Cocaine-dependent Individuals Research Articles

Combined Use of Cognitive Behavioral Therapy (CBT) and Its Healing Impact on Drug Abusers Who Are Addicted to Drugs: A Scoping Review

Aims: The aim of this study is to assist individuals in healing from addiction; it is essential to implement a combination of interventions, such as CBT, that are proven to be effective in treating drug abuse with a holistic approach that integrates psychological and social aspects for optimal results, according to empirical evidence. Methods: The search databases for this study were PubMed, ScienceDirect, and Google Scholar. Identify articles published in the last 10 years (2014-2024), Randomized Control Trials (RCTs), English and Indonesian, Full-Text, and Teenagers to the Elderly. Using the PRISMA flowchart, data extraction and scoping with keywords (English): "Drug Addict OR Substance Abuse AND Cognitive Behaviour Therapy AND Dependence OR Substance-Related Disorder" and keywords in the Indonesian language "Pecandu Narkoba OR Penyalahguna Zat AND Cognitive Behaviour Therapy AND Ketergantungan OR Gangguan Terkait Zat." Results: The study found eight articles that met the criteria, the main findings showed the use of Modified Cognitive Behavioral Therapy (M-CBT) in enhancing recovery motivation among cocaine-dependent individuals. Interventions such as galantamine, C-CBT, and computer-based CBT also show promise in reducing cocaine use. Additionally, combining CBT with contingency management (CM) facilitates changes in neural activity related to cognitive control. CBT paired with MET+ABI+ATTI and Female-Specific CBT (FS-CBT) effectively addresses alcohol use in adolescents and women. Conclusion: This study highlights various CBT approaches that can be combined, such as M-CBT for cocaine independence and computer-based CBT, as well as the combination of CBT with contingent management that influences neural activity related to cognitive control.

Resting-State Functional Connectivity of the Dorsal and Ventral Striatum, Impulsivity, and Severity of Use in Recently Abstinent Cocaine-Dependent Individuals.

Previous studies have focused on both ventral striatum (VS) and dorsal striatum (DS) in characterizing dopaminergic deficits in addiction. Animal studies suggest VS and DS dysfunction each in association with impulsive and compulsive cocaine use during early and later stages of addiction. However, few human studies have aimed to distinguish the roles of VS and DS dysfunction in cocaine misuse. We examined VS and DS resting-state functional connectivity (rsFC) of 122 recently abstinent cocaine-dependent individuals (CDs) and 122 healthy controls (HCs) in 2 separate cohorts. We followed published routines in imaging data analyses and evaluated the results at a corrected threshold with age, sex, years of drinking, and smoking accounted for. CDs relative to HCs showed higher VS rsFC with the left inferior frontal cortex (IFC), lower VS rsFC with the hippocampus, and higher DS rsFC with the left orbitofrontal cortex. Region-of-interest analyses confirmed the findings in the 2 cohorts examined separately. In CDs, VS-left IFC and VS-hippocampus connectivity was positively and negatively correlated with average monthly cocaine use in the prior year, respectively. In the second cohort where participants were assessed with the Barratt Impulsivity Scale (BIS-11), VS-left IFC and VS-hippocampus connectivity was also positively and negatively correlated with BIS-11 scores in CDs. In contrast, DS-orbitofrontal cortex connectivity did not relate significantly to cocaine use metrics or BIS-11 scores. These findings associate VS rsFC with impulsivity and the severity of recent cocaine use. How DS connectivity partakes in cocaine misuse remains to be investigated.

Cues Associated with Social Defeat Stress Recruit CRF in the Nucleus Accumbens and Invigorate Drug‐Seeking following Abstinence from Cocaine

