RESUMEN

RATIONALE: Cocaine use disorder (CUD) is a brain disorder for which there is no Food and Drug Administration-approved pharmacological treatment. Evidence suggests that glutamate and metabotropic glutamate receptor subtype 5 (mGlu5) play critical roles in synaptic plasticity, neuronal development, and psychiatric disorders. OBJECTIVE: In the present study, we tested the hypothesis that the mGlu5 receptor is functionally involved in intravenous cocaine self-administration and assessed the effects of sex and cocaine exposure history. METHODS: We used a preclinical model of CUD in rats that were allowed long access (LgA; 6 h/day) or short access (ShA; 1 h/day) to intravenous cocaine (750 µg/kg/infusion [0.1 ml]) self-administration. Rats received acute intraperitoneal or oral administration of the mGlu5 receptor negative allosteric modulator mavoglurant (1, 3, and 10 mg/kg) or vehicle. RESULTS: Both intraperitoneal and oral mavoglurant administration dose-dependently reduced intravenous cocaine self-administration in the first hour and in the entire 6 h session in rats in the LgA group, with no effect on locomotion. In the ShA group, mavoglurant decreased locomotion but had no effects on cocaine self-administration. We did not observe significant sex × treatment interactions. CONCLUSIONS: These findings suggest that the mGlu5 receptor is involved in escalated cocaine self-administration. These findings support the development of clinical trials of mavoglurant to evaluate its potential therapeutic benefits for CUD.

RESUMEN

BACKGROUND: Illicit stimulant use remains a public health concern that has been associated with multiple adverse outcomes, including cognitive deficits. The effects of stimulant use on cognition may be particularly deleterious in persons with HIV. Stimulant use intensity may be an important factor in the magnitude of observed deficits over time. METHODS: We completed neurocognitive testing in a sample of people who use stimulants with (n = 84) and without HIV (n = 123) at baseline and up to 4 follow-up time points over approximately 1 year. Participants reported on substance use at each visit, including frequency of use and stimulant dependence. Mixed effects models examined the relationship between stimulant-related factors and neurocognitive function over time. RESULTS: Participants were mostly male (57%), African American (86%), and 47.41 years old on average. All participants actively used stimulants at enrollment and use remained prevalent throughout the follow-up period, with an average of ≥24 days of use in the past 90 days at all time points. Retention was excellent, with 86% completing all 4 follow-up assessments. Mixed effects models showed that stimulant dependence was associated with lower neurocognitive performance independent of HIV status (p = 0.002), whereas frequency of use had a greater negative impact on performance in participants with HIV compared to those without HIV (p = 0.045). CONCLUSIONS: Our key finding is that stimulant-related factors are associated with neurocognitive performance over time, but in complex ways. These findings have important implications for harm reduction approaches, particularly those that target cognitive function.

RESUMEN

Crack-cocaine dependence is a severe condition with a high mortality rate. This single case study report details the first deep brain stimulation (DBS) trial targeting the sub-thalamic nucleus (STN) for crack-cocaine dependence. The investigation aimed to assess the effects of STN-DBS on cocaine craving and cocaine use, as well as STN-DBS safety and tolerance in this indication. In this pilot study, we performed double blind cross-over trials, with "ON-DBS" vs. "SHAM-DBS" for 1-month periods. STN-DBS failed to reduce cocaine craving and use. An episode of DBS-induced hypomania occurred after several weeks of cocaine intake at stimulation parameters previously well tolerated. Future research on cocaine dependence should be conducted after a prolonged abstinence period and/or explore novel types of stimulation patterns.

