Treat Cocaine Use Research Articles

Cocaine affects astrocyte activation and iNOS expression

It is estimated that there are more than two million people addicted to cocaine in the United States. How cocaine affects neuronal functions has been extensively studied. Astrocytes, an important member of the neurovascular unit, also play significant roles in brain pathology. However, their role in cocaine use disorder is unclear. Astrocytes are glial cells that support the neurons and maintain the blood‐brain barrier. Astrocytes can express inducible nitric oxide synthase (iNOS) that is responsible for the transient production of nitric oxide (NO). Both iNOS and NO have been reported to be actively involved in cocaine addiction. We hypothesize that cocaine can cause astrocyte activation and inflammation, resulting in iNOS upregulation, which can in turn, affect both neuronal and brain microvascular endothelial functions. To test this hypothesis, an in vitro astrocyte culture model and an in vivo chronic cocaine mouse model were used. In the in vitro model, human astrocytes from the cerebrocortex were treated with cocaine (10μM) (or lipopolysaccharide at 2μg/mL as the positive control) for 24 hours. iNOS expression was measured using solid‐phase ELISA. Astrocyte activation was assessed by immunofluorescence microscopy for Glial Fibrillary Acidic Protein (GFAP) expression. Changes in astrocyte morphology were quantified using a Sholl analysis. In the in vivo model, wild type C57BL/6 mice were treated with cocaine (30 mg/kg per day through intraperitoneal injection) for two weeks. Mouse brain tissue, especially in the prefrontal cortex, was collected and fixed with paraformaldehyde before slicing. Astrocyte activation and number were quantified using immunofluorescence microscopy (of GFAP). Astrocyte iNOS expression was measured using an iNOS ELISA kit (using collected mouse brain homogenate). The results demonstrated that lipopolysaccharide (LPS, the endotoxin) significantly increased iNOS expression after 24hr treatment. Cocaine, in comparison, had a more significant impact in iNOS upregulation in early passages of cultured astrocytes. Sholl analysis demonstrated that cocaine and LPS both induced significant morphological changes and reduced the number of astrocyte processes. Results obtained from the in vivo studies indicated that chronic cocaine treatment significantly decreased the number of astrocytes in the mouse prefrontal cortex, while increasing iNOS expression. In summary, astrocytes can respond to cocaine stimulation in vitro and in vivo, likely through iNOS‐medicated inflammatory responses. Therefore, investigation in the role of astrocytes in cocaine addiction may bring insight to new therapeutic target to treat cocaine use disorder.

Genetic and epigenetic analysis of the serotonin 2A receptor in the context of cocaine abuse

ABSTRACT Despite more than 2 million American cocaine users monthly, there is no approved drug for treating cocaine use disorder. Cocaine use disorder has a multifactorial aetiology, including both genetic and environmental factors. Both cocaine use and genetic variations demonstrably alter DNA methylation and gene expression in the brain in a complex manner. How these factors interact in the context of cocaine abuse in humans is unknown. We propose that we can identify potential drug targets for treating cocaine use disorders by examining genetic, epigenetic, and expression changes in the brains of individuals that abused cocaine. In this study, we identified the interaction between the epigenetics changes (DNA CpG methylation) and genetic variants (SNPs) in the HTR2A gene in the context of cocaine addiction by using brain tissue collected from individuals that overdosed on cocaine (N = 14) and healthy matched controls (N = 16). We generated DNA CpG methylation profiles in eight regions of HTR2A harbouring frequent SNPs, measuring both allelic and total methylation, and compared these methylation profiles with HTR2A mRNA expression. Furthermore, we examined the influence of common variants rs6311 and rs6313 on cocaine abuse, methylation, and gene expression. We found evidence that rs6311 regulates HTR2A methylation, consistent with earlier studies. Furthermore, the minor alleles for rs6311 and rs6313 are associated with significantly increased expression of a splice isoform in which exon 2 is truncated in both cocaine and control samples. These results reveal specific roles for HTR2A in the context of cocaine abuse, highlighting opportunities to modulate this target for treating cocaine use disorder.

The effects of combination levodopa-ropinirole on cognitive improvement and treatment outcome in individuals with cocaine use disorder: A bayesian mediation analysis

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

MC-100093, a Novel β-Lactam Glutamate Transporter-1 Enhancer Devoid of Antimicrobial Properties, Attenuates Cocaine Relapse in Rats.

