Blackwell Science, LtdOxford, UKADDAddiction1359-6357© 2005 Society for the Study of Addiction 100•••• Original Article Cabergoline, hydergine, levodopa/carbidopa Steven Shoptaw et al. RESEARCH REPORT Randomized controlled pilot trial of cabergoline, hydergine and levodopa/carbidopa: Los Angeles Cocaine Rapid Efficacy Screening Trial (CREST) Steven Shoptaw1, Donnie W. Watson2, Chris Reiber1, Richard A. Rawson1, Margaret A. Montgomery3, Maria D. Majewska3 & Walter Ling1 UCLA Integrated Substance Abuse Programs, Los Angeles, CA1 , Friends Research Institute, Inc., Los Angeles, CA2 and National Institute on Drug Abuse, Division of Treatment Research and Development, Bethesda, MD, USA3 Correspondence to: ABSTRACT Steven Shoptaw PhD UCLA/Integrated Substance Abuse Programs Aim This study tested three dopaminergic medications against a common 11075 Santa Monica Blvd unmatched placebo condition: hydergine 1 mg three times daily (n = 15); Suite 200 levodopa/carbidopa 25/100 mg three times daily (n = 15); cabergoline 0.5 mg Los Angeles per week (n = 15); and placebo three times daily (n = 15) as potential pharma- CA 90025 USA cotherapies for cocaine dependence. E-mail: [email protected] Design The four-parallel group, Cocaine Rapid Efficacy Screening Trial (CREST) design featured a 2-week baseline period followed by randomization to an 8-week medication condition that included 1 hour per week of cognitive RESEARCH REPORT behavioral drug counseling. A safety evaluation was conducted 4 weeks after termination. Measures Outcomes included cocaine metabolites measured in urine, reten- tion and self-reports for drug use, cocaine craving, clinical improvement, mood and HIV risk behaviors. Results Participants assigned to receive cabergoline provided more urine sam- ples negative for cocaine metabolites (42.4%) than those assigned to receive pla- cebo (25.0%), a statistically significant difference after controlling for baseline differences in self-reported cocaine use (F = 2.95, df = 3; P = 0.05). Cabergoline- treated participants demonstrated a significant improvement over placebo from baseline to week 8 when measured using the Addiction Severity Index (ASI) employment subscale (overall change = - 0.09, SD = 0.10, t = 2.36, P < 0.05). Safety and adverse event measures showed similar rates and types of complaints by treatment condition. Conclusions These results, combined with the apparent safety of cabergoline when used with this population, provide empirical support for conducting a larger study of the medication. KEYWORDS Cabergoline, cocaine, hydergine, levodopa/ carbidopa, out-patient. INTRODUCTION the nucleus accumbens are part of a cascade that com- prises the brain’s reward circuitry (see Self & Nestler Cocaine produces multiple effects on the brain and the 1995). Substances including opiates, ethanol, nicotine relationship of these to the development of cocaine depen- (Calabresi et al. 1989; Nisell et al. 1994; Pontieri et al. dence is not entirely understood. It is known that dopam- 1996) and cannabinoids (Chen et al. 1990) also indirectly ine neurons in the ventral tegmental area that project into cause release of dopamine from the ventral tegmental area © 2005 Society for the Study of Addiction Addiction, 100 (Suppl. 1), 78–90 Cabergoline, hydergine, levodopa/carbidopa 79 (Imperato & DiChiara 1986; Leone et al. 1991; Johnson & itary adenomas (Colao et al. 2000), and in the control of North 1992). Cocaine acts to inhibit the uptake of dopam- clinical and hormonal features of dopamine-sensitive ine after its release into the synapse, thereby increasing acromegalic patients (Muratori et al. 1997). Among synaptic dopamine at the nucleus accumbens. humans, cabergoline improves motor functions damaged Medications that modify dopamine neurotransmitter by Parkinson’s disease when used alone or in combination levels should alter cocaine use in humans (see Jentsch with L-dopa in a dose-related fashion (Inzelberg et al. & Taylor 1999). Laboratory rats self-administer both 1995; Ahlskog et al. 1996; Hutton et al. 1996; Steiger et al. amphetamine (Hoebel et al. 1983) and dopamine (Dwor- 1996) and relieved Parkinsonian symptoms in mon- kin et al. 1986) directly into the nucleus accumbens. keys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- Bilateral injections of dopamine receptor antagonists into induced nigrostriatal depletion (Calon et al. 2000). These the nucleus accumbens or lesions of the ventral tegmen- reports indicate that cabergoline is efficient in ameliorating tal area neurons that project to the nucleus accumbens disorders associated with dopamine deficiency and hence attenuate the reinforcing effects of cocaine (Dworkin et al. is an appropriate candidate for this screening trial. 