RESUMEN

Resting state functional magnetic resonance imaging (fMRI) has been used to study functional connectivity of brain networks in addictions. However, most studies to-date have focused on the default mode network (DMN) with fewer studies assessing the executive control network (ECN) and salience network (SN), despite well-documented cognitive executive behavioral deficits in addictions. The present study assessed the functional and effective connectivity of the ECN, DMN, and SN in cocaine dependent subjects (CD) (n = 22) compared to healthy control subjects (HC) (n = 22) matched on age and education. This study also investigated the relationship between impulsivity measured by delay discounting and functional and effective connectivity of the ECN, DMN, and SN. The Left ECN (LECN), Right ECN (RECN), DMN, and SN functional networks were identified using FSL MELODIC independent component analysis. Functional connectivity differences between CD and HC were assessed using FSL Dual Regression analysis and FSLNets. Effective connectivity differences between CD and HC were measured using the Parametric Empirical Bayes module of Dynamic Causal Modeling. The relationship between delay discounting and functional and effective connectivity were examined using regression analyses. Dynamic causal modeling (DCM) analysis showed strong evidence (posterior probability > 0.95) for CD to have greater effective connectivity than HC in the RECN to LECN pathway when tobacco use was included as a factor in the model. DCM analysis showed strong evidence for a positive association between delay discounting and effective connectivity for the RECN to LECN pathway and for the DMN to DMN self-connection. There was strong evidence for a negative association between delay discounting and effective connectivity for the DMN to RECN pathway and for the SN to DMN pathway. Results also showed strong evidence for a negative association between delay discounting and effective connectivity for the RECN to SN pathway in CD but a positive association in HC. These novel findings provide preliminary support that RECN effective connectivity may differ between CD and HC after controlling for tobacco use. RECN effective connectivity may also relate to tobacco use and impulsivity as measured by delay discounting.

RESUMEN

Introduction: Cocaine use disorder (CUD) is a disabling disease associated with high rates of relapse and intense cravings. Patients with CUD struggle to adhere to treatment, which contributes to relapse and frequent readmissions to residential rehab (RR) facilities. Preliminary studies suggest that N-acetylcysteine (NAC) attenuates cocaine-induced neuroplasticity and, therefore, may assist with cocaine abstinence and adherence to treatment. Methods: This retrospective cohort study obtained data from 20 RR facilities across Western New York. Eligible subjects were 18 or older, diagnosed with CUD, and were divided based on their exposure to 1200 mg NAC twice daily during RR. The primary outcome was treatment adherence measured by outpatient treatment attendance rates (OTA). Secondary outcomes included length of stay (LOS) in RR and craving severity on a 1 to 100 visual analog scale. Results: One hundred eighty-eight (N = 188) patients were included in this investigation: NAC, n = 90; control, n = 98. NAC did not significantly impact OTA (% appointments attended), NAC 68%; control 69%, (P = .89) or craving severity NAC 34 ± 26; control 30 ± 27, (P = .38). Subjects treated with NAC had a significantly longer average LOS in RR compared with controls, NAC 86 ± 30; control 78 ± 26, (P = .04). Discussion: In this study, NAC did not impact treatment adherence but was associated with a significantly longer LOS in RR for patients with CUD. Owing to limitations, these results may not be applicable to the general population. More rigorous studies examining NAC's impact on treatment adherence in CUD are warranted.

RESUMEN

Borderline personality disorder (BPD) and substance use disorders (SUDs) commonly co-occur across various settings. However, little research has examined how BPD features relate to specific types of SUDs. This study examined whether BPD features assessed shortly after incarceration were differentially related to symptoms of dependence on alcohol, cannabis, cocaine, and opioids experienced in the 12 months prior to incarceration among 510 people recently incarcerated in jail. Follow-up multigroup analyses evaluated whether gender or race moderated the relation of BPD features to the four SUDs. Using structural equational modeling, the relationships of BPD features were compared to each of the four preincarceration dependence symptoms. BPD features were significantly related to dependence on each of the four substances, but the link between BPD features and cocaine dependence was stronger than BPD's association with alcohol, cannabis, or opioid dependence. These findings generalized across men and women and across White and Black people.

Asunto(s)

RESUMEN

Psychostimulant use disorder is a major health issue around the world with enormous individual, family-related and societal consequences, yet there are no effective pharmacological treatments available. In this review, a target-based overview of pharmacological treatments toward psychostimulant addiction will be presented. We will go through therapeutic approaches targeting different aspects of psychostimulant addiction with focus on three major areas; 1) drugs targeting signalling, and metabolism of the dopamine system, 2) drugs targeting either AMPA receptors or metabotropic glutamate receptors of the glutamate system and 3) drugs targeting the severe side-effects of quitting long-term psychostimulant use. For each of these major modes of intervention, findings from pre-clinical studies in rodents to clinical trials in humans will be listed, and future perspectives of the different treatment strategies as well as their potential side-effects will be discussed. Pharmaceuticals modulating the dopamine system, such as antipsychotics, DAT-inhibitors, and disulfiram, have shown some promising results. Cognitive enhancers have been found to increase aspects of behavioural control, and drugs targeting the glutamate system such as modulators of metabotropic glutamate receptors and AMPA receptors have provided interesting changes in relapse behaviour. Furthermore, CRF-antagonists directed toward alleviating the symptoms of the withdrawal stage have been examined with interesting resulting changes in behaviour. There are promising results investigating therapeutics for psychostimulant addiction, but further preclinical work and additional human studies with a more stratified patient selection are needed to prove sufficient evidence of efficacy and tolerability.