Cocaine use disorder currently lacks Food and Drug Administration-approved treatments. In rodents, the glutamate transporter-1 (GLT-1) is downregulated in the nucleus accumbens after cocaine self-administration, and increasing the expression and function of GLT-1 reduces the reinstatement of cocaine seeking. The β-lactam antibiotic ceftriaxone upregulates GLT-1 and attenuates cue- and cocaine-induced cocaine seeking without affecting motivation for natural rewards. Although ceftriaxone shows promise for treating cocaine use disorder, it possesses characteristics that limit successful translation from bench to bedside, including poor brain penetration, a lack of oral bioavailability, and a risk of bacterial resistance when used chronically. Thus, we aimed to develop novel molecules that retained the GLT-1-enhancing effects of ceftriaxone but displayed superior drug-like properties. Here, we describe a new monocyclic β-lactam, MC-100093, as a potent upregulator of GLT-1 that is orally bioavailable and devoid of antimicrobial properties. MC-100093 was synthesized and tested in vitro and in vivo to determine physiochemical, pharmacokinetic, and pharmacodynamic properties. Next, adult male rats underwent cocaine self-administration and extinction training. During extinction training, rats received one of four doses of MC-100093 for 6-8 days prior to a single cue-primed reinstatement test. Separate cohorts of rats were used to assess nucleus accumbens GLT-1 expression and MC-100093 effects on sucrose self-administration. We found that 50 mg/kg MC-100093 attenuated cue-primed reinstatement of cocaine seeking while upregulating GLT-1 expression in the nucleus accumbens core. This dose did not produce sedation, nor did it decrease sucrose consumption or body weight. Thus, MC-100093 represents a potential treatment to reduce cocaine relapse. SIGNIFICANCE STATEMENT: Increasing GLT-1 activity reliably reduces drug-seeking across classes of drugs; however, existing GLT1-enhancers have side effects and lack oral bioavailability. To address this issue, novel GLT-1 enhancers were synthesized, and the compound with the most favorable pharmacokinetic and pharmacodynamic properties, MC-100093, was selected for further testing. MC-100093 attenuated cued cocaine seeking without reducing food seeking or locomotion and upregulated GLT-1 expression in the nucleus accumbens.

Acute impact of self-guided mental imagery on craving in cocaine use disorder: a mixed-methods analysis of a randomized controlled trial.

A quantitative-qualitative 'mixed-methods' analysis of data collected for a randomized controlled trial that was stopped prematurely. UK National Health Service addictions treatment clinic and outpatient clinical research facility (laboratory). Adults with CUD. The original target sample was 120. All participants enrolled at the point the original trial was stopped were included (38 enrolled, 31 completed study). Personalized (3-minute) cue-exposure (handling cocaine paraphernalia and watching video of drug preparation), immediately followed by a single 5-minute, audio-recorded, self-guided and verbally described imagery task with random assignment to one of four conditions: two mental imagery memory re-experiences (positive image before initiation to cocaine use or a negative image of a 'worst time' adverse cocaine use episode) or two future simulations (positive theme of recovery from CUD or negative theme of worsened CUD). Task transcripts were rated for imagery detail using five dimensions using a six-point scale of imagery detail (ID) (total score=0-25) and thematically coded. The outcome measure was cocaine craving using the Craving Experiences Questionnaire-strengths version (CEQ-S11; score=0-110) reported at baseline, arrival at the laboratory, and immediately after the cue-exposure and mental imagery tasks. A mixed-effects, longitudinal, restricted linear regression, with the past-positive imagery condition as referent, showed main effects of reduced craving after the imagery task (b=-29.2, 95% confidence interval (CI)=-45.3 to -13.1, P-value <0.001) and increased craving for the future-negative task (b=14.2, 95% CI=0.1-28.4, P-value 0.049). There was a future-negative task by post-imagery craving interaction (b=28.1, 95% CI=0.1-56.1, P-value 0.049). A theory-driven, deductive/inductive qualitative analysis of the transcripts revealed six major themes: sensory characteristics, CUD vicious cycle, self-care, emotions and appraisals, social role and CUD recovery. Positively themed simulations included interpersonal connections and rewarding activity; negative images included personal adversity, with appraisals of self-criticism and hopelessness. Transcripts with more imagery detail were not associated with significantly greater reductions in craving in the positive or negative imagery task (r =-0.32, 95% CI=-0.69 to 0.13 and r=0.06, 95% CI=-0.58 to 0.53, respectively). In people with cocaine use disorder, after cue-exposure, a self-guided imagery task with positive themes reduced craving, whereas mental imagery simulating worsened cocaine use disorder did not appear to.

