Pilot study of the effects of lisdexamfetamine on cocaine use: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Amphetamine analogs have been demonstrated to have some efficacy in reducing use in cocaine dependent individuals. However, these agents also have potential for abuse. Lisdexamfetamine (LDX), a lysine+dextroamphetamine formulation, has been approved for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) and as a prodrug, has less abuse potential. OBJECTIVE: This pilot study sought to evaluate the safety, tolerability, and efficacy of LDX as a candidate treatment for cocaine dependence. METHODS: A randomized, double-blind, placebo-controlled parallel group study served to evaluate LDX in 43 cocaine-dependent individuals: (1) placebo (PBO; 0mg, n=21), (2) LDX (70mg, n=22). Participants received medication for 14 weeks. Cocaine use was determined based on urine analysis for benzoylecgonine (BE; a cocaine metabolite). RESULTS: Retention rates were higher though not significantly different in the PBO (71.4%) than the LDX condition (57.1%). Compared to those in the PBO condition, those receiving LDX were more likely to report experiencing (ps<0.05) diarrhea (45.5% vs. 14.3%), headaches (45.5% vs. 9.5%), and anxiety (31.8% vs. 4.8%). No differences in medication conditions were observed for blood pressure, heart rate, or body weight. In the randomized sample, no differences in cocaine use were seen. Those receiving LDX reported significantly less craving for cocaine than participants receiving PBO. CONCLUSIONS: LDX did not significantly reduce cocaine use compared to PBO in the randomized sample.

Elevated Expression of Serotonin 5-HT(2A) Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine.

The dopamine mesocorticoaccumbens pathway which originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens and prefrontal cortex is a circuit important in mediating the actions of psychostimulants. The function of this circuit is modulated by the actions of serotonin (5-HT) at 5-HT(2A) receptors (5-HT(2A)R) localized to the VTA. In the present study, we tested the hypothesis that virally mediated overexpression of 5-HT(2A)R in the VTA would increase cocaine-evoked locomotor activity in the absence of alterations in basal locomotor activity. A plasmid containing the gene for the 5-HT(2A)R linked to a synthetic marker peptide (Flag) was created and the construct was packaged in an adeno-associated virus vector (rAAV-5-HT(2A)R-Flag). This viral vector (2 µl; 10(9-10) transducing units/ml) was unilaterally infused into the VTA of male rats, while control animals received an intra-VTA infusion of Ringer's solution. Virus-pretreated rats exhibited normal spontaneous locomotor activity measured in a modified open-field apparatus at 7, 14, and 21 days following infusion. After an injection of cocaine (15 mg/kg, ip), both horizontal hyperactivity and rearing were significantly enhanced in virus-treated rats (p < 0.05). Immunohistochemical analysis confirmed expression of Flag and overexpression of the 5-HT(2A)R protein. These data indicate that the vulnerability of adult male rats to hyperactivity induced by cocaine is enhanced following increased levels of expression of the 5-HT(2A)R in the VTA and suggest that the 5-HT(2A)R receptor in the VTA plays a role in regulation of responsiveness to cocaine.

Validity and Reliability of the Abbreviated Barratt Impulsiveness Scale in Spanish (BIS-15S).

OBJECTIVE: This study determined the validity and reliability of a new, abbreviated version of the Spanish Barratt Impulsiveness Scale (BIS-15S) in Colombian subjects. METHOD: The BIS-15S was tested in non-clinical (n=283) and clinical (n=164) native Spanish-speakers. Intra-scale reliability was calculated using Cronbach's α, and test-retest reliability was measured with Pearson correlations. Psychometric properties were determined using standard statistics. A factor analysis was performed to determine BIS-15S factor structure. RESULTS: 447 subjects participated in the study. Clinical subjects were older and more educated compared to non-clinical subjects. Impulsivity scores were normally distributed in each group. BIS-15S total, motor, non-planning and attention scores were significantly lower in non-clinical vs. clinical subjects. Subjects with substance-related disorders had the highest BIS-15S total scores, followed by subjects with bipolar disorders and bulimia nervosa/binge eating. Internal consistency was 0.793 and test-retest reliability was 0.80. Factor analysis confirmed a three-factor structure (attention, motor, non-planning) accounting for 47.87% of the total variance in BIS-15S total scores. CONCLUSIONS: The BIS-15S is a valid and reliable self-report measure of impulsivity in this population. Further research is needed to determine additional components of impulsivity not investigated by this measure.