Cocaine‐dependent individuals experience intense drug cravings in anticipation of imminent drug availability. Notably, acute stressors can further exacerbate the heightened state of arousal produced by drug‐related stimuli and increase propensity to seek and consume drug – rendering individuals highly susceptible to relapse. The present studies extend ongoing work examining the stress peptide corticotropin releasing factor (CRF) as a candidate mechanism for maladaptive arousal evoked by drug‐predictive stimuli. In rats, CRF enhances instrumental behavior directed towards gaining access to cocaine, in part through local control of DA transmission in the nucleus accumbens (NAc). Because CRF modulates motivational states in both appetitive and aversive contexts, we explored the extent to which an ecologically relevant stressor (ie social defeat) augments cocaine self‐administration under a chained operant response sequence (ie seeking‐taking), and whether NAc‐CRF is recruited. On alternating days, male Long‐Evans rats were exposed to acute social defeat in the presence of a compound stimulus (CS+: peppermint odor + 3kHz tone) or placed in an empty cage (CS‐: almond odor + 25kHz tone) for 4 sessions each. Microdialysis conducted in the presence of the conditioned cues revealed that the stress‐CS+ produced a rapid increase in both CRF and DA in the NAc, which was temporally distinct from a delayed rise in corticosterone. Separate rats were trained to self‐administer cocaine under a chained schedule of reinforcement (FI‐FR) in order to dissociate anticipatory (‘drug‐seeking’) from consummatory (‘drug‐taking’) behavior. Completion of a fixed‐interval (5m) produced access to continuous cocaine reinforcement (FR1) on a separate lever (5m). Here, accelerating responding across the FI captures an index of arousal in anticipation of impending drug‐availability – ostensibly, when craving is heightened. After a 7d drug‐free (ABST) period, rats were reintroduced to the drug context to self‐administer cocaine in the presence of either the stress‐paired stimuli (CS+) or neutral cues (CS‐) in a counterbalanced manner. Compared to pre‐ABST baseline, responding during the FI was elevated under both stimulus conditions, presumably reflecting an “incubation”‐like enhancement of behavior. Critically, CS+ exposure produced significantly higher anticipatory responding for cocaine than the neutral condition (CS+> CS‐ > Baseline), suggesting that stress stimuli augmented the effects of ABST. Cocaine intake was unaffected by either condition. These data support the concept that environmental stressors can amplify the impact of being re‐exposed to a drug‐context after a period of abstinence, such to invigorate putative “drug‐seeking” behavior. Anticipation of threat may engage common motivational salience circuits that generate arousal during cocaine expectation, whereas the unconditioned aspects of drug‐reward are differentially controlled. Ongoing studies seek to further clarify the functional role of stress‐evoked NAc‐CRF in cocaine‐related behavior.

Brain systems in cocaine abstinence-induced anxiety-like behavior in rodents: A review

Cocaine use disorder (CUD) is a significant public health issue that generates substantial personal, familial, and economic burdens. Still, there are no FDA-approved pharmacotherapies for CUD. Cocaine-dependent individuals report anxiety during withdrawal, and alleviation of anxiety and other negative affective states may be critical for maintaining drug abstinence. However, the neurobiological mechanisms underlying abstinence-related anxiety in humans or anxiety-like behavior in rodents are not fully understood. This review summarizes investigations regarding anxiety-like behavior in mice and rats undergoing cocaine abstinence, as assessed using four of the most common anxiety-related assays: the elevated plus (or its derivative, the elevated zero) maze, open field test, light-dark transition test, and defensive burying task. We first summarize available evidence that cocaine abstinence generates anxiety-like behavior that persists throughout protracted abstinence. Then, we examine investigations concerning neuropeptide, neurotransmitter, and neuromodulator systems in cocaine abstinence-induced anxiety-like behavior. Throughout, we discuss how differences in sex, rodent strain, cocaine dose and dosing strategy, and abstinence duration interact to generate anxiety-like behavior.

Mean corrected generalized estimating equations for longitudinal binary outcomes with report bias.

Cocaine addiction is an important public health problem worldwide. Cognitive-behavioral therapy is a counseling intervention for supporting cocaine-dependent individuals through recovery and relapse prevention. It may reduce patients' cocaine uses by improving their motivations and enabling them to recognize risky situations. To study the effect of cognitive behavioral therapy on cocaine dependence, the self-reported cocaine use with urine test data were collected at the Primary Care Center of Yale-New Haven Hospital. Its outcomes are binary, including both the daily self-reported drug uses and weekly urine test results. To date, the generalized estimating equations are widely used to analyze binary data with repeated measures. However, due to the existence of significant self-report bias in the self-reported cocaine use with urine test data, a direct application of the generalized estimating equations approach may not be valid. In this paper, we proposed a novel mean corrected generalized estimating equations approach for analyzing longitudinal binary outcomes subject to reporting bias. The mean corrected generalized estimating equations can provide consistently and asymptotically normally distributed estimators under true contamination probabilities. In the self-reported cocaine use with urine test study, accurate weekly urine test results are used to detect contamination. The superior performances of the proposed method are illustrated by both simulation studies and real data analysis.

