. To date, no effective therapy has been established to treat cocaine dependence but mirtazapine—as well as prazosin used in preclinical and clinical trials—has been shown to decrease cocaine behavioral effects. Therefore, our hypothesis was that the effectiveness of mirtazapine might improve when used in combination with prazosin. This study investigated the combined effect of mirtazapine and prazosin on cocaine-induced locomotor activity impairment in rats subjected to locomotor sensitization testing. We found that chronic treatment with the mirtazapine-prazosin combination significantly improved the effect of single mirtazapine dosing on cocaine-induced locomotor activity and on the induction and expression of cocaine sensitization. These results suggest that the combined use of mirtazapine and prazosin may be a potentially effective treatment to attenuate induction and expression of locomotor sensitization to cocaine.

Relationship between craving and plasma leptin concentrations in patients with cocaine addiction

BackgroundThere is robust evidence indicating an overlap between neurobiological circuitry and pathways that regulate addictions and those that regulate appetite and food intake. Rodent work suggests a role of the appetitive peptide leptin in cocaine-seeking behaviours. The goal of this study was to investigate the possible relationship between plasma leptin concentrations and cocaine craving and use in patients seeking treatment for cocaine dependence. MethodsPatients (N=43) with a DSM-IV diagnosis of cocaine dependence were studied before starting detoxification (baseline; T0) and then again 14days after (T1; only those patients who abstained from cocaine during the study). Blood samples for plasma leptin concentrations were collected and cocaine craving was assessed using the Brief Cocaine Craving Questionnaire (Brief-CCQ). Food craving was also assessed using a food Visual Analogue Scale (f-VAS). Barratt Impulsiveness Scale (BIS) was used to evaluate impulsivity. ResultsPlasma leptin concentrations at T0 significantly correlated with baseline Brief-CCQ scores (r=0.34, p<0.05). Furthermore, plasma leptin concentrations at T1 significantly correlated with the baseline amount of cocaine used (r=0.5, p<0.05). There were no significant correlations between plasma leptin concentrations and f-VAS scores either at T0 or T1 (p’s>0.05). ConclusionsThe present study suggests a potential relationship between plasma leptin concentrations and cocaine craving and use. Future mechanistic studies are needed to determine whether manipulations of leptin signalling may lead to novel pharmacological approaches to treat cocaine addiction.

Dose- and time-dependent effects of mirtazapine on the expression of cocaine-induced behavioral sensitization in rats

Relapse to cocaine use is a major problem in the clinical treatment of cocaine dependence. Antidepressant medications have been studied as potential therapeutic drugs to relieve a cocaine dependence disorder. Mirtazapine is an antidepressant implicated in reducing behavioral alterations induced by drugs of abuse. We have reported elsewhere that 30mg/kg mirtazapine administered for 30 days during cocaine extinction significantly attenuated the induction and expression of cocaine-induced locomotor sensitization and decreased the duration of the cocaine-induced locomotor effect. This study focused on exploring whether different mirtazapine dosing regimens could optimize and/or improve the effect of 30mg/kg mirtazapine administered for 30 days on cocaine-induced locomotor activity during the expression phase of behavioral sensitization. Our study revealed that the daily dosing regimen with a fixed dose of mirtazapine (30mg/kg ip) over 60 days improved the decrease in cocaine-induced locomotor activity and behavioral sensitization obtained by dosing of 30mg mirtazapine for 30 days. In addition, it showed that a dosing regimen of 30mg/Kg mirtazapine for 30 days managed to reduce cocaine toxicity. These results suggested that dosage of mirtazapine for 30 consecutive days may be an effective therapy.

Comparable efficacy of behavioral and pharmacological treatments among African American and White cocaine users

ABSTRACTMultiple randomized clinical trials (RCTs) have evaluated a range of treatments for cocaine dependence, but few of these have focused specifically on the racial diversity observed among cocaine-dependent patients. The present analyses evaluated racial variation in cocaine use and addiction-related psychosocial outcomes at baseline and follow-up among 388 African American and White adults participating in 1 of 5 RCTs evaluating a range of pharmacological and behavioral treatments for cocaine use disorders. General linear modeling (GLM) indicated significant racial variation in cocaine and psychosocial indicators at baseline. At baseline, there were significant racial differences in the number of days paid for work in the 30 days prior to the study, age, days of cocaine use in the past month, age of first cocaine use, psychosocial problems (i.e., employment, cocaine, legal, and family), public assistance status, and prevalence of lifetime anxiety disorders. There were no significant main or interaction effects of race and study on treatment outcomes at posttreatment. These findings suggest that despite significant racial differences at baseline, the pharmacological and behavioral treatments resulted in fairly comparable outcomes across racial groups in these 5 RCTs.