Agonist-like pharmacotherapy for stimulant dependence: preclinical, human laboratory, and clinical studies.

A variety of natural and synthetic agents have long been used for stimulant properties, with nontherapeutic use producing multiple waves of stimulant abuse and dependence. The multitude of effects of stimulants exist on continua, and accordingly, here we characterize stimulant abuse/dependence and candidate pharmacotherapies in this manner. Behavioral therapy and medications have been investigated for treatment of stimulant abuse/dependence. Effectiveness of some behavioral interventions has been demonstrated. Most medications studied have been found to lack efficacy. However, an expanding literature supports use of agonist-like medications to treat stimulant abuse/dependence, a strategy effective for nicotine and opiate dependence. The agonist-like conceptualization for stimulant dependence posits that medications with properties similar to that of the abused drug, but possessing lesser abuse liability, will normalize neurochemistry and stabilize behavior, thus reducing drug use. Data suggest use of a range of medications, from l-dopa/carbidopa to amphetamine preparations, depending on the severity of use. This report reviews preclinical, human laboratory, and clinical trial data supporting the agonist-like approach, including risks and benefits. Future directions for development of agonist-like medications are also discussed.

Validity and reliability of the abbreviated barratt impulsiveness scale in spanish (BIS-15S)

Introduction: This study determined the validity and reliability of a new, abbreviated version of the Spanish Barratt Impulsiveness Scale (BIS-15S) in Colombian subjects. Method: The BIS-15S was tested in non-clinical (n=283) and clinical (n=164) native Spanish-speakers. Intra-scale reliability was calculated using Cronbach’s , and test-retest reliability was measured with Pearson correlations. Psychometric properties were determined using standard statistics. A factor analysis was performed to determine BIS-15S factor structure. Results: 447 subjects participated in the study. Clinical subjects were older and more educated compared to non-clinical subjects. Impulsivity scores were normally distributed in each group. BIS-15S total, motor, non-planning and attention scores were significantly lower in non-clinical vs. clinical subjects. Subjects with substance related disorders had the highest BIS-15S total scores, followed by subjects with bipolar disorders and bulimia nervosa/binge eating. Internal consistency was 0.793 and test-retest reliability was 0.80. Factor analysis conformed a three-factor structure (attention, motor, non-planning) accounting for 47.87% of the total variance in BIS-15S total scores. Conclusions: The BIS-15S is a valid and reliable self-report measure of impulsivity in this population. Further research is needed to determine additional components of impulsivity not investigated by this measure...

Introducción: Determinar la validez y confiabilidad de una nueva versión abreviada de la Escala de Impulsividad de Barratt (BIS-15S) en la población colombiana. Método: El BIS-15S fue aplicado a sujetos hispanoparlantes no clínicos (n=283) y clínicos (n=164). Sus propiedades psicométricas se establecieron con pruebas estadísticas estandarizadas y sus factores principales se analizaron para determinar la estructura de los factores del instrumento. Resultados: 447 sujetos participaron en el estudio. Los sujetos clínicos fueron mayores y más educados que los sujetos no clínicos. Los puntajes estuvieron distribuidos normalmente en las dos poblaciones. Los puntajes total, motor, de no planeación y atención del BIS-15S fueron ignificativamente menores en sujetos no clínicos, comparados con sujetos clínicos. Los puntajes de los sujetos con abuso/dependencia a drogas fueron los más altos, seguidos de aquellos de sujetos con trastornos bipolares y bulimia nerviosa/trastorno por atracones. La consistencia interna del BIS-15S fue 0,793; su confiabilidad prueba-reprueba, 0,80. El análisis de factores conformó tres factores principales (motor, no planeación y atención) responsables de 47,87% de la varianza del puntaje total del BIS-15S. Conclusiones: El BIS-15S es una medida válida y confiable del rasgo impulsividad en la población colombiana. Son necesarios estudios adicionales para establecer otras dimensiones del rasgo no medidas por el instrumento...