Methylation of the serotonin transporter gene moderates the depressive subjective effect of cocaine

Genetic variation in the serotonin transporter (SLC6A4) has been shown to moderate the acute subjective effects of cocaine. Methylation of the SLC6A4 gene is associated with decreased transcription of the serotonin transporter, leading to increased serotonin in the synapse. In this study, methylation of the SLC6A4 gene was investigated in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N = 53) were intravenously administered cocaine (40 mg) and saline in a randomized order. The subjective effects of cocaine were self-reported using a visual analog scale starting prior to the administration of cocaine (−15 min) or saline and up to 20 min after infusion. Participants were evaluated for methylation of the SLC6A4 promoter region and 5-HTTLPR genotype. A series of ANCOVAs for SLC6A4 methylation (high/low) were run for each of ten subjective and three cardiovascular effects controlling for age, sex [utilizing the sex-determining region Y protein (SRY)], and population structure (determined from ancestry informative markers and STRUCTURE software). Participants with SLC6A4 hypermethylation reported greater subjective response to cocaine for ‘depressed’ relative to participants with SLC6A4 hypomethylation (experiment-wise p = 0.002). These findings indicate that SLC6A4 methylation moderates the ‘depressed’ subjective effect of cocaine in non-treatment-seeking cocaine-dependent participants.

Methylation of the tyrosine hydroxylase gene is dysregulated by cocaine dependence in the human striatum

SummaryCocaine dependence is a chronic, relapsing disorder caused by lasting changes in the brain. Animal studies have identified cocaine-related alterations in striatal DNA methylation; however, it is unclear how methylation is related to cocaine dependence in humans. We generated methylomic profiles of the nucleus accumbens using human postmortem brains from a cohort of individuals with cocaine dependence and healthy controls (n = 25 per group). We found hypermethylation in a cluster of CpGs within the gene body of tyrosine hydroxylase (TH), containing a putative binding site for the early growth response 1 (EGR1) transcription factor, which is hypermethylated in the caudate nucleus of cocaine-dependent individuals. We replicated this finding and found it to be specific to striatal neuronal nuclei. Furthermore, this locus demonstrates enhancer activity which is attenuated by methylation and enhanced by EGR1 overexpression. These results suggest that cocaine dependence alters the epigenetic regulation of dopaminergic signaling genes.

Reward-Related Responses and Tonic Craving in Cocaine Addiction: An Imaging Study of the Monetary Incentive Delay Task.

BackgroundCocaine addiction is associated with altered sensitivity to natural reinforcers and intense drug craving. However, previous findings on reward-related responses were mixed, and few studies have examined whether reward responses relate to tonic cocaine craving.MethodsWe combined functional magnetic resonance imaging and a monetary incentive delay task to investigate these issues. Imaging data were processed with published routines, and the results were evaluated with a corrected threshold. We compared reward responses of 50 cocaine-dependent individuals (CDs) and 45 healthy controls (HCs) for the ventral striatum (VS) and the whole brain. We also examined the regional responses in association with tonic cocaine craving, as assessed by the Cocaine Craving Questionnaire (CCQ) in CDs. We performed mediation analyses to evaluate the relationship between regional responses, CCQ score, and recent cocaine use.ResultsThe VS showed higher activation to large as compared with small or no wins, but this reward-related activity did not differ between CDs and HCs. The precentral gyrus (PCG), anterior insula, and supplementary motor area showed higher activation during large vs no wins in positive correlation with the CCQ score in CDs. Mediation analyses suggested that days of cocaine use in the prior month contributed to higher CCQ scores and, in turn, PCG reward responses.ConclusionsThe results highlight a unique relationship between reward responses of the primary motor cortex, tonic cocaine craving, and recent cocaine use. The motor cortex may partake in the cognitive motor processes critical to drug-seeking behavior in addicted individuals.

