Topiramate impairs cognitive function in methadone-maintained individuals with concurrent cocaine dependence

Widespread cocaine use by methadone maintenance patients contributes to increased health risks and poor treatment outcomes (Dobler-Mikola et al., 2005). No pharmacological agent to date has been approved to treat cocaine dependence. Topiramate, an agonist for gamma-aminobutyric acid A (GABA-A) receptors and antagonist at glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and glutamate kainate 1 (Glu-K1) receptors, has shown promise as a pharmacotherapy across a range of substance use disorders. In animal models, GABA agonists are associated with reduced responsiveness to cocaine, conditioned cues, and self-administration (Barrett, Negus, Mello, & Caine, 2005; Weerts, Froestl, & Griffiths, 2005), and glutamate antagonists are associated with reduced cocaine reinforcement, reinstatement, and cocaine seeking (Kalivas, 2004), and may help to increase motivation to quit cocaine among non-treatment seekers (Dakwar, Levin, Foltin, Nunes, & Hart, 2013). Human studies of topiramate support its potential for treating substance use disorders. In clinical trials, topiramate treatment resulted in longer cocaine abstinence (Johnson et al., 2013; Kampman et al., 2004; Kampman et al, 2013) and reduced methamphetamine use and relapse (Elkashef et al., 2012) compared to placebo. Topiramate has shown effectiveness in treating alcohol dependence (Baltieri, Daro, Ribeiro, & de Andrade, 2008; Johnson, Rosenthal, et al., 2007; Shinn & Greenfield, 2010). In male – but not female – tobacco smokers, topiramate was associated with improved quit rates, reduced withdrawal symptoms, and less post-cessation weight gain (Anthenelli, Blom, McElroy, & Keck, 2008). Case and retrospective studies found that topiramate was effective for reducing withdrawal symptoms during opioid detoxification (Zullino, Cottier, & Besson, 2002; Zullino et al., 2004). Topiramate has also shown some success as a treatment for disorders sharing symptoms or comorbid with substance use, including impulsive-compulsive disorders (e.g., binge eating, obsessive-compulsive disorder) and posttraumatic stress disorder (Berlin et al., 2011; Reas & Grilo, 2014; Shinn & Greenfield, 2010; Watts et al., 2013). High adverse event rates and attrition limit its acceptability. Potential cognitive side effects raise concerns about topiramate use (Loring, Williamson, Meador, Wiegand, & Hulihan, 2011). Topiramate studies have found impairments in learning and memory, psychomotor function, and language in patients with drug dependence (Johnson, Roache, et al., 2007; Johnson, Rosenthal, et al., 2007), epilepsy (Eddy, Rickards, & Cavanna, 2011), and migraine (Romigi et al., 2008) as well as in healthy volunteers (Park & Kwon, 2008). Johnson, Roache, et al. (2007) used a double-blind, placebo-controlled, crossover design to measure acute cognitive effects of topiramate (0mg, 100mg, 200mg) administered prior to intravenous methamphetamine (0mg, 15mg, 30mg) in recently abstinent, non-treatment seeking methamphetamine-dependent participants (n=10). They found evidence of both improved and worsened cognitive performance, which could present compliance barriers for individuals that endorse cognitive enhancement as a significant reason for continued methamphetamine use (Brecht et al., 2004; Cretzmeyer et al., 2004; von Mayrhauser, Brecht, & Anglin, 2002). A clinical trial of topiramate (300 mg/day) for alcohol dependence treatment (n=371) found a greater rate of cognitive adverse events (i.e., worsening of concentration) in the treatment group compared to those receiving placebo (14.8% vs. 3.2%) (Johnson, Rosenthal, et al., 2007). The efficacy of topiramate treatment for cocaine dependence in methadone maintenance patients should be evaluated in light of possible cognitive effects. Although healthy adults have shown some cognitive difficulties following topiramate administration, the single study including persons with methamphetamine dependence (Johnson, Roache, et al. 2007) found mixed results. Individuals with chronic substance use disorders may be sensitive to topiramate's cognitive side effects due to an increased likelihood of low functional reserve and pre-morbid cognitive impairment (Fein & Di Sclafani, 2004; Ivanov, Schulz, London, & Newcorn, 2008; Yucel, Lubman, Solowij, & Brewer, 2007). Abuse of opiates and cocaine has been associated with cognitive impairment and could potentially exacerbate the cognitive side effects of topiramate (Beveridge, Gill, Hanlon, & Porrino, 2008; Lundqvist, 2010; Mintzer et al., 2007; Zacny, 1995). The present study sought to provide an assessment of topiramate's effects on cognitive performance in individuals dually dependent on cocaine and opioids as part of a treatment trial of topiramate for cocaine dependence during methadone maintenance treatment.