Varenicline Reduces Alcohol Self-Administration in Heavy-Drinking Smokers

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06519, USA.
Biological psychiatry (Impact Factor: 10.26). 03/2009; 66(2):185-90. DOI: 10.1016/j.biopsych.2009.01.029
Source: PubMed


Alcohol and tobacco dependence are highly comorbid disorders, with preclinical evidence suggesting a role for nicotinic acetylcholine receptors (nAChRs) in alcohol consumption. Varenicline, a partial nicotinic agonist with high affinity for the alpha4beta2 nAChR receptor, reduced ethanol intake in rodents. We aimed to test whether varenicline would reduce alcohol consumption and alcohol craving in humans.
This double-blind, placebo-controlled investigation examined the effect of varenicline (2 mg/day vs. placebo) on alcohol self-administration using an established laboratory paradigm in non-alcohol-dependent heavy drinkers (n = 20) who were daily smokers. Following 7 days of medication pretreatment, participants were first administered a priming dose of alcohol (.3 g/kg) and subjective, and physiologic responses were assessed. A 2-hour alcohol self-administration period followed during which participants could choose to consume up to 8 additional drinks (each .15 g/kg).
Varenicline (.5 +/- SE = .40) significantly reduced the number of drinks consumed compared to placebo (2.60 +/- SE = .93) and increased the likelihood of abstaining from any drinking during the self-administration period. Following the priming drink, varenicline attenuated alcohol craving and reduced subjective reinforcing alcohol effects (high, like, rush, feel good, intoxicated). Adverse events associated with varenicline were minimal and, when combined with alcohol, produced no significant effects on physiologic reactivity, mood, or nausea.
This preliminary investigation demonstrated that varenicline significantly reduced alcohol self-administration and was well tolerated, alone and in combination with alcohol in heavy-drinking smokers. Varenicline should be investigated as a potential treatment for alcohol use disorders.