RESUMEN

Background: Different drugs damage the frontal cortices, particularly the prefrontal areas involved in both emotional and cognitive functions, with a consequence of decoding emotion deficits for people with substance abuse. The present study aimed to explore the cognitive impairments in drug abusers through facial, body and disgust emotion recognition, expanding the investigation of emotions processing, measuring accuracy and response velocity. Methods: We enrolled 13 addicted to cocaine and 12 alcohol patients attending treatment services in Italy, comparing them with 33 matched controls. Facial emotion and body posture recognition tasks, a disgust rating task and the Barrat Impulsivity Scale were included in the experimental assessment. Results: We found that emotional processes are differently influenced by cocaine and alcohol, suggesting that these substances impact diverse cerebral systems. Conclusions: Drug abusers seem to be less accurate on elaboration of facial, body and disgust emotions. Considering that the participants were not cognitively impaired, our data support the hypothesis that emotional impairments emerge independently from the damage of cognitive functions.

RESUMEN

BACKGROUND: In the context of changing cannabis and other drug policy and regulation, concerns may arise regarding drug treatment access and use. We assessed cannabis/cocaine-related dependence and treatment in Argentina, Chile, and Uruguay. METHODS: Nationally representative cross-sectional household surveys of people ages 15-64 in Argentina (4 surveys, 2006-2017), Chile (7 surveys, 2006-2018), and Uruguay (4 surveys, 2006-2018) were harmonized. We estimated weighted prevalences of cannabis or cocaine-related (cocaine or cocaine paste) dependence, based on meeting 3+ past-year ICD-10 dependence criteria. We estimated weighted prevalences of past-year alcohol/drug treatment use (Argentina, Chile) or use/seeking (Uruguay) among people with past-year cannabis/cocaine-related dependence. We tested model-based prevalence trends over time and described individual-level treatment correlates by country. RESULTS: Cannabis/cocaine dependence prevalence increased in the region starting in 2010-2011, driven by cannabis dependence. Adjusted cannabis dependence prevalence increased from 0.7% in 2010 to 1.5% in 2017 in Argentina (aPD=0.8, 95% CI= 0.3, 1.2), from 0.8% in 2010 to 2.8% in 2018 in Chile (aPD=2.0, 95% CI= 1.4, 2.6), and from 1.4% in 2011 to 2.4% in 2018 in Uruguay (aPD=0.9, 95% CI= 0.2, 1.6). Cocaine-related dependence increased in Uruguay, decreased in Argentina, and remained stable in Chile. Among people with past-year cannabis/cocaine dependence, average alcohol/drug treatment use prevalence was 15.3% in Argentina and 6.0% in Chile, while treatment use/seeking was 14.7% in Uruguay. Alcohol/drug treatment prevalence was lower among people with cannabis dependence than cocaine-related dependence. Treatment correlates included older ages in all countries and male sex in Argentina only. CONCLUSION: Alcohol/drug treatment use among people with cannabis/cocaine-related dependence remained low, signaling an ongoing treatment gap in the context of growing cannabis dependence prevalence in the region. Additional resources may be needed to increase treatment access and uptake. Future studies should assess contributors of low treatment use, including perceived need, stigma, and service availability.

Asunto(s)

RESUMEN

BACKGROUND: Cocaine 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. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: The 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.

Asunto(s)

RESUMEN

Cocaine dependence (CD) is highly comorbid with personality disorders, with implications for poorer treatment response. The neurobiological mechanisms of this comorbidity are unclear. We aimed to test the role of comorbid personality disorders in the neuroanatomy of CD. We examined 4 groups using high-resolution structural neuroimaging, psychological questionnaires and cognitive tests: CD (n = 19), CD and personality disorder type B (CD + B, n = 21), CD and personality disorder C (CD + C, n = 13) and 21 controls. We compared groups in neuroanatomy and hypothesised that (i) CD would show altered striatal areas ascribed to reward processing (i.e., accumbens, caudate and putamen), (ii) CD + B and CD + C would show altered areas supporting emotional regulation/social valuation and anxiety/avoidance (i.e., OFC and amygdala). The CD + B group had larger caudate volumes than CD (p = .01, d = 0.94) and reduced lateral OFC thickness than CD + C (p = .056, d = 0.71). Exploratory correlations showed that altered neural integrity of the OFC and of the caudate nucleus in these groups exacerbated with worse personality disorder severity and impulsivity scores. CD with and without comorbid personality disorders may have partially distinct underlying mechanisms and targets for treatment.