Novel approach to data analysis in cocaine-conditioned place preference.

Only a subgroup of human drug users progress from initial drug taking to drug addiction. The learned associations between the effects of the drug and the environment in which it is experienced is an important aspect of the progression to continued drug taking and drug seeking. These associations can be modeled using the conditioned place preference (CPP) paradigm, although no current method of CPP analysis allows for the identification of within-group variability among subjects. In this study, we adapted a 'criterion' method of analysis to separate 'CPP expressing' from 'non-CPP expressing' rats to study more directly within-group variability in the CPP paradigm. Male Sprague-Dawley rats were conditioned with cocaine (5, 10, 20 mg/kg) or saline in an unbiased three-chamber CPP apparatus in either a single-trial or four-trial CPP procedure. A classification and regression tree analysis of time spent in the cocaine-paired chamber established a time of 324 s spent in the cocaine-paired chamber as the criterion for cocaine CPP expression. This criterion effectively discriminated control from cocaine-conditioned rats and was reliable for rats trained in both single trial and four-trial CPP procedures. The criterion method showed an enhanced ability to detect effective doses of cocaine in the single-trial CPP procedure and a blockade of CPP expression by MK 212 (0.125 mg/kg) treatment in a subgroup of rats. These data support the utility of the criterion analysis as an adjunct to traditional methods that compare group averages in CPP.

High-dose naltrexone therapy for cocaine-alcohol dependence.

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

Cocaine dependence and concurrent marijuana use: a comparison of clinical characteristics.

BACKGROUND/OBJECTIVES: Marijuana is the most commonly used illicit substance, yet among the least studied in medication development research. Cocaine-dependent individuals frequently also use marijuana; however, little is known about the effect of this combined use on treatment presentation. METHODS: Marijuana use was assessed in 1183 individuals seeking outpatient treatment for cocaine dependence. Based on past 30 days of use, the sample was divided into three groups: (1) patients reporting no recent marijuana use (n = 634); (2) occasional use (n = 403); (3) and frequent concurrent marijuana use (n = 146). Differences on baseline measures of substance use, addiction severity (ASI), psychopathology, and sociodemographic characteristics were examined as a function of level of marijuana use. RESULTS: Frequent marijuana users were more likely to be female, Caucasian, and younger than other groups. Cocaine-dependent patients with frequent marijuana use also used more cocaine and alcohol, and reported more medical, legal, and psychiatric problems, including antisocial personality disorder. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Cocaine-dependent patients with frequent marijuana use present for treatment with more severe impairment. Accounting for this heterogeneity among participants may improve treatment outcome.

Effects of oral methamphetamine on cocaine use: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: No medication is currently approved for the treatment of cocaine dependence, but several preclinical and clinical reports suggest agonist-like medications, e.g., amphetamine analogues, may be a productive strategy for medication development. OBJECTIVE: This current proof-of-concept study sought to evaluate the safety, tolerability, and effectiveness of methamphetamine as a candidate treatment for cocaine dependence. METHODS: A randomized, double-blind, placebo-controlled study served to evaluate three treatment conditions in 82 cocaine-dependent individuals: (1) placebo (0mg, 6x/day; n=27), (2) immediate release (IR) methamphetamine (5mg, 6x/day; n=30), (3) sustained release (SR) methamphetamine (30 mg first pill, 1x/day; 0mg 5x/day; n=25). The study employed a sequential, two-phase design (i.e., 4 weeks of medication and counseling followed by 4 weeks of medication/counseling plus a contingency management procedure). RESULTS: Both preparation forms of methamphetamine were well-tolerated, with similar retention to placebo (0mg, 33%; 30 mg IR, 30%, 30 mg SR, 32%). Methamphetamine SR was associated with decreased sleep and increased weight loss. Medication adherence rates were high for the first dose of the day (95%), while adherence for subsequent capsules was lower. Those in the SR condition exhibited consistently lower rates of cocaine-positive urine samples (0mg, 60%; 30 mg IR, 66%; 30 mg SR, 29%), p<0.0001, and reported the greatest reduction in craving for cocaine, p<0.05. CONCLUSIONS: SR methamphetamine significantly reduced cocaine use and craving. Additional research is warranted to develop and evaluate agonist-like medications that may effectively treat cocaine dependence.