Download full-text


Available from: Marina R Picciotto,
    • "oncurrent con - sumption of alcohol . Surprisingly , we observed a lack of varenicline effect on alcohol self - administration in msP rats . While this find - ing differs from previous studies showing a reduction of alcohol consumption both in rodents and humans following varenicline administration ( Fucito et al . , 2011 ; Kamens et al . , 2010 ; McKee et al . , 2009 ; Mitchell et al . , 2012 ; Steensland et al . , 2007 ) , a lack of effi - cacy of varenicline on alcohol drinking has also been previously reported in both rodents and humans ( Ginsburg and Lamb , 2013 ; Plebani et al . , 2013 ; Randall et al . , 2015 ) . Moreover , in a recent place conditioning study varenicline was unable to prevent"
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Alcohol and nicotine are largely co-abused. Here, we investigated whether concurrent exposure to both addictive drugs influences each other's consumption and whether varenicline attenuates alcohol consumption in the presence of nicotine. Methods: Marchigian Sardinian alcohol-preferring (msP) rats trained to simultaneously self-administer oral alcohol (10% v/v) and intravenous nicotine (30μg/kg/inf) were used. Additional groups of rats were trained to self-administer either alcohol or nicotine. Further, msP rats were also trained to self-administer nicotine followed by 22-h/day access to alcohol and water in a two bottle free choice paradigm or water alone. The effects of varenicline (0.0, 0.3, 1.0, 3.0mg/kg, p.o.) on alcohol and nicotine consumption were tested. Results: In a self-administration paradigm, msP rats showed a significantly high level of alcohol and nicotine intake when the drugs were administered alone. However, when access to both drugs occurred concomitantly, the number of nicotine infusions self-administered was significantly decreased. Nicotine self-administration was markedly reduced by varenicline regardless of whether it was self-administered alone or concurrently with alcohol. In a two bottle choice test, varenicline significantly decreased nicotine self-administration but had no influence on alcohol consumption. Conclusion: Varenicline is highly efficacious in decreasing nicotine self-administration either alone or in combination with alcohol. However, varenicline failed to influence both operant responding for alcohol and home-cage alcohol drinking in msP animals. Taken together, our findings suggest that the effects of varenicline could be specific to nicotine under conditions where excessive alcohol drinking is facilitated by genetic factors as in msP rats.
    Drug and Alcohol Dependence 09/2015; DOI:10.1016/j.drugalcdep.2015.09.002 · 3.42 Impact Factor
  • Source
    • "The aim of this study is to test this claim in humans by examining the relationship between SR and alcohol craving as a function of alcoholism development. Based on previous studies that have shown significant correlations between craving and alcohol self-administration over and above SR variables (McKee et al. 2009, 2008; O'Malley et al. 2002) and on the content of craving scales that position craving as a theoretically more proximal variable to actual alcohol consumption (e.g. ' All I want to do now is have a drink'; Bohn et al. 1995), alcohol craving was selected as the primary dependent variable of interest. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pre-clinical neurobiological models of addiction etiology including both the allostatic model and incentive sensitization theory suggest that alcohol consumption among alcohol-dependent (AD) individuals will be dissociated from hedonic reward as positive reinforcement mechanisms wane in later stage dependence. The aims of this study are to test this claim in humans by examining the relationship between dimensions of subjective responses to alcohol (SR) and alcohol craving across levels of alcohol exposure. Non-treatment-seeking drinkers (n = 205) completed an i.v. alcohol challenge (final target breath alcohol concentration = 0.06 g/dl) and reported on SR and craving. Participants were classified as light-to-moderate drinkers (LMD), heavy drinkers (HD) or AD. Analyses examined group differences in SR and craving response magnitude, as well as concurrent and predictive associations between SR domains and craving. At baseline, LMD and AD reported greater stimulation than HD, which carried over post-alcohol administration. However, stimulation was dose-dependently associated with alcohol craving in HD only. Furthermore, lagged models found that stimulation preceded craving among HD only, whereas this hypothesized pattern of results was not observed for craving preceding stimulation. Sedation was also positively associated with craving, yet no group differences were observed. In agreement with the prediction of diminished positive reinforcement in alcohol dependence, this study showed that stimulation/hedonic reward from alcohol did not precede craving in AD, whereas stimulation was dose-dependently associated with and preceded craving among non-dependent HD. © 2015 Society for the Study of Addiction.
    Addiction Biology 08/2015; DOI:10.1111/adb.12293 · 5.36 Impact Factor
  • Source
    • "Recent laboratory studies in humans and animals have shown that varenicline, relative to placebo, reduces alcohol consumption (Steensland et al., 2007; McKee et al., 2009). Further, although not all clinical trials have reported reduced drinking in participants treated with varenicline relative to placebo (Plebani et al., 2013), a review of all trials supported the use of varenicline as a treatment to reduce alcohol consumption (Erwin and Slaton, 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preclinical and emerging clinical evidence indicates that varenicline, a nicotinic partial agonist approved for smoking cessation, attenuates alcohol seeking and consumption. Reductions of alcohol craving have been observed under varenicline treatment and suggest effects of the medication on alcohol reward processing, but this hypothesis remains untested. In this double-blind, placebo-controlled randomized experimental medicine study, 29 heavy drinkers underwent a functional magnetic resonance imaging scan after 2 weeks of varenicline (2mg/d) or placebo administration. During functional magnetic resonance imaging, participants performed the Alcohol-Food Incentive Delay task, where they could earn points for snacks or alcohol. At baseline and after 3 weeks of medication, participants underwent intravenous alcohol self-administration sessions in the laboratory. During the functional magnetic resonance imaging scan, participants in the varenicline group (N=17) reported lower feelings of happiness and excitement on subjective mood scales when anticipating alcohol reward compared with the placebo group (N=12). Linear mixed effects analysis revealed that anticipation of alcohol reward was associated with significant blood oxygen level dependent activation of the ventral striatum, amygdala, and posterior insula in the placebo group; this activation was attenuated in the varenicline group. The varenicline group showed no difference in intravenous alcohol self-administration relative to the placebo group for either session. Participants with higher insula activation when anticipating alcohol reward showed higher alcohol self-administration behavior across groups. Our findings suggest that varenicline decreases blood oxygen level dependent activation in striato-cortico-limbic regions associated with motivation and incentive salience of alcohol in heavy drinkers. This mechanism may underlie the clinical effectiveness of varenicline in reducing alcohol intake and indicates its potential utility as a pharmacotherapy for alcohol use disorders. Published by Oxford University Press on behalf of CINP 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    The International Journal of Neuropsychopharmacology 07/2015; DOI:10.1093/ijnp/pyv068 · 4.01 Impact Factor
Show more