Asunto(s)

RESUMEN

Social cognition plays a crucial role in the development and treatment of cocaine dependence. However, studies investigating social cognition, such as empathy and its underlying neural basis, are lacking. To explore the neural interactions among reward and memory circuits, we applied effective connectivity analysis on resting-state fMRI data collected from cocaine-dependent subjects. The relationship between effective connectivity within these two important circuits and empathy ability - evaluated with the Interpersonal Reactivity Index (IRI) - was assessed by machine learning algorithm using multivariate regression analysis. In accordance with the neurocircuitry disruptions of cocaine addiction, the results showed that cocaine-dependent subjects relative to healthy controls had altered resting state effective connectivity between parts of the memory and reward systems. Furthermore, effective connectivity between the memory and reward system could predict the fantasy empathy (FE) subscale scores in cocaine dependence. Overall, our findings provide further evidence for the neural substrates of social cognition in cocaine-dependent patients. These new insights could be useful for the development of new treatment programs for this substance dependency disorder.

Asunto(s)

RESUMEN

A large and growing body of literature supports the association between cocaine addiction and impulsivity. The aim of the study was to test whether pretreatment screening for adult ADHD, and self-report and behavioral measures of impulsivity have prognostic utility in clinical practice with cocaine users. We enrolled a cohort of N = 86 treatment-seeking cocaine users, assisted by a public addiction service, in a 24 week study. At baseline, we performed screening for adult ADHD, assessed the presence of co-occurring mental disorders, and applied measures of drug use severity, trait-like impulsivity (Barratt Impulsiveness Scale; BIS-11), decision-making (Iowa Gambling Task; IGT), risk-taking (Balloon Analogue Risk Task; BART), and ability to inhibit cognitive interference (Stroop Color Word Test; SCWT). Patients positive to the screening for ADHD showed a higher level of self-reported impulsivity and a longer history of drug use, but did not differ from those without ADHD in adherence to psychosocial treatments and number of negative urines for cocaine during the 24 weeks. Among all of the self-report and behavioral measures used, only IGT BIS-11 was associated with cocaine abstention. The small effect size and the problematic direction of the associations found do not give strong support to the routine use of self-regulation measures to guide clinical decisions in public addiction treatment settings.

Asunto(s)

RESUMEN

We tested the predictive validity of the Progress Assessment (PA), a brief counselor administered tool for use in measurement-based care for substance use disorders. The PA includes 5 items assessing relapse risk and 5 items assessing factors protective against relapse. Data were drawn from a completed study of continuing care for cocaine dependence (McKay et al., 2013) and includes 12 months of follow-up on158 participants (76% male) who received brief telephone or face-to-face sessions. Each session began with the administration of the PA, followed by cognitive-behavioral counseling tied to the results of the PA and anticipated risky situations. Outcome was assessed via urine toxicology every 3 months. As administered in an effectiveness trial, average PA risk and protective scales within each 3-month segment of the study predicted urine toxicology results at the end of that period, with higher risk scores and lower protective scores predicting greater rates of cocaine positive urine drug screens. PA scores did not predict dropout from continuing care participation. The 10-item PA shows promise as a pragmatic clinical tool for ongoing monitoring during continuing care for substance dependence.

Asunto(s)