Obsessive-Compulsive Disorder Symptoms in Huntington’s Disease: A Case Report / Síntomas del trastorno obsesivocompulsivo en la enfermedad de Huntington: reporte de caso

Introduction: Few cases of obsessive-compulsive disorder (OCD) symptoms preceding the clinical onset of Huntington Disease (HD) or during later stages of the disease have been reported in the literature, but the nature of this association and its neurobiological mechanisms have not been well-investigated. Objectives: To review the scientific literature regarding OCD symptoms in patients with HD and describe a case study from our clinic. Methods: Extensive literature searches were performed to identify reports of patients with concurrent HD and OCD symptoms. Results: Recent studies and the current case report suggest that OCD symptoms may predate or coincide with motor, affective or behavioral symptoms in patients with HD. The development of OCD and HD symptoms may involve structural and functional changes affecting the orbital and medial prefrontal cortex, ventromedial caudate nucleus, and pallidal sites. Conclusions: Some patients with HD develop symptoms associated with OCD. Progressive and differential neuropathological changes in the ventromedial caudate nucleus and related neural circuits may underlie this association. No specific treatment strategy has been developed to treat these patients; however some medications attenuate associated symptoms. Further testing is needed to determine the neurobiological mechanisms of these disorders.

Introducción: Algunos reportes de caso indican que pacientes con enfermedad de Huntington (EH) pueden presentar síntomas obsesivo-compulsivos (TOC) antes del desarrollo de la enfermedad y durante ésta, pero no se ha estudiado la naturaleza de esta asociación y sus mecanismos neurobiológicos. Objetivos: Revisar la literatura científica acerca de la asociación entre EH y síntomas TOC y reportar el caso de un paciente con estas condiciones. Método: Búsqueda selectiva de literatura relevante. Resultados: Estudios recientes y el caso aquí reportado sugieren que los síntomas TOC pueden presentarse antes de la EH y durante ésta. El desarrollo concurrente de estas patologías puede estar mediado por cambios estructurales y funcionales de la corteza prefrontal orbital y medial, región ventromedial del núcleo caudado y regiones palidales. Conclusiones: Algunos pacientes con EH desarrollan síntomas de TOC. Cambios neuropatológicos progresivos y diferenciales en el caudado ventromedial y circuitos dependientes pueden mediar esta asociación. No se ha desarrollado una estrategia terapéutica para el tratamiento de estos pacientes; sin embargo, algunos medicamentos parecen ofrecer mejoría sintomática parcial a los sujetos afectados. Se requieren mayores estudios acerca de los mecanismos neuropatológicos involucrados en esta asociación.

Obsessive-Compulsive Disorder Symptoms in Huntington's Disease: A Case Report.

INTRODUCTION: Few cases of obsessive-compulsive disorder (OCD) symptoms preceding the clinical onset of Huntington Disease (HD) or during later stages of the disease have been reported in the literature, but the nature of this association and its neurobiological mechanisms have not been well-investigated. OBJECTIVES: To review the scientific literature regarding OCD symptoms in patients with HD and describe a case study from our clinic. METHODS: Extensive literature searches were performed to identify reports of patients with concurrent HD and OCD symptoms. RESULTS: Recent studies and the current case report suggest that OCD symptoms may predate or coincide with motor, affective or behavioral symptoms in patients with HD. The development of OCD and HD symptoms may involve structural and functional changes affecting the orbital and medial prefrontal cortex, ventromedial caudate nucleus, and pallidal sites. CONCLUSIONS: Some patients with HD develop symptoms associated with OCD. Progressive and differential neuropathological changes in the ventromedial caudate nucleus and related neural circuits may underlie this association. No specific treatment strategy has been developed to treat these patients; however some medications attenuate associated symptoms. Further testing is needed to determine the neurobiological mechanisms of these disorders.