Salience and default mode network dysregulation in chronic cocaine users predict treatment outcome.

While chronic cocaine use is associated with abnormalities in both brain structure and function within and interactions between regions, previous studies have been limited to interrogating structure and function independently, and the detected neural differences have not been applied to independent samples to assess the clinical relevance of results. We investigated consequences of structural differences on resting-state functional connectivity in cocaine addiction and tested whether resting-state functional connectivity of the identified circuits predict relapse in an independent cohort. Subjects included 64 non-treatment-seeking cocaine users (NTSCUs) and 67 healthy control subjects and an independent treatment-completed cohort (n = 45) of cocaine-dependent individuals scanned at the end of a 30-day residential treatment programme. Differences in cortical thickness and related resting-state functional connectivity between NTSCUs and healthy control subjects were identified. Survival analysis, applying cortical thickness of the identified regions, resting-state functional connectivity of the identified circuits and clinical characteristics to the treatment cohort, was used to predict relapse. Lower cortical thickness in bilateral insula and higher thickness in bilateral temporal pole were found in NTSCUs versus healthy control subjects. Whole brain resting-state functional connectivity analyses with these four different anatomical regions as seeds revealed eight weaker circuits including within the salience network (insula seeds) and between temporal pole and elements of the default mode network in NTSCUs. Applying these circuits and clinical characteristics to the independent cocaine-dependent treatment cohort, functional connectivity between right temporal pole and medial prefrontal cortex, combined with years of education, predicted relapse status at 150 days with 88% accuracy. Deficits in the salience network suggest an impaired ability to process physiologically salient events, while abnormalities in a temporal pole-medial prefrontal cortex circuit might speak to the social-emotional functional alterations in cocaine addiction. The involvement of the temporal pole-medial prefrontal cortex circuit in a model highly predictive of relapse highlights the importance of social-emotional functions in cocaine dependence, and provides a potential underlying neural target for therapeutic interventions, and for identifying those at high risk of relapse.

Psychostimulant drugs for cocaine dependence.

Cocaine dependence is a severe disorder for which no medication has been approved. Like opioids for heroin dependence, replacement therapy with psychostimulants could be an effective therapy for treatment. To assess the effects of psychostimulants for cocaine abuse and dependence. Specific outcomes include sustained cocaine abstinence and retention in treatment. We also studied the influence of type of drug and comorbid disorders on psychostimulant efficacy. This is an update of the review previously published in 2010. For this updated review, we searched the Cochrane Drugs and Alcohol Group Trials Register, CENTRAL, MEDLINE, Embase and PsycINFO up to 15 February 2016. We handsearched references of obtained articles and consulted experts in the field. We included randomised parallel group controlled clinical trials comparing the efficacy of a psychostimulant drug versus placebo. We used standard methodological procedures expected by Cochrane. We included 26 studies involving 2366 participants. The included studies assessed nine drugs: bupropion, dexamphetamine, lisdexamfetamine, methylphenidate, modafinil, mazindol, methamphetamine, mixed amphetamine salts and selegiline.We did not consider any study to be at low risk of bias for all domains included in the Cochrane 'Risk of bias' tool. Attrition bias was the most frequently suspected potential source of bias of the included studies. We found very low quality evidence that psychostimulants improved sustained cocaine abstinence (risk ratio (RR) 1.36, 95% confidence interval (CI) 1.05 to 1.77, P = 0.02), but they did not reduce cocaine use (standardised mean difference (SMD) 0.16, 95% CI -0.02 to 0.33) among participants who continued to use it. Furthermore, we found moderate quality evidence that psychostimulants did not improve retention in treatment (RR 1.00, 95% CI 0.93 to 1.06). The proportion of adverse event-induced dropouts and cardiovascular adverse event-induced dropouts was similar for psychostimulants and placebo (RD 0.00, 95% CI -0.01 to 0.01; RD 0.00, 95% CI -0.02 to 0.01, respectively). When we included the type of drug as a moderating variable, the proportion of patients achieving sustained cocaine abstinence was higher with bupropion and dexamphetamine than with placebo. Psychostimulants also appeared to increase the proportion of patients achieving sustained cocaine and heroin abstinence amongst methadone-maintained, dual heroin-cocaine addicts. Retention to treatment was low, though, so our results may be compromised by attrition bias. We found no evidence of publication bias. This review found mixed results. Psychostimulants improved cocaine abstinence compared to placebo in some analyses but did not improve treatment retention. Since treatment dropout was high, we cannot rule out the possibility that these results were influenced by attrition bias. Existing evidence does not clearly demonstrate the efficacy of any pharmacological treatment for cocaine dependence, but substitution treatment with psychostimulants appears promising and deserves further investigation.

