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
  • Source
    • "In particular, NRT is a safe, FDAapproved treatment option that significantly reduces nicotine withdrawal symptoms, thereby increasing the likelihood of remaining abstinent from nicotine following smoking cessation (Hartmann-Boyce et al., 2013;Stead et al., 2012). NRTLitten et al., 2013;McKee et al., 2009;Mitchell et al., 2012) Cocaine Limited (Plebani et al., 2012) Bupropion Reward Nicotine FDA approved Cocaine Mixed (Margolin et al., 1995;Poling et al., 2006;Shoptaw et al., 2008) Methamphetamine Limited (Elkashef et al., 2008) Naltrexone Reward Opioids FDA approved Alcohol FDA approved Nicotine Mixed (e.g.,Covey et al., 1999;King and Meyer, 2000;King et al., 2012;O'Malley et al., 2006;Toll et al., 2010;Wong et al., 1999) Amphetamine Limited (Jayaram-Lindstr€ om et al., 2005) Cocaine Limited (Schmitz et al., 2001) Topiramate Reward Alcohol Promising (e.g.,Baltieri et al., 2008;Batki et al., 2014;Blodgett et al., 2014;Johnson, 2004;Johnson and Ait-Daoud, 2010;Johnson et al., 2003Johnson et al., , 2007aKomanduri, 2003;Kranzler et al., 2014;Krupitsky et al., 2007;Martinotti et al., 2014;Miranda et al., 2008;Paparrigopoulos et al., 2011;Rubio et al., 2004;Rustembegovic et al., 2001) Nicotine Mixed (Anthenelli et al., 2008;Johnson et al., 2005;Khazaal et al., 2006;Oncken et al., 2014;Reid et al., 2007;Sofuoglu et al., 2006) Methamphetamine Limited (Elkashef et al., 2012;Johnson et al., 2007a) Cocaine Limited (Johnson et al., 2013;Kampman et al., 2004Kampman et al., , 2013Nuijten et al., 2014;Reis et al., 2008;Umbricht et al., 2014) Opioids Limited (Zullino et al., 2002Zullino et al., , 2005) Gabapentin Unknown Alcohol Promising (e.g.,Anton et al., 2009Anton et al., , 2011Brower et al., 2008;Furieri and Nakamura-Palacios, 2007;Mason et al., 2009Mason et al., , 2014Trevisan et al., 2008;see Greutman et al., 2015) Cannabis Limited (Lile et al., 2014;Mason et al., 2012) Cocaine Mixed (e.g.,Berger et al., 2005;Bisaga et al., 2006;Gonz alez et al., 2007;Hart et al., 2004Hart et al., , 2007aMyrick et al., 2001;Raby and Coomaraswamy, 2004) Methadone Other (withdrawal) Opioids FDA approved Buprenorphine Other (withdrawal) Opioids FDA approved Nicotine replacement Other (withdrawal) Nicotine FDA approved works to reduce cravings associated with smoking cessation by delivering nicotine to the body in various forms (i.e., chewing gum, lozenges, transdermal patch, inhalers, and nasal sprays) that do not involve tobacco (Fiore et al., 2008). In summary, agonist therapies are among the most efficacious treatments for opioid and nicotine use disorders. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Existing pharmacological treatments for alcohol use disorder (AUD) and other substance use disorders (SUDs) have demonstrated only modest efficacy. Although the field has recently emphasized testing and developing new compounds to treat SUDs, there are numerous challenges inherent to the development of novel medications, and this is particularly true for SUDs. Thus, research to date has tended toward the “repurposing” approach, in which medications developed to treat other mental or physical conditions are tested as SUD treatments. Often, potential treatments are examined across numerous drugs of abuse. Several repurposed medications have shown promise in treating a specific SUD, but few have shown efficacy across multiple SUDs. Examining similarities and differences between AUD and other SUDs may shed light on these findings and offer directions for future research.Methods This qualitative review discusses similarities and differences in neural circuitry and molecular mechanism(s) across alcohol and other substances of abuse, and examines studies of pharmacotherapies for AUD and other SUDs.ResultsSubstances of abuse share numerous molecular targets and involve much of the same neural circuitry, yet compounds tested because they putatively target common mechanisms have rarely indicated therapeutic promise for multiple SUDs.Conclusions The lack of treatment efficacy across SUDs may be partially explained by limitations inherent in studying substance users, who comprise a highly heterogeneous population. Alternatively, medications may fail to show efficacy across multiple SUDs due to the fact that the differences between drug mechanisms are more important than their commonalities in terms of influencing treatment response. We suggest that exploring these differences could support novel treatment development, aid in identifying existing medications that may hold promise as treatments for specific SUDs, and ultimately advance translational research efforts.
    Full-text · Article · Sep 2015 · Alcoholism Clinical and Experimental Research
    • "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.
    No preview · Article · Sep 2015 · Drug and Alcohol Dependence
  • 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.
    Full-text · Article · Aug 2015 · Addiction Biology
Show more