Elsevier

Neuropharmacology

Volume 85, October 2014, Pages 493-498
Neuropharmacology

Short-term, low-dose varenicline administration enhances information processing speed in methamphetamine-dependent users

https://doi.org/10.1016/j.neuropharm.2014.05.045Get rights and content

Highlights

  • Varenicline significantly improved RT on the n-back for visual stimuli.

  • Following Varenicline, there was a trend for improvement in RT for auditory stimuli.

  • Varenicline's effect on RT was more evident in those performing poorly at baseline.

Abstract

Long-term, high-dose methamphetamine (METH) use is associated with decrements in neurocognition and, given the association between impaired neurocognition and poorer treatment outcomes in individuals dependent on alcohol and drugs, it is considered to be a neglected area of critical concern. The objective of this study was to determine whether varenicline, a partial agonist at α4β2- and a full agonist at α7-nicotinic acetylcholine receptors, enhances attention/information processing speed, episodic memory, and working memory in non-treatment seeking METH-dependent participants. Twenty-six participants were randomly assigned to receive oral placebo or oral varenicline (titrated up to 1 mg) over 5 days during three separate inpatient phases, and 17 completed each inpatient phase. Participants were predominately male (71%) and Caucasian (71%). Varenicline significantly improved reaction time on the n-back for visual stimuli (F(1,47) = 5.369, p = 0.025, η2 = 0.103), and a trend was observed for improvement in reaction time for auditory stimuli (F(1,47) = 3.141, p = 0.083, η2 = 0.063). For those study participants whose reaction time was in the lower half of the distribution at baseline, the effect was even more pronounced for auditory (F(1,22) = 5.287, p = 0.031, η2 = 0.194) and visual (F(1,22) = 11.981, p = 0.002, η2 = 0.353) stimuli relative to placebo. In contrast, varenicline did not modulate mean or maximum span of working memory or performance on tests of episodic memory or attention (p's > 0.05). Given the potential importance of this finding, it should be replicated in a larger sample over a longer treatment period with a higher dose of varenicline (2 mg).

Trial registration

clinicalTrials.gov Identifier NCT01571167.

Introduction

The United States Department of Health and Human Services estimated that there were 440,000 current (past month) and 133,000 new methamphetamine (METH) users in 2012 (Substance Abuse and Mental Health Services Administration, 2012). This trend is particularly problematic given that METH-dependence is associated with the onset of impaired neurocognition (Cruickshank and Dyer, 2009). Although the prevalence of neurocognitive impairment as a consequence of METH-dependence has been a source of debate (Hart et al., 2012), the results of studies from different laboratories have consistently documented the presence of impaired neurocognition in a subset of individuals who engaged in long-term, high-dose METH use (Cherner et al., 2010, Dean et al., 2013, Dean et al., 2012, Kalechstein et al., 2003). Importantly, METH-associated neurocognitive impairment has been identified as a neglected area of critical concern (Kalechstein et al., 2010, Sofuoglu, 2010, Sofuoglu et al., 2013), particularly given the association between neurocognitive impairment and poor treatment outcomes in other addictive conditions, such as cocaine- (Aharonovich et al., 2008, Aharonovich et al., 2006, Aharonovich et al., 2003), cannabis- (Sofuoglu et al., 2013) and alcohol-dependence (Bates et al., 2002, Bates et al., 2013).

It is noteworthy that METH-associated neurocognitive impairment can be ameliorated, at least to some degree, using modafinil, an agent that modulates catecholamine function. For example, administration of modafinil, 400 mg/day for 3 days, significantly improved response accuracy on the n-back, a measure of working memory, in those study participants who demonstrated relatively poor performance at baseline (Kalechstein et al., 2010). Two other studies showed that acute modafinil exposure, 200 mg, single dose, improved performance on a reversal learning task (Ghahremani et al., 2011), and reduced reaction time variability on a measure of sustained attention (Dean et al., 2011).

An important neurotransmitter system of interest for the treatment of METH dependence is the cholinergic system, and there is ample evidence to support this approach. For example, a recent study from our laboratory showed that the cholinesterase inhibitor rivastigmine (3 and 6 mg for 7 days) improved working memory in cocaine-dependent individuals (Mahoney et al., 2014). Data from studies and clinical trials utilizing rodent models of neurocognition suggest that varenicline, a partial agonist at α4β2- and a full agonist at α7-nicotinic acetylcholine receptors, improves cognition across multiple domains, including attention and working memory (Rollema et al., 2009). More recently, varenicline administration enhanced performance on a working memory task in cocaine experienced monkeys (Gould et al., 2011). Based on the foregoing, we sought to determine whether short-term administration of varenicline would improve performance on measures of attention/information processing speed, episodic memory, and working memory in non-treatment seeking, METH-dependent volunteers who were also nicotine-dependent.

Section snippets

Institutional review

This study was approved by the Baylor College of Medicine and Michael E. DeBakey Veterans Association Medical Center (MEDVAMC) Institutional Review Boards.

Participants

Candidates were recruited from the Houston metropolitan area through newspaper and radio advertisements, and completed an initial telephone screen to assess basic eligibility. Potential participants then underwent an in-person assessment at the Research Commons of the MEDVAMC to determine study eligibility. During the in-person interview,

Results

Twenty-six subjects were enrolled and 17 subjects completed the protocol. Demographics of the participants included in the final analyses are provided in Table 2.

Preliminary analyses revealed that demographic indices, such as age, estimated premorbid IQ, and education were not correlated with performance on the measures of neurocognition (data not shown). Similarly, indices of substance use, such as years of use, frequency of recent use, and amount used per day were not correlated with

Discussion

This is the first study to examine the effects of short-term oral varenicline on neurocognition in non-treatment seeking METH-dependent volunteers. Moreover, it is the first study to demonstrate that a cholinergic agonist can enhance aspects of neurocognition, i.e. reaction time, in this cohort. The magnitude of the effect of varenicline on reaction time, indexed as eta squared, was medium or large, depending on the analytic approach. In addition, baseline neurocognition was stable over short

Author contributions

Conceived and designed the experiment (RD, ADK, JJM); Performed the experiment (JJM); Analyzed the data: (ADK, JJM); Wrote the paper: (RD, ADK, CDV, JJM).

RD served as an expert witness for Pfizer in the Chantix (varenicline) litigation, for which he received compensation. No other author has a financial relationship with commercial interests to report.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Michael E. DeBakey VA Medical Center, Houston, TX.

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    Supported by NIH: DA027134 (RD).

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