Contingency management is effective in promoting abstinence and retention in treatment among crack cocaine users in Brazil: A randomized controlled trial.

Crack cocaine dependence has become a severe public health problem in Brazil, and current psychosocial approaches to this problem have shown little or no effectiveness. Although contingency management is among the most effective behavioral treatments for substance use disorders, it has never been applied in the treatment of crack cocaine-dependent individuals in Brazil. The aim of this study was to evaluate the efficacy of incorporating contingency management into standard outpatient treatment for crack cocaine dependence, as well as the impact that doing so has on treatment attendance, retention in treatment, maintenance of abstinence, and the frequency of substance use. We evaluated 65 treatment-seeking, crack cocaine-dependent individuals, randomized to receive 12 weeks of standard treatment plus contingency management (STCM; n = 33) or 12 weeks of standard treatment alone (STA; n = 32). Those in the STCM group received monetary incentives for being abstinent, earning up to US$235.50 if they remained abstinent throughout the entire treatment period. The STCM group participants attended a mean of 19.5 (SD = 14.9) treatment sessions, compared with 3.7 (SD = 5.9) for the STA group participants (p < .01). Those in the STCM group were 3.8, 4.6, and 68.9 times more likely to be retained in treatment at weeks 4, 8, and 12 than were those in the STA group. The likelihood of detecting 4, 8, and 12 weeks of continuous abstinence was 17.7, 9.9, and 18.6 times higher in the STCM group than in the STA group (p < .05). Compared to the STA group, the STCM group submitted a significantly higher proportion of negative samples for crack cocaine, delta-9-tetrahydrocannabinol, and alcohol (p < .001) when all expected samples were included in the denominator but not when only submitted samples were considered. The average monthly cost/participant for incentives was $29.00. Contingency management showed efficacy in a sample of Brazilian crack cocaine users. The intervention holds promise for broader application in international settings. (PsycINFO Database Record

Anticipatory reward processing among cocaine-dependent individuals with and without concurrent methadone-maintenance treatment: Relationship to treatment response

BackgroundCocaine dependence among opioid-dependent methadone-maintained individuals is a significant public health problem and is particularly challenging to treat. The neurobiology of this clinically complex population has not been previously assessed using fMRI. MethodsfMRI data from cocaine-dependent, methadone-maintained (CD-MM) patients (n=24), cocaine-dependent (CD) patients (n=20) and healthy comparison (HC) participants (n=21) were acquired during monetary incentive delay task performance. All patients were scanned prior to treatment for cocaine dependence. Between-group differences in anticipatory reward and loss processing were assessed using whole-brain ANOVAs in SPM12 (pFWE<0.05). Correlations between durations of abstinence during treatment and BOLD responses within the insula and caudate were also explored. ResultsMain effects of diagnostic group, primarily involving decreased BOLD responses among CD-MM patients in comparison to HCs, were observed during anticipatory reward and loss processing within regions of posterior cingulate cortex, precuneus, inferior frontal gyrus and dorsolateral prefrontal cortex. BOLD responses within the right caudate were negatively associated with percentage of cocaine-negative urines during treatment among CD-MM patients, but not among non-methadone-maintained CD patients. ConclusionsThese data suggest neurofunctional differences that may be related to treatment outcomes for behavioral therapies between cocaine-dependent individuals with and without methadone-maintenance treatment. These findings may relate to differences in treatment efficacies and to the elevated relapse rates observed in methadone-maintained populations.

