Using an established alcohol self-administration paradigm (30
), we found that varenicline compared with placebo significantly reduced the number of drinks consumed by heavy-drinking smokers and increased the likelihood of remaining completely abstinent during the 2-hour self-administration period. This result is consistent with preclinical findings (29
) examining ethanol seeking and choice and further supports a role for nAChR effects in alcohol consumption. Varenicline also attenuated alcohol craving and subjective reinforcing alcohol effects (e.g., intoxicated) following consumption of the priming drink. Moreover, alcohol craving in response to the priming drink was significantly associated with subsequent alcohol consumption, accounting for half of the variance in drinks consumed. The magnitude of the effect of varenicline on drinks consumed and craving responses is similar to what is demonstrated with naltrexone using an identical laboratory paradigm (30
). Given that naltrexone has demonstrated efficacy for the treatment of alcohol use disorders (47
), this suggests that the observed effects with varenicline have clinical relevance.
On the basis of these findings, we speculate that varenicline may reduce drinking in a similar manner to how it works for smoking: 1) by acting as a partial agonist at α4β2 receptors stimulating adequate levels of dopamine release to prevent alcohol craving and 2) by acting as a competitive antagonist blocking the effect of alcohol at nAChRs to augment dopamine levels further, thus inhibiting alcohol-related reinforcement, craving, and self-administration behavior. A recent microdialysis study (48
) lends support to this hypothesized mechanism. Following 5 days of varenicline pretreatment, an acute injection of varenicline completely abolished the extracellular NA dopamine response to alcohol and nicotine coadministration. Additionally, it is possible that varenicline shifted the pharmacodynamic effect of the priming drink to the right. In contrast to the placebo condition, varenicline attenuated the ability of the priming drink to prompt further ad libitum consumption. Future work examining the mechanisms underlying these findings would further clarify nAChR effects on alcohol consumption.
Overall, varenicline was well tolerated in heavy-drinking smokers during this short-term laboratory study. Side effects experienced during the pretreatment week were minimal, consistent with those observed in smokers undergoing smoking cessation treatment, and rates did not differ between varenicline and placebo groups. When varenicline was combined with alcohol during the laboratory session, we observed no effect of medication on physiologic reactivity or mood ratings in response to the low-dose priming drink. Additionally, adverse effects (nausea, dizzy, jittery) assessed throughout the laboratory session were minimal and did not differ by medication. Although these effects must be replicated in larger samples and studied at higher alcohol doses, our findings indicate that combining varenicline with low doses of alcohol appears safe and well tolerated. This finding is of immediate clinical relevance for the approved use of varenicline in smoking cessation given that the majority of smokers drink (3
). Although there has been concern that varenicline is associated with neuropsychiatric side effects (49
), a recent report examining varenicline for smoking cessation in smokers with psychiatric conditions (including alcohol problems) found that varenicline was safe, well tolerated, and did not exacerbate mental illness (50
Our results, in combination with preclinical findings (29
), suggest that varenicline warrants further development as a treatment for alcohol use disorders. However, our results were obtained in heavy-drinking smokers (with 45% meeting criteria for current alcohol abuse), and it remains to be determined whether these findings will extend to those with alcohol dependence. Among smokers, the potential of varenicline as a dual treatment for alcohol and tobacco disorders should be investigated. Diseases related to tobacco use are the leading cause of morbidity and mortality in alcoholics (51
), and the relative risk of mortality increases with the combined versus singular abuse of alcohol and tobacco (52
). Medications such as varenicline, which may target shared neurobiological substrates of alcohol and nicotine use, hold promise in this regard (2
Varenicline should also be investigated as a primary treatment for alcohol use disorders. Although our study was conducted in smokers, they were not deprived of nicotine, suggesting that varenicline affects alcohol drinking independent of its effects on nicotine withdrawal. Moreover, the preclinical studies of varenicline demonstrating reductions in ethanol seeking and consumption were conducted in nicotine-naïve animals (29
). Future studies in heavy drinkers and alcohol-dependent drinkers who are nonsmokers are indicated. Although we selected the recommended dose for smoking cessation for this study, the dose may not be the optimal one to target drinking behavior. Preclinical investigations of the effect of varenicline on alcohol consumption (29
) and dopamine response (48
) have not demonstrated linear dose effects, supporting the need for a dose-ranging study.
In summary, our results suggest that the nAChR system holds promise as a medication target for alcohol use disorders. In heavy-drinking smokers, we found that varenicline significantly reduced drinking and increased the likelihood of remaining completely abstinent during the self-administration session. Reductions in drinking behavior were associated with attenuated craving responses following the consumption of the priming drink. Given that varenicline was found to be well tolerated, alone and in combination with alcohol, clinical trials examining varenicline as a primary treatment for alcohol use disorders and as a potential dual treatment for alcohol and tobacco use disorders should be pursued.