Effects of acute topiramate dosing on methamphetamine-induced subjective mood

Abstract

Clinical studies have shown that topiramate, a sulphamate-substituted fructopyranose derivative, might be an efficacious treatment for alcohol dependence, smoking cessation within an alcohol-dependent population, and cocaine dependence. Mechanistically, topiramate's therapeutic effects have been hypothesized to be due to inhibition of cortico-mesolimbic dopamine function, the primary substrate that governs the acquisition, maintenance, and reinstatement of goal-directed behaviour towards seeking abused drugs. Predicated on this hypothesis, we tested in 10 methamphetamine-dependent individuals (three females) whether low- or high-dose (15 or 30 mg i.v.) methamphetamine-induced positive subjective effects and reinforcement can be antagonized by low- or high-dose (100 or 200 mg orally) topiramate using a placebo-controlled, cross-over, factorial design. Methamphetamine administration was associated with orderly, prototypical, and significant increases on measures of stimulation, euphoria, craving, and reinforcement; however, some dysphoric symptoms also emerged. Topiramate alone showed a non-significant trend towards mild reductions in positive mood and reinforcement; yet topiramate appeared to accentuate the appreciation of methamphetamine-induced stimulation and euphoria significantly, but not craving or reinforcement. The experimental combination of topiramate and methamphetamine appeared to be safe and well tolerated, with few adverse events. Acute dosing with up to 200 mg topiramate appears to enhance, rather than attenuate, the positive subjective effects of methamphetamine. Perhaps this indicates a partial inhibition of methamphetamine's reinforcing effects. Thus, testing chronically administered or higher doses, or both, of topiramate would be necessary to determine conclusively whether or not it can attenuate the positive subjective and reinforcing effects of methamphetamine.

Effects of topiramate on cue-induced cigarette craving and the response to a smoked cigarette in briefly abstinent smokers

“…Indeed, drowsiness experienced by the topiramate group may have contributed to this perception. This proposed mechanism for enhanced rewarding effects is consistent with the previous study on topiramate interactions with methamphetamine (Johnson et al 2006). …”

“…This finding is consistent with a recent report that acute topiramate treatment (25 and 50 mg) enhanced the subjective strength and rewarding effects of intravenous nicotine (0.5 and 1.0 mg/kg) (Sofuoglu et al 2006). Studies on methamphetamine found similar results in which intravenous methamphetamine-induced (15 and 30 mg) ratings of euphoria and stimulation were enhanced by topiramate (100 and 200 mg) pretreatment (Johnson et al 2006). This latter study also found evidence that topiramate reduced positive subjective mood (Johnson et al 2006), similar with the present finding that topiramate produced an overall increase in symptoms of nicotine withdrawal.…”

“…Studies on methamphetamine found similar results in which intravenous methamphetamine-induced (15 and 30 mg) ratings of euphoria and stimulation were enhanced by topiramate (100 and 200 mg) pretreatment (Johnson et al 2006). This latter study also found evidence that topiramate reduced positive subjective mood (Johnson et al 2006), similar with the present finding that topiramate produced an overall increase in symptoms of nicotine withdrawal. Taken together, these findings demonstrate that topiramate treatment enhances the rewarding effects of nicotine.…”

Addiction to Amphetamines and Methamphetamines

“…Topiramate a GABA agonist/AMPA antagonist medication was tested in an interaction study with methamphetamine which showed that topiramate enhanced some of the positive effects of methamphetamine. This was attributed to possible PK interaction on methamphetamine metabolism (Johnson et al 2007). A multisite outpatient trial of topiramate 200 mg for reducing meth use was negative for the primary outcome.…”

Global DNA methylation is influenced by smoking behaviour

“…Epigenetic promoter methylation, especially of the p16 gene, due to tobacco smoking has been suggested to be one important pathway in the pathogenesis of lung cancer (Kim et al, 2001;von Zeidler et al, 2004;Dammann et al, 2005). Changes in specific promoter methylation have also been suspected to be associated with tobacco smoking and with a poor prognosis in lung cancer (Kikuchi et al, 2006;Johnson et al, 2006). In addition, an association of lung cancer with global DNA methylation has been found (Piyathilake et al, 2001).…”