Effect of Varenicline Combined with High-Dose Alcohol on Craving, Subjective Intoxication, Perceptual Motor Response, and Executive Cognitive Function in Adults with Alcohol Use Disorders: Preliminary Findings.

BACKGROUND: Varenicline has been found to decrease alcohol-motivated behaviors. Recent warnings regarding aversive events associated with varenicline used in conjunction with alcohol warrant further investigation into the safety of the drug when combined with alcohol. The purpose of this preliminary investigation was to examine the effect of combining varenicline with a high, fixed dose of alcohol on subjective reactivity and cognitive function in adults with alcohol use disorders (AUDs). METHODS: This double-blind, placebo-controlled preliminary investigation examined the effects of varenicline (0, 1, 2 mg/d) on subjective reactivity, cognition, perceptual motor function, and physiologic reactivity to a fixed dose of alcohol (vs. nonalcohol control beverage) using an established laboratory paradigm in smokers and nonsmokers meeting criteria for AUDs (n = 44). All participants had completed a parent varenicline study evaluating alcohol self-administration. Each subject completed 2 fixed-dose laboratory sessions assessing reactivity to a high-dose alcohol (0.08 g/dl) or a nonalcoholic control beverage, order counterbalanced. RESULTS: Varenicline attenuated alcohol-related increases in subjective intoxication and alcohol-related decreases in executive cognitive function. At baseline, varenicline reduced alcohol craving and diastolic blood pressure, and increased associative learning, working memory, and perceptual motor function. Varenicline produced nonspecific effects on diastolic blood pressure and heart rate. Overall, there were few differences in effects between 1 and 2 mg/d varenicline versus placebo. CONCLUSIONS: These preliminary results continue to support the safety and use of varenicline in combination with alcohol in individuals meeting criteria for AUDs.

Developing and validating a human laboratory model to screen medications for smoking cessation.

INTRODUCTION: To facilitate translational work in medications development for smoking cessation, we have developed a human laboratory analogue of smoking lapse behavior. Our paradigm models 2 critical features of smoking lapse: the ability to resist the first cigarette and subsequent ad libitum smoking. In this paper we present the results of 2 studies designed to develop and validate the effect of nicotine deprivation on smoking lapse behavior. METHODS: Study 1 (n = 30) was designed to develop the model parameters by examining varying levels of nicotine deprivation (1, 6, and 18 hr; within-subject) and identifying optimum levels of monetary reinforcement to provide while modeling the ability to resist smoking. Study 2 was designed to validate the model by screening smoking cessation medications with known clinical efficacy. Subjects (n = 62) were randomized to either varenicline 2 mg/day, bupropion 300 mg/day, or placebo, and we then modeled their ability to resist smoking and subsequent ad libitum smoking. RESULTS: In Study 1, increasing levels of nicotine deprivation and decreasing levels of monetary reinforcement decreased the ability to resist smoking. In Study 2, the lapse model was found to be sensitive to medication effects among smokers who demonstrated a pattern of heavy, uninterrupted, and automated smoking (i.e., smoked within 5 min of waking). Ratings of craving, mood, withdrawal, and subjective cigarette effects are presented as secondary outcomes with results mirroring clinical findings. CONCLUSIONS: Our smoking lapse model demonstrates promise as a translational tool to screen novel smoking cessation medications. Next steps in this line of research will focus on evaluating predictive validity.

Nicotine deprivation and trait impulsivity affect smokers' performance on cognitive tasks of inhibition and attention.