Resting state hypothalamic and dorsomedial prefrontal cortical connectivity of the periaqueductal gray in cocaine addiction.

Cocaine-dependent (CD) individuals demonstrate significant anxiety and dysphoria during withdrawal, a negative emotional state that may perpetuate drug seeking and consumption. An extensive body of work has focused on characterizing reward circuit dysfunction, but relatively little is known about the pain circuit during cocaine withdrawal. In an earlier study, we highlighted how cue-elicited functional connectivity between the periaqueductal gray (PAG), a subcortical hub of the pain circuit, and ventromedial prefrontal cortex supports tonic craving in recently abstinent CD. The functional organization of the brain can be characterized by intrinsic connectivities, and it is highly likely that the resting state functional connectivity (rsFC) of the PAG may also be altered in association with cocaine use variables. Here, we examined this issue in 52 CD and 52 healthy control (HC) participants. Imaging data were processed with published routines, and the findings were evaluated with a corrected threshold. In a covariance analysis, CD as compared with HC showed higher PAG rsFC with the hypothalamus, dorsomedial prefrontal, and inferior parietal cortices. Further, these connectivities were correlated negatively with tonic cocaine craving and recent cocaine use, respectively. Higher hypothalamic and frontoparietal rsFC with the PAG may reflect a compensatory process to regulate craving and compulsive drug use. The findings provide additional evidence in humans implicating the PAG circuit and may help research of the role of negative reinforcement in sustaining habitual drug use in cocaine addiction.

Common and gender-specific associations with cocaine use on gray matter volume: Data from the ENIGMA addiction working group.

Gray matter volume (GMV) in frontal cortical and limbic regions is susceptible to cocaine‐associated reductions in cocaine‐dependent individuals (CD) and is negatively associated with duration of cocaine use. Gender differences in CD individuals have been reported clinically and in the context of neural responses to cue‐induced craving and stress reactivity. The variability of GMV in select brain areas between men and women (e.g., limbic regions) underscores the importance of exploring interaction effects between gender and cocaine dependence on brain structure. Therefore, voxel‐based morphometry data derived from the ENIGMA Addiction Consortium were used to investigate potential gender differences in GMV in CD individuals compared to matched controls (CTL). T1‐weighted MRI scans and clinical data were pooled from seven sites yielding 420 gender‐ and age‐matched participants: CD men (CDM, n = 140); CD women (CDW, n = 70); control men (CTLM, n = 140); and control women (CTLW, n = 70). Differences in GMV were assessed using a 2 × 2 ANCOVA, and voxelwise whole‐brain linear regressions were conducted to explore relationships between GMV and duration of cocaine use. All analyses were corrected for age, total intracranial volume, and site. Diagnostic differences were predominantly found in frontal regions (CD < CTL). Interestingly, gender × diagnosis interactions in the left anterior insula and left lingual gyrus were also documented, driven by differences in women (CDW < CTLW). Further, lower right hippocampal GMV was associated with greater cocaine duration in CDM. Given the importance of the anterior insula to interoception and the hippocampus to learning contextual associations, results may point to gender‐specific mechanisms in cocaine addiction.

Dysregulation of Decision Making Related to Metabotropic Glutamate 5, but Not Midbrain D3, Receptor Availability Following Cocaine Self-administration in Rats

BackgroundCompulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships among drug-induced alterations, cocaine taking, and maladaptive decision-making processes, however, are difficult to establish in humans. MethodsWe assessed decision making in adult male rats using a probabilistic reversal learning task and used positron emission tomography with the [11C]-(+)-PHNO and [18F]FPEB radioligands to quantify regional dopamine D2/3 and metabotropic glutamate 5 (mGlu5) receptor availability, respectively, before and after 21 days of cocaine or saline self-administration. Tests of motivation and relapse-like behaviors were also conducted. ResultsWe found that self-administration of cocaine, but not of saline, disrupted behavior in the probabilistic reversal learning task measured by selective impairments in negative-outcome updating and also increased cortical mGlu5 receptor availability following 2 weeks of forced abstinence. D2/3 and, importantly, midbrain D3 receptor availability was not altered following 2 weeks of abstinence from cocaine. Notably, the degree of the cocaine-induced increase in cortical mGlu5 receptor availability was related to the degree of disruption in negative-outcome updating. ConclusionsThese findings suggest that cocaine-induced changes in mGlu5 signaling may be a mechanism by which disruptions in negative-outcome updating emerge in cocaine-dependent individuals.