RESUMEN

We integrated genomic and bioinformatic analyses, using data from the largest genome-wide association study of cocaine dependence (CD; n = 6546; 82.37% with CD; 57.39% male) and the largest postmortem gene-expression sample of individuals with cocaine use disorder (CUD; n = 36; 51.35% with CUD; 100% male). Our genome-wide analyses identified one novel gene (NDUFB9) associated with the genetic predisposition to CD in African-Americans. The genetic architecture of CD was similar across ancestries. Individual genes associated with CD demonstrated modest overlap across European-Americans and African-Americans, but the genetic liability for CD converged on many similar tissue types (brain, heart, blood, liver) across ancestries. In a separate sample, we investigated the neuronal gene expression associated with CUD by using RNA sequencing of dorsal-lateral prefrontal cortex neurons. We identified 133 genes differentially expressed between CUD case patients and cocaine-free control subjects, including previously implicated candidates for cocaine use/addiction (FOSB, ARC, KCNJ9/GIRK3, NR4A2, JUNB, and MECP2). Differential expression analyses significantly correlated across European-Americans and African-Americans. While genes significantly associated with CD via genome-wide methods were not differentially expressed, two of these genes (NDUFB9 and C1qL2) were part of a robust gene coexpression network associated with CUD involved in neurotransmission (GABA, acetylcholine, serotonin, and dopamine) and drug addiction. We then used a "guilt-by-association" approach to unravel the biological relevance of NDUFB9 and C1qL2 in the context of CD. In sum, our study furthers the understanding of the genetic architecture and molecular neuropathology of human cocaine addiction and provides a framework for translating biological meaning into otherwise obscure genome-wide associations.SIGNIFICANCE STATEMENT Our study further clarifies the genetic and neurobiological contributions to cocaine addiction, provides a rapid approach for generating testable hypotheses for specific candidates identified by genome-wide research, and investigates the cross-ancestral biological contributions to cocaine use disorder/dependence for individuals of European-American and African-American ancestries.

Asunto(s)

RESUMEN

OBJECTIVE: The present investigation tested the association of a novel measure of brain activation recorded during a simple motor inhibition task with a GRM8 genetic locus implicated in risk for substance dependence. METHODS: 122 European-American adults were genotyped at rs1361995 and evaluated against DSM-IV criteria for Alcohol Dependence, Cocaine Dependence, Conduct Disorder, and Antisocial Personality Disorder. Also, their brain activity was recorded in response to rare, so-called "No-Go" stimuli presented during a continuous performance test. Brain activity was quantified with two indices: (1) the amplitude of the No-Go P300 electroencephalographic response averaged across trials; and (2) the inter-trial variability of the response. RESULTS: The absence of the minor allele at the candidate locus was associated with all of the evaluated diagnoses. In comparison to minor allele carriers, major allele homozygotes also demonstrated increased inter-trial variability in No-Go P300 response amplitude but no difference in average amplitude. CONCLUSIONS: GRM8 genotype is associated with Alcohol and Cocaine Dependence as well as personality risk factors for dependence. The association may be mediated through an inherited instability in brain function that affects cognitive control. SIGNIFICANCE: The present study focuses on a metric and brain mechanism not typically considered or theorized in studies of patients with substance use disorders.

Asunto(s)

RESUMEN

Pathological gambling and cocaine dependence are highly pervasive disorders. Functional neuroimaging evidence implicates aberrant activity of prefrontal striatal pathways in both disorders. It is unclear if the neuroanatomy of these areas is also affected. Participants with pathological gambling (n = 18), cocaine dependence (n = 19) and controls (n = 21) underwent high-resolution structural MRI scan and cognitive assessments. In line with emerging functional neuroimaging findings, we hypothesised (i) lower volumes of corticostriatal areas ascribed to decision-making/inhibitory control, craving and reward processing (i.e., orbitofrontal cortex, inferior frontal gyrus, amygdala, striatum, insula) in both pathological gamblers and cocaine dependent participants versus controls; (ii) selected dopaminergic/glutamatergic pathways directly taxed by cocaine (i.e., superior, dorsolateral and anterior cingulate cortices) would be altered in cocaine dependent versus control participants only. Analyses were conducted with a bonferroni correction. Our results showed that both pathological gambling and cocaine dependent participants, compared to controls, had larger volumes of the right inferior frontal gyrus (ps <.01, ds = 0.66 and 0.62). Cocaine dependent participants had lower nucleus accumbens and medial orbitofrontal cortex volumes than pathological gamblers (ps <.05, ds = 0.51 and 0.72), with the latter being predicted by higher negative urgency scores. Inferior frontal gyrus volume may reflect common alterations of cocaine and gambling addictions, whereas cocaine dependence may be uniquely associated with reduced volume in dorsolateral and middle frontal regions. Cocaine's supra-physiological effects on mesolimbic neurons may explain reduced accumbens-orbitofrontal structure compared to gambling.

