The cardiovascular and subjective effects of methamphetamine combined with γ-vinyl-γ-aminobutyric acid (GVG) in non-treatment seeking methamphetamine-dependent volunteers

https://doi.org/10.1016/j.pbb.2009.08.007Get rights and content

Abstract

γ-Vinyl-γ-aminobutyric acid (GVG) elevates central nervous system γ-aminobutyric acid (GABA) levels by irreversibly inhibiting GABA transaminase. An open-label clinical trial in humans suggested that GVG may reduce cocaine and methamphetamine use. To test safety and to obtain preliminary data on efficacy of GVG for treating methamphetamine dependence, we conducted a double-blind, placebo-controlled, parallel group study of GVG interaction with the cardiovascular and subjective effects produced by methamphetamine. Non-treatment seeking methamphetamine-dependent volunteers received either GVG (N = 8) or placebo (N = 9) by random assignment. GVG treatment was initiated at 1 g/day and increased to 5 g/day. After reaching the target dose of 5 g/day, participants received methamphetamine (15 + 30 mg, IV), and cardiovascular and subjective effects were assessed. No serious adverse events were noted, and the total number of adverse events was similar between the treatment groups. Considering the full time course and peak effects independently, no significant differences were detected between the groups for systolic or diastolic blood pressures, or heart rate, following methamphetamine exposure. Some methamphetamine-induced cardiovascular changes approached significance (p < 0.10) and may warrant attention in future trials. Methamphetamine-induced subjective effects (“any drug effect”, “high”, “crave methamphetamine”) were statistically similar between GVG and placebo treatment groups. Pharmacokinetic data indicate that GVG treatment did not alter methamphetamine or amphetamine plasma levels, and there was no association between methamphetamine or amphetamine plasma levels and peak cardiovascular effects. Taken together, the data indicate that GVG treatment is generally well tolerated but not efficacious in attenuating the positive subjective effects of methamphetamine in the laboratory.

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.

Section snippets

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.

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