Randomized controlled trial of d-cycloserine in cocaine dependence: Effects on contingency management and cue-induced cocaine craving in a naturalistic setting.

Cocaine dependence constitutes a significant public health concern. This randomized, double-blind, placebo-controlled trial tested a novel approach to reducing cocaine use among cocaine-dependent individuals with d-cycloserine, a drug known to enhance learning and some learning-based therapies. Urine samples and cocaine craving were assessed across three phases: induction (Weeks 1-2), treatment (Weeks 3-5; urinalysis-based contingency management plus exposure therapy), and posttreatment (Weeks 6-7). During the treatment phase, either 50 mg of d-cycloserine or placebo was administered after delivery of urinalysis feedback with potential monetary reward and before exposure therapy sessions in naturalistic contexts individually associated with cocaine use. d-cycloserine significantly improved learning on an operant laboratory task. Contingency management significantly reduced cocaine use and craving. d-cycloserine did not significantly affect cocaine use or craving in the treatment phase. Craving significantly increased for the d-cycloserine group during the post treatment phase. Therefore, although the study showed that d-cycloserine was capable of improving learning, enhancement of learning-based therapy was not observed. Moreover, no differences in behavioral measures of cocaine demand (cocaine purchasing task) or monetary or sexual delay discounting were observed across phases or between groups in any phase. These results are somewhat consistent with previous findings suggesting that d-cycloserine administration increases cocaine craving, although they differ from other findings showing that d-cycloserine administration reduces alcohol or nicotine cravings. Methodological variables (e.g., guided vs. unguided exposure therapy sessions, length of extinction exposure) likely play a role in dissimilar findings observed across studies. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

N-acetylcysteine reduces cocaine-seeking behavior and anterior cingulate glutamate/glutamine levels among cocaine-dependent individuals.

N-acetylcysteine (NAC) is a cystine prodrug shown to reduce cocaine- and cue-primed reinstatement of cocaine-seeking behavior in preclinical studies. In this inpatient study, the effects of NAC maintenance versus placebo on cocaine-seeking behavior were examined during cocaine-primed and unprimed self-administration sessions among non-treatment-seeking, cocaine-dependent individuals. Twelve participants completed this double-blind, placebo-controlled, within-subject crossover study. Each participant was maintained for 1 week (Sat-Fri) on NAC (1200-mg TID; 3600 mg/day total) and 1 week on placebo (0-mg TID); medication order was randomized. A subset of participants underwent proton magnetic resonance spectroscopy scans (n = 8) on the third day of medication (Mon) to assess neurochemistry in the rostral anterior cingulate (rACC; voxel = 4.5 cm3 ). In four randomized sessions (Tue-Fri) each week, each participant could earn unit amounts of cocaine (10 mg, fixed) versus money ($0.50 vs. $1.50) on a choice, progressive ratio schedule after insufflating active versus placebo cocaine-priming doses (110 mg vs. 4 mg). Relative to the placebo priming dose, the active cocaine priming dose (110 mg) increased cocaine-seeking behavior (p = .003). NAC reduced cocaine-primed cocaine-seeking behavior compared with placebo levels (p = .044) but did not alter placebo-primed cocaine-seeking behavior. The larger money alternative ($1.50) suppressed cocaine-seeking behavior relative to the smaller money alternative ($0.50; p = .011). Compared with placebo levels, NAC significantly decreased rACC glutamate + glutamine levels (p = .035) and numerically decreased rACC glutamate levels (p = .085). These preliminary findings indicate that NAC suppresses cocaine-seeking behavior in some, but not all, experimental scenarios. Further, our findings suggest NAC may exert its therapeutic effects by modulating excitatory tone in the rACC.