A delta-opioid receptor genetic variant is associated with abstinence prior to and during cocaine dependence treatment

IntroductionAn intronic polymorphism in the delta-opioid receptor gene (OPRD1) was previously associated with cocaine dependence in African-Americans. However, it is not known if the polymorphism (rs678849) is associated with dependence-related phenotypes within the cocaine dependent population. MethodsCocaine and alcohol dependent subjects were randomized to either topiramate or placebo. Abstinence from cocaine use was confirmed by urine drug screens for benzoylecgonine three times per week. Cocaine withdrawal and craving were assessed at randomization using the Cocaine Selective Severity Assessment (CSSA) and Minnesota Cocaine Craving Scale (MCCS), respectively. Subjects were also interviewed using the Addiction Severity Index (ASI). Genotype at rs678849 was determined for 105 African-American subjects and compared to cocaine abstinence, as well as scores for CSSA, MCCS, and ASI. ResultsAfrican-American patients with the C/T or T/T genotypes (n=40) were more likely to be abstinent at the first urine drug screen and more likely to be abstinent for the week prior to randomization compared to patients with the C/C genotype (n=65). Subjects carrying the T allele were also more likely to have abstinent weeks over the course of the trial compared to those with the C/C genotype (RR=1.88, 95% CI=1.59-2.22, p=0.0035). No effects of rs678849 genotype on withdrawal, craving, or addiction severity were observed. ConclusionsA polymorphism in OPRD1 appears to be associated with both cocaine dependence and cocaine use during treatment in African-Americans. Follow-up studies to confirm the effect on cocaine use are warranted.

Placebo-controlled evaluation of a bioengineered, cocaine-metabolizing fusion protein, TV-1380 (AlbuBChE), in the treatment of cocaine dependence

BackgroundTV‐1380 (AlbuChE) is a novel recombinant fusion protein of mutated butyrylcholinesterase (BChE) that has increased catalytic efficiency for cocaine metabolism compared to wild-type BChE. MethodsIntra-muscular injections of TV-1380 (150mg or 300mg) or placebo were administered once weekly to participants (n=66–69 per group) in a randomized, double-blind study to evaluate the ability of TV-1380 to facilitate abstinence in treatment-seeking, cocaine-dependent individuals. The primary endpoint was the proportion of participants achieving abstinence from cocaine during the last three weeks of the 12 week treatment phase, based on daily self-report of “no use” confirmed by urine testing. ResultsAlthough there were no significant differences between the TV-1380 treatment groups and placebo for the primary endpoint, 6% of participants in the 150mg and 300mg TV-1380 groups and no participants in the placebo group achieved abstinence. For the only declared secondary endpoint, there was a dose-dependent increase in the group mean percentage of urine samples testing negative for cocaine metabolites during weeks 5–12 (8.1% and 14.6% for the 150mg and 300mg TV-1380 groups, respectively, compared to 4.7% for the placebo group; p=0.0056 for 300mg vs. placebo). No meaningful differences in adverse events were seen between treatment groups. ConclusionsWhile the apparent reduction in cocaine use may be of insufficient magnitude to justify further trials of TV-1380 in cocaine dependence, the results argue for development of improved enzymes with greater catalytic activity.

Development of a translational model to screen medications for cocaine use disorder I: Choice between cocaine and food in rhesus monkeys

BackgroundHomologous cocaine self-administration procedures in laboratory animals and humans may facilitate translational research for medications development to treat cocaine dependence. This study, therefore, sought to establish choice between cocaine and an alternative reinforcer in rhesus monkeys responding under a procedure back-translated from previous human studies and homologous to a human laboratory procedure described in a companion paper. MethodsFour rhesus monkeys with chronic indwelling intravenous catheters had access to cocaine injections (0, 0.043, 0.14, or 0.43mg/kg/injection) and food (0, 1, 3, or 10 1g banana-flavored food pellets). During daily 5h sessions, a single cocaine dose and a single food-reinforcer magnitude were available in 10 30-min trials. During the initial “sample” trial, the available cocaine and food reinforcer were delivered non-contingently. During each of the subsequent nine “choice” trials, responding could produce either the cocaine or food reinforcer under an independent concurrent progressive-ratio schedule. ResultsPreference was governed by the cocaine dose and food-reinforcer magnitude, and increasing cocaine doses produced dose-dependent increases in cocaine choice at all food-reinforcer magnitudes. Effects of the candidate medication lisdexamfetamine (0.32–3.2mg/kg/day) were then examined on choice between 0.14mg/kg/injection cocaine and 10 pellets. Under baseline conditions, this reinforcer pair maintained an average of approximately 6 cocaine and 3 food choices. Lisdexamfetamine dose-dependently decreased cocaine choice in all monkeys, but food choice was not significantly altered. ConclusionsThese results support utility of this procedure in rhesus monkeys as one component of a platform for translational research on medications development to treat cocaine use disorder.