Increased nicotine deprivation and impulsivity have been associated with relapse but the degree to which they together influence cognitive processing has not been explored. We examined the effects of increasing levels of nicotine deprivation on cognitive processing, and assessed the relationship of trait impulsivity with these effects in daily smokers (n=30). Using a within-subject design with three deprivation conditions (nondeprived, 5-hr, 17-hr), volunteers completed the Conners' Continuous Performance Task-II and the Cued Go/No-Go Task. Trait impulsivity was assessed at intake with the Barratt Impulsiveness Scale (Patton et al., 1995). Mixed-model regression analyses revealed deprivation slowed reaction time, increased errors, increased variability in responding, and increased failures of inhibitory control. Performance at 17 hours of deprivation was most likely to be affected. Significant deprivation and impulsivity interactions indicated impulsiveness was negatively correlated with deprivation-associated performance decrements. Less impulsive smokers were more affected by deprivation, demonstrating greater impairment. Research is needed to understand mechanisms by which impulsivity confers greater risk for relapse. Our results suggest deprivation may not increase relapse risk among impulsive smokers by increasing impairment of cognitive processing.

Effect of Lowering the Dose of Varenicline on Alcohol Self-administration in Drinkers With Alcohol Use Disorders.

OBJECTIVES: Varenicline (2 mg/d) has been shown to be efficacious in reducing alcohol consumption. A lower dose of varenicline may be effective in reducing alcohol use while minimizing the potential for side effects. METHODS: This double-blind, placebo-controlled investigation examined the effect of varenicline (0, 1, 2 mg/d) on alcohol consumption in nontreatment-seeking adults meeting the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) criteria for alcohol use disorders (N = 60). Following 7 days of medication pretreatment, participants were administered a low fixed dose of alcohol (0.3 g/dL), and subjective and physiologic responses were assessed. A 2-hour ad libitum alcohol self-administration period followed. We also explored relationships between plasma varenicline levels and consumption. RESULTS: Overall, frequency and severity of adverse events were minimal. The 1 mg/d dose reduced the frequency of insomnia compared with the 2 mg/d dose. The 2 mg/d varenicline dose versus placebo reduced alcohol craving and showed limited effect on reduced alcohol consumption. Alcohol craving and consumption did not differ between the 1 mg/d varenicline dose versus placebo. Trough varenicline plasma levels greater than or equal to 3 ng/mL were associated with reduced drinking and levels greater than or equal to 5 ng/mL were associated with reduced heavy drinking. CONCLUSIONS: Overall, we found no evidence supporting an effect of 1 mg/d varenicline on craving or consumption, suggesting that doses of varenicline less than 2 mg/d may not be effective in reducing alcohol-related outcomes. Importantly, results suggest that higher plasma levels of varenicline may be needed to maximize the effect of varenicline on alcohol consumption and should be investigated in drinkers meeting criteria for alcohol use disorders.

Effects of the nicotinic receptor antagonist mecamylamine on ad-lib smoking behavior, topography, and nicotine levels in smokers with and without schizophrenia: a preliminary study.

Individuals with schizophrenia have higher plasma nicotine levels in comparison to non-psychiatric smokers, even when differences in smoking are equated. This difference may be related to how intensely cigarettes are smoked but this has not been well studied. Mecamylamine (MEC), a non-competitive nicotinic acetylcholine receptor (nAChR) antagonist, which has been shown to increase ad-lib smoking and to affect smoking topography, was used in the current study as a pharmacological probe to increase our understanding of smoking behavior, smoking topography, and resulting nicotine levels in smokers with schizophrenia. This preliminary study used a within-subject, placebo-controlled design in smokers with schizophrenia (n=6) and healthy control smokers (n=8) to examine the effects of MEC (10mg/day) on ad-lib smoking behavior, topography, nicotine levels, and tobacco craving across two smoking deprivation conditions (no deprivation and 12-h deprivation). MEC, compared to placebo, increased the number of cigarettes smoked and plasma nicotine levels. MEC increased smoking intensity and resulted in greater plasma nicotine levels in smokers with schizophrenia compared to controls, although these results were not consistent across deprivation conditions. MEC also increased tobacco craving in smokers with schizophrenia but not in control smokers. Our results suggest that antagonism of high-affinity nAChRs in smokers with schizophrenia may prompt compensatory smoking, increasing the intensity of smoking and nicotine exposure without alleviating craving. Further work is needed to assess whether nicotine levels are directly mediated by how intensely the cigarettes are smoked, and to confirm whether this effect is more pronounced in smokers with schizophrenia.