Pharmacokinetic study of three different formulations of l-tetrahydropalmatine in brain tissues of rats.

l-Tetrahydropalmatine (l-THP), an active alkaloid compound isolated from Rhizoma Corydalis-yanhusuo, has been reported to possess biological activity for treating cocaine use. To enhance both oral bioavailability and brain penetration, three formulations of l-THP suspension, mixture of l-THP-puerarin and self-microemulsifying drug delivery systems (SMEDDS) were prepared. A sensitive and reliable ultra-high-performance liquid chromatography with tandem mass spectrometry method was developed and validated for the simultaneous determination of l-THP and its active metabolite l-isocorypalmine (l-ICP) in rat brain. Diazepam was used as the internal standard. The chromatographic separation was achieved on a Bonshell ASB C18 column at 30°C using acetonitrile-aqueous formic acid as mobile phase in gradient mode. The linearity was validated over the concentration ranges of 4.00-2,500 ng/ml for l-THP and 0.400-500 ng/ml for l-ICP. Full method validation was within the acceptance limits. The method was successfully used to determine the pharmacokinetics of two analytes following oral administration of these three formulations to rats. A significant difference was observed in the main pharmacokinetic parameters between SMEDDS and the suspension, and a 3.25- and 2.97-fold increase in the relative bioavailability of l-THP and l-ICP, respectively, was observed with the SMEDDS compared with the suspension formulation. It was concluded that SMEDDS enhanced the absorption of l-THP and l-ICP and delayed their release in brain.

GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA.

An emerging preclinical literature suggests that targeting central glucagon-like peptide-1 receptors (GLP-1Rs) may represent a novel approach to treating cocaine use disorder. However, the exact neural circuits and cell types that mediate the suppressive effects of GLP-1R agonists on cocaine-seeking behavior are largely unknown. The laterodorsal tegmental nucleus (LDTg) expresses GLP-1Rs and functions as a neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the primary source of central GLP-1, with midbrain and forebrain nuclei known to regulate cocaine-seeking behavior. The goal of this study was to characterize the role of LDTg GLP-1R-expressing neurons and their projections to the ventral tegmental area (VTA) in the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we showed that administration of the GLP-1R agonist exendin-4 (Ex-4) directly into the LDTg significantly attenuated cocaine seeking at a dose that did not affect sucrose seeking, ad libitum food intake or body weight. Additionally, our studies revealed that selectively activating NTS-to-LDTg circuits attenuated cocaine seeking via a GLP-1R-dependent mechanism. We also demonstrated, for the first time, that GLP-1Rs are expressed primarily on GABAergic neurons in the LDTg and that the efficacy of Ex-4 to reduce cocaine seeking depends, in part, on activation of LDTg-to-VTA GABAergic projections. Taken together, these studies identify a central mechanism by which Ex-4 attenuates cocaine seeking and highlight GABAergic GLP-1R-expressing circuits in the midbrain as important anti-craving pathways in regulating cocaine craving-induced relapse.

Beta-caryophyllene inhibits cocaine addiction-related behavior by activation of PPARα and PPARγ: repurposing a FDA-approved food additive for cocaine use disorder.

