The cardiovascular and subjective effects of methamphetamine combined with γ-vinyl-γ-aminobutyric acid (GVG) in non-treatment seeking methamphetamine-dependent volunteers
Introduction
Pre-clinical research has shown that compounds that modulate mesolimbic dopamine (DA) neurotransmission alter the reinforcing effects of several drugs of abuse. In this regard, γ-aminobutyric acid (GABA) inhibits striatal DA release, and attenuates cocaine-induced increases in extracellular DA in the striatum and nucleus accumbens (Molina et al., 1999). Several, but not all, rodent and non-human primate studies have suggested that compounds that target GABA could be useful treatments for cocaine and methamphetamine dependence.
The compound of interest for the current report was γ-vinyl-γ-aminobutyric acid (GVG), an anti-epileptic medication that irreversibly inhibits GABA transaminase, a key enzyme in the metabolic disposition of GABA. GVG inhibits methamphetamine-, heroin-, and ethanol-induced increases in extracellular DA in the nucleus accumbens in rodents (Gerasimov et al., 1999) and reduces cocaine-induced striatal DA release in non-human primates (Dewey et al., 1998). In addition, GVG blocks conditioned place preference for heroin in the rat (Paul et al., 2001), decreases morphine and cocaine (Kushner et al., 1999) self-administration in rats, and reduces cocaine-seeking behavior in baboons (Weerts et al., 2005). Prefrontal cortical GABA levels are low in cocaine-dependent individuals (Streeter et al., 2005), and magnetic resonance spectroscopy has shown increases in brain GABA levels 2–3-fold above baseline following treatment of human participants with GVG (3 g/day) (Verhoeff et al., 1999).
Collectively, these findings suggest that GVG may be a useful treatment for stimulant dependence. Moreover, results from two open-label trials and one placebo-controlled trial suggest that GVG may reduce cocaine and methamphetamine use. In the first study, involving 20 cocaine-dependent volunteers (most also abused methamphetamine, marijuana, and other drugs), 12 participants dropped out before completion, and most of the 8 who remained had a considerable number of days (~ 50) without cocaine or methamphetamine use (Brodie et al., 2003). A follow-up study confirmed this finding (Brodie et al., 2005) and included participants who met criteria for methamphetamine dependence (N = 10), methamphetamine and cocaine dependence (N = 17), or cocaine dependence (N = 3). Eleven participants dropped out, and among completers, 15 were methamphetamine- and cocaine-free for > 4 consecutive weeks. Preliminary results from a subsequent, double-blind, placebo-controlled trial support the view that GVG has efficacy as a treatment for cocaine dependence (Brodie et al., in press).
As an initial step in the clinical development of GVG for methamphetamine dependence, it is important to assess the safety, tolerability, and to obtain preliminary data on efficacy of the compound in methamphetamine-dependent participants. We therefore conducted a double-blind, placebo-controlled, parallel group study to determine the cardiovascular, subjective, and reinforcing effects of methamphetamine in volunteers treated with GVG or placebo.
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Participants
A total of 17 participants were randomized to receive GVG (n = 8) or placebo (n = 9). Participants were recruited using advertisements and paid for their participation. All participants met DSM-IV-TR criteria for methamphetamine dependence and did not meet criteria for dependence on other drugs other than nicotine or marijuana. Additional inclusion criteria included being between 18 and 45 years of age, having a history of using methamphetamine by the smoked or IV route of administration, and being
Demographics and drug use
Detailed demographic information and drug-use data are provided in Table 1. Participants in the GVG (N = 8) and placebo (N = 9) treatment groups were statistically similar along all demographic and drug-use variables.
Adverse events
There were no serious adverse events recorded during this trial. The type, severity and duration of all other adverse events were comparable between the placebo and GVG groups (Table 2).
Of particular interest in a trial that includes GVG treatment are potential ophthalmological
Discussion
We conducted a double-blind, placebo-controlled, parallel group study to determine the cardiovascular, subjective, and reinforcing effects of methamphetamine in volunteers treated with GVG or placebo. The number, type, severity and duration of all adverse events were comparable between placebo and GVG conditions, and therefore indicate that GVG was well tolerated in this stimulant-addicted population.
In the current report, and as demonstrated previously (De La Garza et al., 2008, Newton et al.,
Acknowledgements
This work was supported by the National Institutes of Health (DA 18185; DA 022539; RR 00865). The authors wish to thank Rachel Fintzy, Elizabeth O'Laco, James J. Mahoney, III, and Rujvi Kamat for assistance with data collection.
References (38)
- et al.
A randomized placebo-controlled trial of gabapentin for cocaine dependence
Drug Alcohol Depend
(2006) - et al.
Clinical efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine dependent methadone-treated patients
Drug Alcohol Depend
(2007) - et al.
Smoked cocaine discrimination in humans: effects of gabapentin
Drug Alcohol Depend
(2005) - et al.
Gabapentin maintenance decreases smoked cocaine-related subjective effects, but not self-administration by humans
Drug Alcohol Depend
(2004) - et al.
Smoked cocaine self-administration by humans is not reduced by large gabapentin maintenance doses
Drug Alcohol Depend
(2007) - et al.
Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence
Drug Alcohol Depend
(2006) - et al.
A pilot trial of topiramate for the treatment of cocaine dependence
Drug Alcohol Depend
(2004) - et al.
Acute administration of the GABA reuptake inhibitor tiagabine does not alter the effects of oral cocaine in humans
Drug Alcohol Depend
(2004) - et al.
Co-administration of gamma-vinyl GABA and cocaine: preclinical assessment of safety
Life Sci
(1999) - et al.
Cocaine and methamphetamine produce different patterns of subjective and cardiovascular effects
Pharmacol Biochem Behav
(2005)
Subjective and cardiovascular effects of cocaine during treatment with amantadine and baclofen in combination
Psychiatry Res
Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence
Drug Alcohol Depend
Tiagabine affects the subjective responses to cocaine in humans
Pharmacol Biochem Behav
Effects of GABAergic modulators on food and cocaine self-administration in baboons
Drug Alcohol Depend
A double-blind, placebo-controlled trial of tiagabine for the treatment of cocaine dependence
Drug Alcohol Depend
A medication screening trial evaluation of reserpine, gabapentin and lamotrigine pharmacotherapy of cocaine dependence
Addiction
Treating cocaine addiction: from preclinical to clinical trial experience with gamma-vinyl GABA
Synapse
Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction
Synapse
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