1988); yet these same dopaminergic medications, when evaluated in treatment-seeking, cocaine-dependent Levodopa/carbidopa humans, show no effects in altering cocaine use. As yet there is no consistent evidence that dopaminergic medi- Levodopa/carbidopa (Sinemet®) is an approved medica- cations reduce cocaine use when evaluated in placebo- tion for the treatment of symptoms of Parkinson’s disease. controlled, randomized trials (Ling & Shoptaw 1997, de Levodopa is a precursor of dopamine and increases the Lima et al. 2002). store of available central dopamine in dopamine-deficient The slate of approved medications with dopaminergic individuals (Cotzias et al. 1969). Carbidopa is a decarbox- activity has yet to be completely studied. Hence, to study ylase inhibitor that acts peripherally to prevent degrada- dopaminergic medications previously untested for tion of levodopa, thereby increasing efficiency of central cocaine dependence, the Los Angeles site for the Clinical dopamine availability. In theory, the dopamine precursor Rapid Efficacy Screening Trial (CREST) program funded action of levodopa/carbidopa may allow for a more rapid by the National Institute on Drug Abuse evaluated three return to natural dopamine levels following cocaine dis- agents compared to a common placebo condition for continuation. An early placebo-controlled, randomized their ability to reduce cocaine use: cabergoline 0.5 mg study of 30 cocaine-dependent participants appearing at once weekly (Dostinex®, a long-acting dopamine receptor an emergency room within 24 hours of their last use of agonist that acts postsynaptically), levodopa/carbidopa cocaine reported no statistically significant differences in 25 mg/100 mg three times daily (Sinemet®, a dopamine ratings of ‘crash’, ‘depression’, ‘anergia’ or ‘craving’ precursor that increases dopamine concentrations pre- when treated using 400 mg levodopa and 100 mg carbi- synaptically) and hydergine 1 mg three times daily (a dopa or placebo (Wolfsohn et al. 1993). Although there mixed dopamine agonist and antagonist). are no published reports of outcomes using levodopa/car- bidopa with cocaine-dependent individuals, its ability to alter dopamine availability make this medication another Evidence supporting these medications appropriate candidate for the screening trial. Cabergoline Hydergine Cabergoline (Dostinex®), a medication with a half-life of 63–69 hours, is approved for treating Parkinson’s disease Hydergine enhances cognition and improves memory and hyperprolactinemia. Cabergoline binds to D2 dopam- in patients with dementia (Thienhaus et al. 1987; ine receptors in the pituitary, which in turn may account Schneider & Olin 1994). In addition, hydergine is thought for its inhibition of prolactin secretion and its use as a to increase cerebral glucose metabolism in the cortex prolactin-lowering agent (Webster et al. 1994). Although (Nagasawa et al. 1990), to improve cognitive deficits and there are no published reports on the use of cabergoline as mood symptoms in elderly patients (Rouy et al. 1989), to a cocaine pharmacotherapy, bromocriptine, another D2 improve sleep and depression in ethanol-related enceph- dopamine receptor agonist, reduced ratings of cocaine alopathy (Datta et al. 1987) and to maintain physical and craving among cocaine-dependent individuals in a double- mental health among healthy individuals (Huber et al. blind, placebo-controlled study (Dackis et al. 1987). 1986). Hydergine enhances cerebral blood flow by caus- Cabergoline is superior to bromocriptine in efficacy and ing vasodilation and its properties as a mixed agonist/ tolerability, and may be regarded as the treatment of choice antagonist at postsynaptic D1 receptors and pre- and for hyperprolactinemic disorders, either idiopathic postsynaptic D2 receptors may account for its ability to (Webster et al. 1993, 1994; Webster 1999) or due to pitu- correct monoamine disturbances in the central nervous © 2005 Society for the Study of Addiction Addiction, 100 (Suppl. 1), 78–90 80 Steven Shoptaw et al. system (Goldstein 1985; Markstein 1985). There are no ications for cocaine dependence. Interested individuals published reports of prior use of hydergine with human telephoned a toll-free number and scheduled an intake cocaine-dependent individuals. The activity of hydergine appointment to meet with a counselor to discuss the at selective dopamine receptor sites also makes this treatment research and meet with a study physician to medication appropriate for screening. conduct the consent process. The design for the CREST paradigm features multiple active medication conditions and a common placebo to Clinical trial phase support efficient safety and efficacy evaluations. The CREST objective was to determine whether any of the The study employed a flexible 2-week,