The two most prominent models to explain the co-use of nicotine and alcohol are: cross reinforcement through the mesolimbic dopamine pathway and cross-tolerance through shared genetic and nicotinic acetylcholine receptor interactions . The first mechanism of comorbidity is cross-reinforcement which is defined as the ability of nicotine to increase the motivation to consume alcohol and vice versa due to a shared neurobiological mechanism . Both nicotine and alcohol have been shown to activate the mesolimbic pathway. For nicotine, previous studies have shown nicotine self-administration to occur to activate the mesolimbic dopamine pathway through the VTA and the activation of nAChRs may stimulate the VTA neurons to release dopamine in the NAcc . Alcohol has also been shown to affect the mesolimbic pathway through interacting with nAChRs that have been shown to increase the rewarding properties of alcohol , and alcohol self-administration has been linked with dopamine release in the NAcc . The second mechanism perpetuating co-use is cross-tolerance. Tolerance is defined as continued use of a fixed amount of a substance resulting in a suppression of the effect, thus a greater amount of the substance is needed to produce the same effect. Both alcohol and nicotine have been shown to lead to tolerance .In the alcohol literature, individuals with a family history of alcohol dependence may experience a blunted sensitivity to the effects of alcohol , thus leading to potentially greater alcohol consumption. Of note, current smokers have been shown to have a diminished intoxicating effect of alcohol in comparison to non-smokers or former smokers . A second hypothesis contributing to cross-tolerance is the role of nicotinic receptors,cannabis indoor greenhouse as alcohol has been shown to alter the function of several nAChR subtypes, and subsequently alter neurotransmitter transmission at these receptors .
A previous study found that alcohol-induced impairments in coordination were reduced by nicotine via nAChR sub-type function, specifically alpha-7 sub-types further suggesting the role of these receptors in cross-tolerance of nicotine and alcohol . Taken together, these are two possible mechanisms of action whereby nicotine and alcohol continue to potentiate the rewarding effects of the opposing substance, while increasing use through cross-tolerance, resulting in the observed high rates of co-use. Human laboratory studies serve as one methodological avenue by which some of these mechanisms of action have been examined in humans. Alcohol may increase the rewarding aspects of cigarette smoking as it has been associated with greater satisfaction of the cigarette and relief of craving a cigarette . Administering alcohol to those who co-use is associated with dose-dependent increases craving for cigarettes , and this effect may be mediated by the stimulating effects of alcohol . Conversely, nicotine administration has been shown to increase alcohol consumption in both animal studies and human studies . Nicotine has also been shown to increase the sedative effects of alcohol . Notably, a majority of studies have focused on the effect of alcohol on nicotine use and less research thus far has examined the effect of nicotine on alcohol. Interestingly, there has been some evidence to suggest that the effects of nicotine on alcohol may differ by gender. Acheson and colleagues found an increase in alcohol consumption among men but not women. An ecological momentary assessment study demonstrated that when both substances were administered simultaneously, there was a joint increase in craving for both cigarettes and alcohol . Taken together, these studies highlight how individuals who co-use do qualify as a unique subgroup of heavy drinking smokers with a distinctive clinical profile and treatment needs In sum, there is ample evidence highlighting the strong bidirectionality of these two substances and their associated long-term health consequences. Emerging evidence continues to support the two mechanisms of cross-reinforcement and cross-tolerance; however translational research is needed to bridge the gap between earlier pre-clinical studies and examining these mechanisms of action in human studies.
As mentioned above, more research to date has examined the impact of alcohol use on cigarette smoking. While this bidirectional relationship exists, there is evidence to suggest that alcohol may more strongly influence cigarette smoking than vice versa. This may in part be due to the lack of research examining the impact of nicotine on alcohol and may highlight the robust role of alcohol increasing the complexity of treatment for smoking cessation. One of the major difficulties in treating heavy drinking smokers is the increased likelihood they have of experiencing a smoking lapse while drinking particularly in the early stages of their smoking cessation attempt where time between initial smoking lapse and return to daily smoking has been associated with pre-treatment confidence . Estimates suggest that up to 95% of smokers who experience a smoking lapse will progress to relapse . Previous studies have shown that smokers who smoke more during their first lapse, and experience greater hedonic ratings, have a greater risk of progressing to relapse . This first lapse has been hypothesized to represent the transition from abstinence to relapse with regular smoking has . Earlier smoking cessation trials often excluded smokers with current or past AUD, resulting in under representation of smokers with alcohol problems in pharmacotherapy smoking cessation trials . Given the impact of alcohol on smoking quit attempts and the overlapping neurobiological mechanisms that maintain co-use, it is imperative to address alcohol use in smoking cessation treatment for heavy drinking smokers. Few studies to date have examined behavioral treatments for combined cigarette and alcohol use that did not involve some form of pharmacotherapy. One pilot study examined whether including personalized feedback on alcohol response phenotype would improve brief intervention outcomes among young adult heavy drinking smokers . At 6-month follow-up, the group with the personalized feedback reported decreasing their drinking and smoking co-use by 39% which was comparably greater than the reductions made by the group that did not receive personalized alcohol feedback .