Interpersonal Risk Factors for Suicide in Cocaine Dependence: Association with Self‐Esteem, Personality Traits, and Childhood Abuse

Studies have linked cocaine dependence to suicidality. According to the Interpersonal Theory of Suicide, suicidal behavior becomes likely with the simultaneous presence of perceived burdensomeness (PB), lack of (or thwarted) belongingness (TB), and acquired fearlessness about death (FAD). Here, we examined personality and other variables, including depression, self-esteem, childhood abuse, and substance use, as predictors of these risk factors in cocaine-dependent individuals (CDs). Seventy CDs and 70 healthy controls (HCs) participated. We examined group differences in a group-by-sex analysis of variance and identified predictors of PB, TB, and FAD in stepwise regressions. CDs exhibited elevated PB and TB but not FAD, compared to HCs. CDs also exhibited elevated harm avoidance, novelty seeking, depression, and lower self-esteem and reward dependence. Females reported elevated sexual abuse, harm avoidance, reward dependence, depression, but lower FAD, relative to males, among CDs and HCs. Among CDs, PB was predicted by lower self-esteem and greater emotional abuse; TB was predicted by lower self-esteem and reward dependence, as well as greater emotional and sexual abuse; and FAD was predicted by lower harm avoidance and greater physical abuse. Interventions targeting suicidality in cocaine dependence should take into consideration self-esteem, personality traits, and childhood abuse.

The neural interface between negative emotion regulation and motivation for change in cocaine dependent individuals under treatment

BackgroundEmotion regulation is important for cocaine addiction treatment success, particularly during early abstinence. In addition, the neural underpinnings of emotion processing overlap with those of motivation and goal-directed behavior. We examined if the neural underpinnings of emotion maintenance and its regulation correlate with cocaine treatment motivation. MethodsForty-five cocaine dependent individuals (CDIs) starting outpatient treatment in a public specialized addiction treatment clinic in Granada (Spain) underwent fMRI scans while performing a Reappraisal task, and completed the University of Rhode Island Change Assessment Scale (URICA), to measure treatment motivation. We conducted correlation analyses to examine the association between emotion maintenance and regulation related brain activation and URICA’s Readiness to Change scores. We also explored links between Emotional reports during the fMRI reappraisal task, duration of abstinence, and anxiety and depression symptoms. ResultsReadiness to Change scores were positively correlated with activations in the right dorsolateral prefrontal and right parietal cortices, the midbrain (p ≤ 0.001, cluster extents ≥109 voxels), and basolateral amygdala (PFWE-SVC<0.05), while negatively with emotion maintenance related activation in the same cortical areas and activations in the dorsomedial frontal cortex, the nucleus accumbens and the left fusiform gyrus. Emotional reactivity negatively correlated with right dorsolateral prefrontal cortex reappraisal related activation (r= -0.40, p = 0.007), and the Regulate score positively correlated with the left fusiform gyrus emotion maintenance related activation (r = 0.31, p = 0.04). ConclusionsEmotional related activation in frontoparietal, accumbens, fusiform, amygdala and midbrain regions engaged during emotion regulation and its maintenance correlate with early treatment motivation in CDIs.

Perspectives of cocaine users on addiction recovery: a qualitative study following a CRA + vouchers programme

Addiction recovery has gained considerable attention over the past few years. Despite the diffuse conceptualization of ‘recovery’, a range of studies have been conducted on what recovery means. Even though cocaine is the most frequently used stimulant drug, little qualitative research has been done on recovery from cocaine addiction. This study provides more insight into the personal perspectives of (former) cocaine-dependent individuals. In-depth interviews (n = 23) were conducted in a cocaine-specific treatment programme (CRA + vouchers) in Belgium. According to respondents, cocaine addiction recovery is a process that concerns an identity shift, building on personal strengths and utilizing sources of support from the close social network and society. The results showed some specific features regarding the recovery process of individuals in recovery from cocaine addiction, since ‘socially integrated’ cocaine users had a head start due to advantages such as being employed and having a social network. Support should be tailored to the specific needs of individuals in recovery and social networks and communities that support recovery are needed.

Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca2+ channels.

Cocaine-associated memories are critical drivers of relapse in cocaine-dependent individuals that can be evoked by exposure to cocaine or stress. Whether these environmental stimuli recruit similar molecular and circuit-level mechanisms to promote relapse remains largely unknown. Here, using cocaine- and stress-primed reinstatement of cocaine conditioned place preference to model drug-associated memories, we find that cocaine drives reinstatement by increasing the duration that mice spend in the previously cocaine-paired context whereas stress increases the number of entries into this context. Importantly, both forms of reinstatement require Cav1.2 L-type Ca2+ channels (LTCCs) in cells of the prelimbic cortex that project to the nucleus accumbens core (PrL→NAcC). Utilizing fiber photometry to measure circuit activity in vivo in conjunction with the LTCC blocker, isradipine, we find that LTCCs drive differential recruitment of the PrL→ NAcC pathway during cocaine- and stress-primed reinstatement. While cocaine selectively activates PrL→NAcC cells prior to entry into the cocaine-paired chamber, a measure that is predictive of duration in that chamber, stress increases persistent activity of this projection, which correlates with entries into the cocaine-paired chamber. Using projection-specific chemogenetic manipulations, we show that PrL→NAcC activity is required for both cocaine- and stress-primed reinstatement, and that activation of this projection in Cav1.2-deficient mice restores reinstatement. These data indicate that LTCCs are a common mediator of cocaine- and stress-primed reinstatement. However, they engage different patterns of behavior and PrL→NAcC projection activity depending on the environmental stimuli. These findings establish a framework to further study how different environmental experiences can drive relapse, and supports further exploration of isradipine, an FDA-approved LTCC blocker, as a potential therapeutic for the prevention of relapse in cocaine-dependent individuals.

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.

State-Dependent Effects of Ventromedial Prefrontal Cortex Continuous Thetaburst Stimulation on Cocaine Cue Reactivity in Chronic Cocaine Users.

Cue-induced craving is a significant barrier to obtaining abstinence from cocaine. Neuroimaging research has shown that cocaine cue exposure evokes elevated activity in a network of frontal-striatal brain regions involved in drug craving and drug seeking. Prior research from our laboratory has demonstrated that when targeted at the medial prefrontal cortex (mPFC), continuous theta burst stimulation (cTBS), an inhibitory form of non-invasive brain stimulation, can decrease drug cue-related activity in the striatum in cocaine users and alcohol users. However, it is known that there are individual differences in response to repetitive transcranial magnetic stimulation (rTMS), with some individuals being responders and others non-responders. There is some evidence that state-dependent effects influence response to rTMS, with baseline neural state predicting rTMS treatment outcomes. In this single-blind, active sham-controlled crossover study, we assess the striatum as a biomarker of treatment response by determining if baseline drug cue reactivity in the striatum influences striatal response to mPFC cTBS. The brain response to cocaine cues was measured in 19 cocaine-dependent individuals immediately before and after real and sham cTBS (110% resting motor threshold, 3600 total pulses). Group independent component analysis (ICA) revealed a prominent striatum network comprised of bilateral caudate, putamen, and nucleus accumbens, which was modulated by the cocaine cue reactivity task. Baseline drug cue reactivity in this striatal network was inversely related to change in striatum reactivity after real (vs. sham) cTBS treatment (ρ = -.79; p < .001; R 2 Adj = .58). Specifically, individuals with a high striatal response to cocaine cues at baseline had significantly attenuated striatal activity after real but not sham cTBS (t 9 = -3.76; p ≤ .005). These data demonstrate that the effects of mPFC cTBS on the neural circuitry of craving are not uniform and may depend on an individual’s baseline frontal-striatal reactivity to cues. This underscores the importance of assessing individual variability as we develop brain stimulation treatments for addiction.