Cocaine abuse continues to be a serious health problem worldwide. Despite intense research, there is still no FDA-approved medication to treat cocaine use disorder (CUD). In this report, we explored the potential utility of beta-caryophyllene (BCP), an FDA-approved food additive for the treatment of CUD. We found that BCP, when administered intraperitoneally or intragastrically, dose-dependently attenuated cocaine self-administration, cocaine-conditioned place preference, and cocaine-primed reinstatement of drug seeking in rats. In contrast, BCP failed to alter food self-administration or cocaine-induced hyperactivity. It also failed to maintain self-administration in a drug substitution test, suggesting that BCP has no abuse potential. BCP was previously reported to be a selective CB2 receptor agonist. Unexpectedly, pharmacological blockade or genetic deletion of CB1, CB2, or GPR55 receptors in gene-knockout mice failed to alter BCP's action against cocaine self-administration, suggesting the involvement of non-CB1, non-CB2, and non-GPR55 receptor mechanisms. Furthermore, pharmacological blockade of μ opioid receptor or Toll-like receptors complex failed to alter, while blockade of peroxisome proliferator-activated receptors (PPARα, PPARγ) reversed BCP-induced reduction in cocaine self-administration, suggesting the involvement of PPARα and PPARγ in BCP's action. Finally, we used electrical and optogenetic intracranial self-stimulation (eICSS, oICSS) paradigms to study the underlying neural substrate mechanisms. We found that BCP is more effective in attenuation of cocaine-enhanced oICSS than eICSS, the former driven by optical activation of midbrain dopamine neurons in DAT-cre mice. These findings indicate that BCP may be useful for the treatment of CUD, likely by stimulation of PPARα and PPARγ in the mesolimbic system.

Pharmacotherapeutic strategies for treating cocaine use disorder-what do we have to offer?

Cocaine use contines to be a significant public health problem world-wide. However, despite substantial research efforts, no pharmacotherapies are approved for the treatment of cocaine use disorder (CUD). Studies have identified positive signals for a range of medications for treating CUD. These include long-acting amphetamine formulations, modafinil, topiramate, doxazosin and combined topiramate and mixed amphetamine salts extended-release (MAS-ER). However, valid conclusions about a medication's clinical efficacy require nuanced approaches that take into account behavioural phenotypes of the target population (frequency of use, co-abuse of cocaine and other substances, genetic subgroups, psychiatric comorbidity), variables related to the medication (dose, short-/long-acting formulations, titration speed, medication adherence) and other factors that may affect treatment outcomes. Meta-analyses frequently do not account for these co-varying factors, which contributes to a somewhat nihilistic view on pharmacotherapeutic options for CUD. In addition, the predominant focus on abstinence, which is difficult for most patients to achieve, may overshadow more nuanced therapeutic signals. While there is an emphasis on finding new medications with novel mechanisms of action for treating CUD, currently available medications deserve further investigation based on the existing literature. Evaluating refined metrics of treatment success in well-defined subgroups of patients, and further exploring combination therapies and their synergy with behavioural/psychosocial interventions, are promising avenues to establishing effective therapies for CUD.

Learning from lorcaserin: lessons from the negative clinical trial of lorcaserin to treat cocaine use disorder.

Learning from lorcaserin: lessons from the negative clinical trial of lorcaserin to treat cocaine use disorder.

Environmental enrichment during forced abstinence from cocaine self-administration opposes gene network expression changes associated with the incubation effect

Environmental enrichment (EE) is a robust intervention for reducing cocaine-seeking behaviors in animals when given during forced abstinence. However, the mechanisms that underlie these effects are not well-established. We investigated the adult male rat transcriptome using RNA-sequencing (RNA-seq) following differential housing during forced abstinence from cocaine self-administration for either 1 or 21 days. Enriched, 21-day forced abstinence rats displayed a significant reduction in cocaine-seeking behavior compared to rats housed in isolation. RNA-seq of the nucleus accumbens shell revealed hundreds of differentially regulated transcripts between rats of different forced abstinence length and housing environment, as well as within specific contrasts such as enrichment (isolated 21 days vs. enriched 21 days) or incubation (isolated 1 day vs. isolated 21 days). Ingenuity Pathway Analysis affirmed several pathways as differentially enriched based on housing condition and forced abstinence length including RELN, the Eif2 signaling pathway, synaptogenesis and neurogenesis pathways. Numerous pathways showed upregulation with incubation, but downregulation with EE, suggesting that EE may prevent or reverse changes in gene expression associated with protracted forced abstinence. The findings reveal novel candidate mechanisms involved in the protective effects of EE against cocaine seeking, which may inform efforts to develop pharmacological and gene therapies for treating cocaine use disorders. Furthermore, the finding that EE opposes multiple pathway changes associated with incubation of cocaine seeking strongly supports EE as a therapeutic intervention and suggests EE is capable of preventing or reversing the widespread dysregulation of signaling pathways that occurs during cocaine forced abstinence.

TAAR1 agonists attenuate extended-access cocaine self-administration and yohimbine-induced reinstatement of cocaine-seeking.