Asunto(s)

RESUMEN

BACKGROUND: This project offers new epidemiological estimates for DSM-IV cocaine dependence among sub-groups of newly incident cocaine users in the United States (US), including estimated attack rates for 21 dependence-related cocaine side effect problems and experiences occurring <12 months after onset. METHOD: In 2002-2016, US National Surveys on Drug Use and Health (NSDUH) sampled, recruited, and assessed cocaine experiences of non-institutionalized civilians. Unweighted estimates for year-pairs (2002-3,…,2015-16) are from 3488 cocaine powder-only initiates and 275 powder-then-crack initiates (all evaluated <12 months after onset). Analysis-weighted attack rate estimates are incidence proportions with 95% confidence intervals (CI), summarized via meta-analysis. RESULTS: Evaluated <12 months after onset, meta-analysis summaries show 5% of powder-only initiates developed cocaine dependence (95% CI = 4%, 6%) versus 22% of powder-then-crack initiates (95% CI = 17%, 29%). For several cocaine side effect problems and experiences (e.g., 'loss of control' indicators) there is a statistically robust crack-associated excess risk. CONCLUSIONS: Three interpretations of observed crack-associated excess risk are especially cogent and deserving of continued inquiry: (1) Powder-then-crack initiates start with heightened dependence risk susceptibilities (i.e., pre-dating onset); (2) Powder-using initiates become cocaine dependent and then start using crack; (3) The cocaine delivery variant of 'crack-smoking' is more toxic than powder insufflation. For powder-then-crack initiates, the cocaine dependence risk (22%) is modestly lower but statistically undifferentiable from a recently estimated risk of heroin dependence <12 months after heroin onset (30%). Clinicians can use these side effect estimates in an evidence-based diagnostic workup when patients disclose new onsets of cocaine use.

Asunto(s)

RESUMEN

BACKGROUND: Cocaine use disorder (CUD) remains a substantial public health problem with no clearly effective pharmacotherapy available. In a prior trial, combined amphetamine and topiramate treatment significantly reduced cocaine use among individuals demonstrating the most frequent use at baseline. This trial targeted such frequent users. METHODS: A double-blind, randomized placebo-controlled trial, testing the combination of mixed amphetamine salts extended-release (MAS-ER) and topiramate or placebo over a 12-week medication phase was conducted. The two-site outpatient trial included 127 adults (96 males) with CUD using at least 9 days in the prior month. MAS-ER was titrated to a maximum dose of 60 mg/day and topiramate to a maximum dose of 100 mg twice/day. The primary outcome was the proportion of individuals who achieved three consecutive abstinent weeks at the end of the study (EOS) as measured by urine toxicology and self-report. RESULTS: The proportion of participants achieving three abstinent weeks at the EOS was significantly (P = .03) larger in the treatment (14.1%) compared to the placebo group (0.0%), while controlling for baseline cocaine use, sex, current alcohol use disorder, and site. Of note, due to conservative cardiac safety-parameters a considerable number of individuals in the treatment group were discontinued from study medication (20.3%). CONCLUSIONS: While these findings provide further evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in CUD adults with frequent use it remains possible that the combination treatment is no more effective than either treatment alone. Despite this, the study provides a valuable "proof of concept."

Asunto(s)

RESUMEN

We investigated the genetic and molecular architecture of cocaine dependence (CD) and cocaine use by integrating genome-/transcriptome-wide analyses. To prioritize candidates for follow-up investigation, we also sought to translate gene expression findings across species. Using data from the largest genome-wide association study (GWAS) of CD to date (n = 3176, 74% with CD), we assessed genomic heritability, gene-based associations, and tissue enrichment. We detected a significant single-nucleotide polymorphism heritability of 28% for CD and identified three genes (two loci) underlying this predisposition: the C1qL2 (complement component C1 q like 2), KCTD20 (potassium channel tetramerization domain containing 20), and STK38 (serine/threonine kinase 38) genes. Tissue enrichment analyses indicated robust enrichment in numerous brain regions, including the hippocampus. We used postmortem human hippocampal RNA-sequencing data from previous study (n = 15, seven chronic cocaine users) to follow up genome-wide results and to identify differentially expressed genes/transcripts and gene networks underlying cocaine use. Cross-species analyses utilized hippocampal gene expression from a mouse model of cocaine use. Differentially expressed genes/transcripts in humans were enriched for the genes nominally associated with CD via GWAS (P < 0.05) and for differentially expressed genes in the hippocampus of cocaine-exposed mice. We identified KCTD20 as a central component of a hippocampal gene network strongly associated with human cocaine use, and this gene network was conserved in the mouse hippocampus. We outline a framework to map and translate genome-wide findings onto tissue-specific gene expression, which provided biological insight into cocaine use/dependence.

Asunto(s)