A double-blind, placebo-controlled trial of reserpine for the treatment of cocaine dependence
ABSTRACT Cocaine's increase of dopamine is strongly associated with its reinforcing properties and, thus, agents that reduce dopamine have received much attention as candidate cocaine-dependence treatments. The potential efficacy of reserpine, a dopamine depletor, for treating cocaine dependence is suggested by both pre-clinical research and a small clinical trial.
One hundred and nineteen participants who met DSM-IV criteria for cocaine dependence were enrolled into this 12-week, double-blind, placebo-controlled outpatient trial. Participants received either reserpine (0.5 mg/day) or matching placebo. All participants received 1h of manualized individual cognitive behavioral therapy on a weekly basis. Outcome measures included cocaine use as determined by self-report confirmed with urine benzoylecgonine results, cocaine craving, addiction severity index scores, and clinical global impression scores. Safety measures included adverse events, EKGs, vital signs, laboratory tests, and the Hamilton Depression Inventory.
Seventy-nine participants (i.e., 66%) completed the 12-week trial. The safety results suggest that reserpine was safe and well tolerated by the participants. The efficacy measures indicated no significant differences between reserpine and placebo.
These results do not support the efficacy of reserpine as a cocaine-dependence treatment.
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- "As DA plays a critical role in motivation, reward, and locomotion, studies have focused on modifying its functions in addicted humans. To counter the DA increase elicited by cocaine, a DA depletor reserpine was tested in humans but found to be ineffective (Winhusen et al., 2007). A D1R antagonist Ecopipam was tested in humans who were addicted to crack cocaine, and was found to reduce self-assessed measures of acute cocaine effects such as the “high” (Romach et al., 1999). "
ABSTRACT: Despite their distinct targets, all addictive drugs commonly abused by humans evoke increases in dopamine (DA) concentration within the striatum. The main DA Guanine nucleotide binding protein couple receptors (GPCRs) expressed by medium-sized spiny neurons of the striatum are the D1R and D2R, which are positively and negatively coupled to cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, respectively. These two DA GPCRs are largely segregated into distinct neuronal populations, where they are co-expressed with glutamate receptors in dendritic spines. Direct and indirect interactions between DA GPCRs and glutamate receptors are the molecular basis by which DA modulates glutamate transmission and controls striatal plasticity and behavior induced by drugs of abuse. A major downstream target of striatal D1R is the extracellular signal-regulated kinase (ERK) kinase pathway. ERK activation by drugs of abuse behaves as a key integrator of D1R and glutamate NMDAR signaling. Once activated, ERK can trigger chromatin remodeling and induce gene expression that permits long-term cellular alterations and drug-induced morphological and behavioral changes. Besides the classical cAMP/PKA pathway, downstream of D1R, recent evidence implicates a cAMP-independent crosstalk mechanism by which the D1R potentiates NMDAR-mediated calcium influx and ERK activation. The mounting evidence of reciprocal modulation of DA and glutamate receptors adds further intricacy to striatal synaptic signaling and is liable to prove relevant for addictive drug-induced signaling, plasticity, and behavior. Herein, we review the evidence that built our understanding of the consequences of this synergistic signaling for the actions of drugs of abuse.Frontiers in Pharmacology 01/2014; 4:172. DOI:10.3389/fphar.2013.00172 · 3.80 Impact Factor