The trace amine-associated receptor 1 (TAAR1) negatively modulates dopamine transmission. Our previous studies demonstrated that TAAR1 agonists attenuated cue- and drug-induced cocaine-seeking and increased the elasticity of the cocaine demand curve, in the short-access cocaine self-administration model. Compulsive use of cocaine, which is an essential criterion of cocaine use disorder, can be induced by extended access to cocaine self-administration. To characterize the role of TAAR1 in compulsive cocaine use, we evaluated the effects of activation of TAAR1 on cocaine intake, cocaine binge and cue-induced cocaine-seeking using the extended-access cocaine self-administration model in adult male Sprague-Dawley rats. We also investigated the role of TAAR1 in stress-triggered cocaine relapse by using the α2 -adrenoceptor antagonist yohimbine-induced reinstatement of cocaine-seeking. The selective TAAR1 partial agonist RO5263397 attenuated cocaine intake and did not develop tolerance during the 10-day extended-access cocaine self-administration. RO5263397 reduced a 12-h binge intake of cocaine after forced abstinence. RO5263397 also decreased cue-induced cocaine-seeking after prolonged abstinence from extended-access cocaine self-administration. Furthermore, RO5263397 and the selective TAAR1 full agonist RO5166017 reduced yohimbine-induced reinstatement of cocaine-seeking behaviour. Activation of TAAR1 attenuated extended-access cocaine self-administration and stress-induced cocaine reinstatement. These results suggest that TAAR1 agonists are promising pharmacological interventions to treat cocaine use disorder and relapse.

Beta‐caryophyllene, a Volatile Phytocannabinoid, Attenuates Cocaine Self‐administration and Relapse in Rats

Cocaine abuse continues to be a serious health problem worldwide. Despite intense research, there is still no FDA‐approved medication to treat cocaine use disorder. The recent search for effective therapeutics has been focused on the endocannabinoid system because of its critical role in the neurobiology of drug addiction. In the last decade, there has been a growing interest in beta‐caryophyllene (BCP), a volatile phytocannabinoid present in high proportions in cannabis and large number of spice and food plants including black pepper, thyme and cloves. This dietary additive that has a CB2 receptor (CB2R) agonist profile, has shown to produce promising therapeutic effects for multiple neuropsychiatric disorders. Surprisingly, the therapeutic potential of BCP in the treatment of drug abuse and addiction has not been explored. Here, using gold standard animal models of drug abuse, we systematically evaluated the potential utility of BCP against cocaine‐related behaviors in rodents and its mechanisms of action. In a series of experiments we found that BCP attenuated cocaine‐enhanced electrical brain‐stimulation reward and optogenetic intracranial self‐stimulation driven by activation of dopamine (DA) neurons in DAT‐cre mice, both outcomes indicating reduced reward. Intriguingly, when administered systemically or orally, BCP attenuated cocaine self‐administration in rats, suggesting an ability to reduce drug abuse. BCP also reduced drug‐primed reinstatement of cocaine seeking and cocaine conditioned place preference, indicative of its preventative effects against relapse. When BCP was substituted for cocaine, rats ceased responding, suggesting BCP has low liability abuse. In regards to the receptor mechanisms, our pharmacological approach (along with our transgenic approach utilizing with CB1, CB2, GPR55 knockout mice) indicates that BCP produces attenuating effects on cocaine self‐administration that are mediated by non‐cannabinoid receptors. We are now exploring the involvement of peroxisome proliferator‐activated receptor (PPAR) and transient receptor potential vanilloid 1 cation channels (TRPV1) in BCP action against cocaine. Our findings suggest that BCP shows exceptional promise as a therapeutic candidate in the treatment of cocaine use disorder. Importantly, given its good oral bioavailability and the advantage of being an already FDA‐approved non‐toxic dietary additive, BCP is a valuable candidate for drug repurposing programs in translational medicine.