A Multicenter, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Long-Acting Injectable Formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) for Cocaine Relapse Prevention

Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) for treatment of cocaine-dependent patients. Design, Setting, and Participants: A 12-week, A multicenter, randomized, placebo-controlled trial conducted between June 2009-July 2011, at 17 Hospital-based drug clinics, in the 15 countries. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 cocaine use disorder. Of the 2800 patients who were assessed between March 10, 2009 to August 10, 2010, 2600 (93%) were eligible and willing to take part in the trial and were enrolled: 1300 were randomly assigned to receive injections of Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) given intramuscularly once in 12 weeks and 1300 to receive Placebo injections, given intramuscularly once in 12 weeks. Only 100 of 2800 patients (3.6%) did not meet the inclusion criteria. Main Outcomes and Measures: The primary endpoints (protocol) were: Confirmed Cocaine abstinence (percentage i.e. the number of patients who achieved complete abstinence during 12 weeks). Confirmed abstinence or “cocaine-free” was defined as a negative urine drug test for cocaines and no self-reported cocaine use. Secondary end points included a number of days in treatment, treatment retention and craving. The study also investigated, on 275 participants, degree and time course of Central Dopamine transporter receptor occupancy following single doses of long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) as well as the plasma concentration of Vanoxerine and 17-hydroxyl Vanoxerine. Safety was assessed by adverse event reporting. Results: Of 2600 participants, mean (SD) age was 28.5 (±5.5) years and 598 (23%) were women. 1300 individuals were randomized to receive injections of Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) and 1300 to receive injections of Placebo. 1417 participants (54.5.0%) completed the trial. Primary Endpoints: Confirmed Cocaine Abstinence: Complete abstinence was sustained by 72% (n = 936) of Vanoxerine patients (patients treated with Vanoxerine Consta 394.2 mg, long-acting depot formulations) compared with 37% (n = 481) of patients treated with Placebo, during weeks 5 - 12. The difference was significant as evaluated using a Chi-square test (χ2 = 672.34, P < 0.0001). Secondary Endpoint: Craving: A statistically and clinically significant reduction in cocaine craving was observed with Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) vs. Placeboby week 4 (P = 0.0048), which persisted every week through 12 (P < 0.0001). Patients given Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) had a 87% decrease in craving from baseline to 12th week. Patients given a Placebo had a 2% increase in craving from baseline to 12th week. Secondary Endpoint: Treatment Retention: Long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) helped significantly more patients complete 12 weeks treatment (n = 936, 72%) compared with Placebo (n = 481, 37%) (χ2 = 635.53, P < 0.0001). Patients on the long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) had longer treatment retention than patients on Placebo. Concentrations of Vanoxerine and 17-Hydroxyl Vanoxerinein Plasma: Analyses were made of 275 study samples. There was no statistically significant difference for plasma Vanoxerine concentrations between days 2 and 84 (p = 0.416). The plasma concentration of Vanoxerine were 70.4 and 94.3 ng/ml and concentrations of 17-hydroxyl Vanoxerine were 10.5 and 13.2 ng/ml, respectively. Plasma levels of Vanoxerine remained above 70 ng/ml for approximately 12 weeks after administration of Vanoxerine, long-acting depot formulations (Vanoxerine Consta 394.2 mg). PET Assessments: Very high central dopamine transporter receptor occupancy by Vanoxerine was detected 1 day after treatments, at which time point the occupancy was 100.0% after Vanoxerine injection (Vanoxerine Consta 394.2 mg). At days 7, 28, 56 and 84 post-Vanoxerine Consta 394.2 mg administration, occupancies were 95% to 79%. Vanoxerine Consta 394.2 mg injection (long-acting intramuscular formulation of Vanoxerine) led to very high occupancy of Central Dopamine transporter receptors in all brain areas examined; nucleus accumbens, caudate nucleus and putamen. Depending on the brain area Central Dopamine transporter receptor occupancy varied between 95.0% and 79% at days 7, 28, 56 and 84 after dosing. High Vanoxerine occupancy (77%) persisted at 12 weeks after the dosings. Adverse Reactions: Adverse events were similar in cocaine-dependent patients treated with the long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) vs. patients treated with Placebo. Conclusions and Relevance: Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) were more effective than Placebo injection in maintaining short-term abstinence from cocaine and should be considered as a treatment option for cocaine-dependent individuals.