Chronic treatment with a serotonin(2) receptor (5-HT(2)R) agonist modulates the behavioral and cellular response to (+)-3,4-methylenedioxymethamphetamine [(+)-MDMA].

3,4-Methylenedioxymethamphetamine [MDMA; ecstasy] evokes a multifaceted subjective experience in human users which includes stimulation, feelings of well-being, mood elevation, empathy towards others as well as distortions in time, sensation and perception. Aspects of this unique psychopharmacology of MDMA are thought to be related to its potent actions to release serotonin (5-HT) and indirectly stimulate the 5-HT(2A) receptor (5-HT(2A)R). In the present studies, we examined the interrelationship between down-regulation of 5-HT(2A)R expression and the behaviorally stimulatory effects generated by acute administration of (+)-MDMA, the most potent enantiomer of (+/-)-MDMA. Male Sprague-Dawley rats were chronically treated with the preferential 5-HT(2A)R agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) which has been shown to down-regulate expression of the 5-HT(2A)R, but not the closely related 5-HT(2C)R. While chronic DOI treatment did not alter the functional sensitivity of either the 5-HT(2A)R or 5-HT(2C)R, this regimen enhanced (+)-MDMA-evoked hyperactivity. Subsequent analysis of c-Fos and 5-HT(2A)R immunoreactivity in brain sections demonstrated that DOI treatment decreased the number of (+)-MDMA-induced c-Fos immunopositive nuclei and 5-HT(2A)R immunostaining in select cortical and striatal areas. These results indicate that chronic DOI exposure results in an enhanced behavioral response to (+)-MDMA and in a pattern of neuronal activation which resembles that seen in psychostimulant sensitization. These data also suggest that expression of the 5-HT(2A)R in the NAc and PFC may play a role in the sensitivity to the locomotor-stimulating effects of (+)-MDMA and in the processes of neural regulation upon repeated psychostimulant administration.

Role of the serotonin 5-HT2A receptor in the hyperlocomotive and hyperthermic effects of (+)-3,4-methylenedioxymethamphetamine.

RATIONALE: Contradictory evidence exists regarding the role of the 5-HT(2A) receptor (5-HT(2A)R) in hyperactivity and hyperthermia elicited by the substituted amphetamine (+)-3,4-methylenedioxymethamphetamine. OBJECTIVES: The present studies examined the ability of the selective 5-HT(2A)R antagonist M100907 to block hyperactivity and hyperthermia produced across the (+)-MDMA dose-effect curve. METHODS: Male rats were pretreated with M100907 (0, 0.25, 0.5, 1, and 2 mg/kg) followed by treatment with (+)-MDMA (0-12 mg/kg); activity was recorded for 90 min followed by determination of rectal temperature. Additionally, we investigated the ability of M100907 (0 and 0.5 mg/kg) to reverse hyperthermia elicited by (+)-MDMA (12 mg/kg). RESULTS: The first study demonstrated that M100907 attenuated hyperactivity in the periphery of the monitor and eliminated rearing induced by (+)-MDMA (3 mg/kg) with no effect on basal activity. In two subsequent studies, (+)-MDMA (0-12 mg/kg) dose-dependently increased peripheral activity and rearing and produced hyperthermia. Pretreatment with M100907 decreased peripheral activity evoked by (+)-MDMA, right-shifted the dose-effect curve for rearing, and blocked (+)-MDMA-induced hyperthermia, while having no effect when administered alone. A final study demonstrated the ability of M100907 (0.5 mg/kg) to reverse hyperthermia produced by (+)-MDMA (12 mg/kg). CONCLUSIONS: These results suggest that the 5-HT(2A)R contributes to the generation of peripheral hyperactivity and rearing and, especially, the hyperthermia evoked by (+)-MDMA and that 5-HT(2A)R antagonists should be further investigated as treatments for the psychological and hyperthermic effects of (+/-)-MDMA.