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- "Moreover, it has been postulated that long-term changes in dopaminergic neurophysiology at the level of the cortex, specifically the orbitofrontal cortex, may underlie cocaine withdrawal symptoms, persistent states of craving, and compulsive drug-seeking behavior (for review see Volkow and Fowler, 2000). Therefore, numerous studies have evaluated agents with dopaminergic activity for efficacy against cocaine in controlled pharmacotherapy trials, including dopamine agonists, such as pergolide (Malcolm et al., 2000), bromocriptine (Handelsman et al., 1997), mazindol (Stine et al., 1995) and levo-dopa (Mooney et al., 2007; Schmitz et al., 2008) and dopamine antagonist-like compounds, such as risperidone (Grabowski et al., 2000, 2004a; Loebl et al., 2008) and the dopamine depleting agent, reserpine (Winhusen et al., 2007). The vast majority of these studies have reported no supportive evidence for efficacy, although a few studies of robust stimulant compounds, such as d-amphetamine (Grabowski et al., 2001, 2004b; Shearer et al., 2003) and methamphetamine (Mooney et al., 2009) have produced statistically significant signals of efficacy. "
ABSTRACT: Background: Cocaine abuse continues to be a significant public health problem associated with morbidity and mortality. To date, no pharmacotherapeutic approach has proven effective for treating cocaine use disorders. Preclinical and clinical evidence suggests that noradrenergic activity may play a role in mediating some effects of cocaine and may be a rational target for treatment. Methods: This double blind, placebo-controlled randomized, parallel group, 12-week outpatient clinical trial enrolled cocaine dependent individuals seeking treatment to examine the potential efficacy of the selective norepinephrine reuptake inhibitor, atomoxetine (80 mg/day; p.o.; n = 25), compared to placebo (n = 25). Subjects were initially stratified on cocaine use (< 15 days or ≥ 15 days of the last 30), age and race using urn randomization. Attendance, medication adherence and study compliance were reinforced with contingency management, and weekly counseling was offered. An array of measures (vital signs, laboratory chemistries, cognitive and psychomotor tests, cocaine craving and urine samples for drug testing) was collected throughout the study and at follow-up. Results: Survival analysis revealed no differences in study retention between the two groups, with approximately 56% of subjects completing the 12-week study (Cox analysis χ(2) = .72; p = .40; Hazard Ratio 1.48 [95% CI 0.62-3.39]). GEE analysis of the proportion of urine samples positive for benzoylecgonine, a cocaine metabolite, revealed no differences between the atomoxetine and placebo groups (χ(2) = 0.2, p = .66; OR = 0.89 [95% CI 0.41-1.74]). Atomoxetine was generally well tolerated in this population. Conclusions: These data provide no support for the utility of atomoxetine in the treatment of cocaine dependence.Drug and alcohol dependence 11/2012; 130(1-3). DOI:10.1016/j.drugalcdep.2012.10.024 · 3.42 Impact Factor
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ABSTRACT: There is currently no FDA-approved medication for cocaine dependence and no standard primary outcome measure for reduction of cocaine use in cocaine-dependence trials. The ability to detect a significant medication effect will depend, in part, on the primary outcome measure utilized. The goal of the present paper is to compare self-report or either of two urine toxicology measures used alone to a relatively new measure -- the SRPHK1 -- which combines self-report, quantitative urine benzoylecgonine levels, and an estimate of the concordance between the two to determine the cocaine-use status of each study day. Datasets from two separate randomized, placebo-controlled cocaine-dependence trials were used to compare four cocaine-use outcome measures. The two data sets yielded very similar findings and suggest that the combined measure is associated with significantly fewer missing data than urine toxicology and that estimated cocaine use varied significantly depending on which measure was used, with the lowest use estimate being yielded by self-report, the highest by the two urine toxicology measures evaluated, and an intermediate value obtained using the combined measure. The results also suggest that the concordance between self-report and urine toxicology is around 90% at the beginning of the clinical trial but decreases to around 75% by the end of the trial. By combining the objectivity of urine toxicology with the reduced incidence of missing data characteristic of self-report, the SRPHK1 may provide advantages over self-report or urine toxicology measures used alone. In any case, the SRPHK1 provides an interesting complement to these other outcome measures and may warrant further evaluation.Drug and Alcohol Dependence 02/2008; 93(1-2):132-40. DOI:10.1016/j.drugalcdep.2007.09.007 · 3.42 Impact Factor