Combined Topiramate and Mixed Amphetamine Salts for Cocaine Use Disorder

Prescribed stimulants and topiramate have had mixed results in treating cocaine use disorder (CUD). Individuals with higher impulsivity may be

Lack of effect of the combination of metyrapone and oxazepam on brain dopamine

The combination of metyrapone and oxazepam (Met-Ox) has recently shown promise as a pharmacotherapy for cocaine use disorder. Metyrapone is available clinically and is typically used to diagnose adrenal insufficiency, while oxazepam is often prescribed to treat anxiety. The combination of low doses of metyrapone and oxazepam has been shown to significantly attenuate cocaine self-administration and cue-reactivity in rats, as well as decrease the number of subjects that used cocaine in a pilot clinical trial. Previous studies in rats suggest that the combination of these two drugs may decrease drug-related behaviors by reducing corticosterone synthesis in the medial prefrontal cortex. Since corticosterone has been associated with increased brain dopamine, these reductions in central corticosterone produced by Met-Ox might be accompanied by a concomitant decrease in dopamine to thereby attenuate drug taking and seeking. Thus, these studies were designed to determine the effects of Met-Ox on dopamine in rats. In vivo microdialysis studies in the medial prefrontal cortex and nucleus accumbens revealed that Met-Ox produced no measurable effects on cocaine-induced increases in dopamine. Further, the combination of these two drugs produced no effect on dopamine in the absence of cocaine. Together, these studies demonstrate that Met-Ox does not exert its effects by altering dopamine, suggesting that it might be possible to treat cocaine use disorder without affecting dopamine, which would lead to reduced side effects and increased compliance.

Patterns of alcohol use among men receiving treatment for heroin and/or cocaine use in England, Brazil and Spain. A cross-country analysis

Introduction: Although alcohol is widely used concurrently with illicit drugs, the role of alcohol in recovery from and relapse to drug use is under-researched. This study investigates drinking patterns and factors associated with harmful drinking among men receiving community treatment for heroin and/or cocaine use.Methods: Secondary analysis of 3 cross-sectional studies in England (n = 153), Brazil (n = 149) and Spain (n = 131) was conducted. Sociodemographic, alcohol consumption (AUDIT), substance use, treatment characteristics, and physical health were assessed. Logistic regression determined factors associated with harmful drinking.Results: 41% of men receiving heroin and/or cocaine treatment met criteria for harmful drinking. Of this, 28% were not receiving treatment for alcohol. Factors identified with harmful drinking among those who were not receiving treatment for alcohol use were as follows: homeless, unemployment/receiving benefits, poly drug use, history of injecting drug(s), hepatitis C seropositive, and receiving treatment for heroin use with/without treatment for cocaine use. Participants from England who met criteria for harmful drinking were more likely to report not receiving treatment for alcohol use than those from Brazil and Spain.Discussion: Findings show that harmful drinking is common among men in treatment for drug use and remains neglected by the services.

Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT1A and TRPV1 receptor mechanisms

Cocaine abuse continues to be a serious health problem worldwide. Despite intense research there is currently no FDA-approved medication to treat cocaine use disorder. The recent search has been focused on agents targeting primarily the dopamine system, while limited success has been achieved at the clinical level. Cannabidiol (CBD) is a U.S. FDA-approved cannabinoid for the treatment of epilepsy and recently was reported to have therapeutic potential for other disorders. Here we systemically evaluated its potential utility for the treatment of cocaine use disorder and explored the underlying receptor mechanisms in experimental animals. Systemic administration (10–40 mg/kg) of CBD dose-dependently inhibited cocaine self-administration, shifted a cocaine dose-response curve downward, and lowered break-points for cocaine self-administration under a progressive-ratio schedule of reinforcement. CBD inhibited cocaine self-administration maintained by low, but not high, doses of cocaine. In addition, CBD (3–20 mg/kg) dose-dependently attenuated cocaine-enhanced brain-stimulation reward (BSR) in rats. Strikingly, this reduction in both cocaine self-administration and BSR was blocked by AM630 (a cannabinoid CB2 receptor antagonist), WAY100135 (a 5-HT1A receptor antagonist), or capsazepine (a TRPV1 channel blocker), but not by AM251 (a CB1 receptor antagonist), CID16020046 (a GPR55 antagonist), or naloxone (an opioid receptor antagonist), suggesting the involvement of CB2, 5-HT1A, and TRPV1 receptors in CBD action. In vivo microdialysis indicated that pretreatment with CBD (10–20 mg/kg) attenuated cocaine-induced increases in extracellular dopamine (DA) in the nucleus accumbens, while CBD alone failed to alter extracellular DA. These findings suggest that CBD may have certain therapeutic utility by blunting the acute rewarding effects of cocaine via a DA-dependent mechanism.

