Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence
Introduction
More people use amphetamine-type stimulants, including methamphetamine (MA), worldwide (35 million) than any illicit drug besides cannabis (United Nations Office on Drugs and Crime, 2004) and MA use currently represents the fastest growing drug problem in the United States (National Association of Counties, 2005). Admissions to treatment for MA abuse and dependence outpaced those for cocaine or heroin abuse in 14 states in the West, Midwest and South (Center for Substance Abuse Research-CESAR, 2005), and in California, more than one-half of all publicly funded treatment provided to drug offenders in lieu of prison was for MA abuse or dependence (Longshore et al., 2004). The increasing rate of Americans seeking treatment for MA problems underscores the need for one or more medications that might effectively be integrated with behavioral therapies to treat MA dependence. Yet, randomized placebo-controlled trials of a variety of available medications, including the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (Batki et al., 1999) and sertraline (Shoptaw et al., 2006), the calcium channel blocker amlodipine (Batki et al., 2001), the tricyclic antidepressant imipramine (Galloway et al., 1996), and the 5HT-3 antagonist ondansetron (Johnson et al., 2004), failed to find a significant effect on MA use for any of these medications compared to placebo. As a result, studies to assess additional medications are needed.
Preclinical and early clinical studies suggest that medications that act on the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may be effective in treating cocaine dependence, and by extension also effective for MA dependence. GABA neurons decrease transmission in the mesolimbic dopamine system, particularly the nucleus accumbens (NAc) and ventral tegmental area (VTA), which are thought to play a role in the reinforcing effects of both cocaine and MA, suggesting that GABA agonists may reduce the reinforcing effects of stimulants (Dewey et al., 1998, Cousins et al., 2002). Baclofen, a selective GABAB agonist, reduced cocaine self-administration in rats (Roberts and Brebner, 2000, Brebner et al., 2000a) and dose-dependently reduced responding for cocaine in baboons (Weerts et al., 2005) and microinjections of baclofen into the striatum, NAc, and especially the VTA resulted in a significant reduction in cocaine-reinforced break points in rats (Brebner et al., 2000b). Baclofen also resulted in significantly greater reductions in cocaine use compared to placebo in a randomized double-blind placebo-controlled screening trial, especially among study participants with the highest baseline levels of cocaine use (Shoptaw et al., 2003).
Another GABAergic agent gabapentin, an anticonvulsant that increases GABA concentrations in the CNS possibly via inhibition of GABA-transaminase (Maneuf et al., 2003, Kelly, 1998), has produced mixed results in studies for cocaine dependence. Gabapentin reduced cocaine cravings and the discriminative stimulus effects of low doses, but not higher doses, of smoked cocaine in humans (Haney et al., 2005a). But gabapentin was not more effective than placebo in reducing cocaine use in randomized placebo-controlled trials (Berger et al., 2005, Bisaga et al., 2006). These studies suggest that although GABAergic medications may show promise as treatments for cocaine dependence, the efficacy of different GABA agonists may vary.
While similarities between the mechanisms of MA and cocaine suggest that the positive results of trials with GABAergic medications for cocaine dependence may extend to MA dependence as well, few studies have evaluated use of GABAergic medications for MA dependence. In preclinical studies, baclofen dose-dependently decreased intravenous self-administration of MA (Ranaldi and Poeggel, 2002) and d-amphetamine (Brebner et al., 2005) in rats and prevented the increases in NAc dopamine concentrations that usually follow amphetamine administration (Brebner et al., 2005). Baclofen dose-dependently attenuated the development and expression of conditioned place preference for MA in rats (Li et al., 2001), while gabapentin attenuated, but did not entirely block, the development of behavioral sensitization to MA, but not cocaine in mice (Itzhak and Martin, 2000). While these preclinical studies are encouraging, clinical studies to determine the safety and potential effectiveness of GABAergic medications for treating MA dependence have not been performed. Therefore, we conducted a randomized placebo-controlled trial comparing baclofen and gabapentin to placebo among MA dependent participants. We hypothesized that compared to participants receiving placebo, participants receiving baclofen or gabapentin would have greater reductions in MA use, longer retention in treatment, greater reductions in depressive symptoms, and greater reductions in MA craving.
Section snippets
Participants
Study participants were 88 treatment-seeking MA dependent outpatients. All participants met the following inclusion criteria: (1) 18 years of age or older, (2) current MA dependence verified by the Structured Clinical Inventory for the Diagnostic and Statistical Manual Version IV (DSM-IV) (SCID), (3) willing and able to comply with study procedures, (4) willing and able to provide written informed consent and (5) if female and of childbearing potential, not pregnant or lactating and willing to
Results
A total of 340 treatment-seeking individuals provided informed consent and entered the 2-week screening period, of which 88 met all inclusion and no exclusion criteria and were randomized. Sixty percent of participants randomized to baclofen completed the 16-week medication period, compared to 34.6% of participants randomized to gabapentin and 40.5% of participants randomized to placebo. Reasons for not completing the study are shown in Fig. 1.
Discussion
In this randomized, double blind, placebo-controlled screening trial investigating the potential effectiveness of baclofen and gabapentin as pharmacotherapy for MA dependence, we found no statistically significant differences for either medication relative to placebo as measured using standard treatment outcome measures including retention, medication adherence, depressive symptoms, craving, and aggregate urine drug screen results, although outcome measures among participants receiving baclofen
Acknowledgement
The authors gratefully acknowledge the support of NIDA grant 1 P50 DA 18185 for the conduct of this study.
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