Randomized placebo-controlled trial of galantamine in individuals with cocaine use disorder

No pharmacotherapies are approved for the treatment of cocaine use disorder (CUD). Galantamine, a cholinesterase inhibitor, has shown initial promise for cocaine use reduction in methadone-maintained individuals with CUD and cognitive improvement in abstinent individuals with past CUD. However, galantamine has not previously tested in individuals with current CUD and no comorbid opioid use disorder or methadone maintenance. The goal of this 13-week, double-blind, placebo-controlled, randomized controlled trial was to test the efficacy of galantamine (8 mg or 16 mg/day; extended release (ER)) for reducing cocaine use and improving cognitive function in individuals with cocaine use disorder (CUD). Ninety-three treatment-seeking cocaine users were randomized to placebo (n = 32), 8 mg/day galantamine (n = 31) or 16 mg/day galantamine (n = 30). The medication was well-tolerated with minimal reports of side-effects. However, there were no significant treatment group differences in cocaine use outcomes (as measured by self-report or urines). The 16 mg galantamine group had a greater improvement in working memory capacity (Backwards Digit Span), but there were no other significant treatment group differences on key cognitive outcomes. These findings did not provide support for the efficacy of galantamine as a treatment for cocaine use in this sample of individuals with CUD.

Medications to treat cocaine use disorders: current options.

Cocaine is a highly addictive substance with serious medical and mental health consequences. Despite these concerns, there are no Food and Drug Administration-approved medications for the treatment of cocaine use disorder (CUD). Although many medication-assisted treatments (MATs) have been investigated, no clear guidelines exist for clinicians treating patients with CUDs. There are a limited number of recent data examining MATs for CUD. Multiple high-quality reviews of existing literature have been performed with psychostimulants, modafinil, bupropion, topiramate and disulfiram showing the most promise. Evidence is limited by heterogeneity of studies, small sample sizes and inconsistent results. The current literature does not strongly support any individual MAT for CUD. Psychosocial interventions, namely contingency management, have the most evidence for treatment of CUD, but it is worth seriously considering MAT for patients who do not respond well to psychosocial interventions alone given limitations in access to care, relatively low risks associated with MAT and significant morbidity associated with CUD. Further research into MAT for CUD is necessary, as the combination of MAT and psychosocial interventions may be better than either alone.

Pharmacotherapy for Cocaine Use Disorder-a Systematic Review and Meta-analysis.

Currently, there are no accepted FDA-approved pharmacotherapies for cocaine use disorder, though numerous medications have been tested in clinical trials. We conducted a systematic review and meta-analysis to better understand the effectiveness of pharmacotherapy for cocaine use disorder. We searched multiple data sources (MEDLINE, PsycINFO, and Cochrane Library) through November 2017 for systematic reviews and randomized controlled trials (RCTs) of pharmacological interventions in adults with cocaine use disorder. When possible, we combined the findings of trials with comparable interventions and outcome measures in random-effects meta-analyses. We assessed the risk of bias of individual trials and the strength of evidence for each outcome using standardized criteria. Outcomes included continuous abstinence (3+ consecutive weeks); cocaine use; harms; and study retention. For relapse prevention studies (participants abstinent at baseline), we examined lapse (first cocaine positive or missing UDS) and relapse (two consecutive cocaine positive or missed UDS'). Sixty-six different drugs or drug combinations were studied in seven systematic reviews and 48 RCTs that met inclusion criteria. Antidepressants were the most widely studied drug class (38 RCTs) but appear to have no effect on cocaine use or treatment retention. Increased abstinence was found with bupropion (2 RCTs: RR 1.63, 95% CI 1.02 to 2.59), topiramate (2 RCTs: RR 2.56, 95% CI 1.39 to 4.73), and psychostimulants (14 RCTs: RR 1.36, 95% CI 1.05 to 1.77), though the strength of evidence for these findings was low. We found moderate strength of evidence that antipsychotics improved treatment retention (8 RCTs: RR 1.33, 95% CI 1.03 to 1.75). Most of the pharmacotherapies studied were not effective for treating cocaine use disorder. Bupropion, psychostimulants, and topiramate may improve abstinence, and antipsychotics may improve retention. Contingency management and behavioral interventions along with pharmacotherapy should continue to be explored. Prospero CRD42018085667.