Arandomized controlled trial examining tobacco quit-lines found the inclusion of a brief alcohol intervention resulted in significantly higher smoking cessation rates for individuals with hazardous drinking . A recent Cochrane review found that individually delivered smoking cessation counseling was more effective than minimal contact , and evidence to suggest a smaller relative benefit in treatment outcomes when participants also received pharmacotherapy, specifically nicotine replacement therapy . The Clinical Practice Guidelines for smoking cessation recommend that pharmacological treatments are used in combination with psychotherapy or behavioral therapy . Next, we briefly review the evidence base for pharmacological treatment of smoking, drinking, and their co-use. Varenicline is a high affinity, partial agonist,cannabis growing equipment at the α4β2 nAChR receptor subtype and was FDA approved in 2006 for the treatment of nicotine dependence. The α4β2 nAChR receptor subtype has been strongly implicated in the addictive properties of nicotine and has become a novel molecular target for smoking cessation medications . The rationale behind using a partial agonist is to leverage the benefits of an agonist in reducing withdrawal symptoms and an antagonist in attenuating the rewarding effects of smoking . In 2009 the FDA issued a black box warning, the strongest safety warning the FDA can administer due to concerns regarding suicidal thoughts and depression with varenicline. A systematic review and meta-analysis examined the neuropsychiatric adverse events associated with varenicline and found no evidence of an increased risk of suicidal ideation or suicide . The authors suggested the initial black box warning was likely due to early studies consisting of observation cohorts that are more likely to be confounded by indication and possible bias regarding industry sponsored trials reporting favorable outcomes to the study sponsor . In 2016, the FDA removed the black box warning. Clinical trials have supported varenicline’s safety and efficacy as a smoking cessation aid . A review of pharmacotherapies for smoking cessation found varenicline as more effective than singe forms of Nicotine Replacement Therapy and bupropion . An additional review also demonstrated that in comparison to an unaided quit attempt, varenicline increases the chances of smoking cessation two- to threefold . Varenicline has also been examined for long-term efficacy and was found to be safe to administer for up to 1 year with efficacy greater than placebo in the short-term and long-term . Despite these results, success rates for varenicline remain low, which may suggest that there are unexplored individual difference factors that may be influencing varenicline’s efficacy. Varenicline has also been examined as a possible treatment for reducing alcohol consumption, as the nAChR receptors in the ventral tegmental area of the brain have been proposed to mediate the reinforcing effects of alcohol . Human laboratory studies have found varenicline to reduce craving, self-administration, and alcohol consumption in comparison to placebo . The first multisite clinical trial examining varenicline for AUD in a sample of smokers and non-smokers found varenicline to reduce percent heavy drinking days, drinks per day, drinks per drinking day, and craving for alcohol in comparison to placebo . There was a similar average treatment effect across smokers and non-smokers . These results support the potential for using varenicline in a sample of smokers to both reduce cigarette and alcohol consumption. Alcohol triggers several neurotransmitter systems and the endogenous opioids plays a key role in mediating the rewarding effects of alcohol . Evidence suggests that alcohol increases the rewarding effects through release of endogenous opioids and interactions with the dopaminergic system .
Previous studies have found that both consumption of alcohol and exposure to alcohol cues prior to drinking may increase dopamine activity in the NAcc highlighting the role of learning and reinforcement on activation of the mesolimbic dopamine pathway . Naltrexone is an FDA approved pharmacotherapy treatment for alcohol use disorder. Naltrexone is a relatively selective opioid antagonist, with the highest affinity for the mu-opioid receptor . Numerous clinical trials supported naltrexone as a safe, tolerable, and effective pharmacotherapy option for reducing drinking days, drinks per drinking day, and relapse rates . A recent meta-analysis of the effect of naltrexone in the human laboratory setting found naltrexone to reduce craving and alcohol self-administration in comparison to placebo . Four biobehavioral mechanisms of action have been suggested to explain the positive effects of naltrexone for alcohol use: reduction of craving for alcohol, blunting the stimulating effects of alcohol, potentiation of sedative and unpleasant effects of alcohol, and increasing cognitive control . Emerging evidence suggests that naltrexone may also be an effective pharmacotherapy option for reducing tobacco use among heavy drinking smokers. The opioidergic system has also been implicated in modulating the pharmacological effects of nicotine . Naltrexone has been shown to improve smoking cessation rates , while also reducing the frequency of heavy drinking days . Interestingly, one study examining data gathered as part of the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence found that smokers who received naltrexone experienced better drinking outcomes than smokers who received placebo . Additionally, naltrexone has been associated with gender differences in response to naltrexone. King and colleagues found women to have greater reductions in weight gain while men had greater reductions in smoking. Previous studies have also examined naltrexone in combination with traditional pharmacotherapies of smoking cessation. Naltrexone in combination with nicotine replacement therapy has been shown to have beneficial outcomes in improving smoking cessation outcomes . Taken together, these results suggest that naltrexone may improve both alcohol and smoking outcomes for this sub-group of heavy drinking smokers. Evidence for pharmacological treatments for this treatment-resistant subgroup of smokers has been limited and thus warrants further investigation. Currently, there are no pharmacological treatments or guidelines specific to heavy drinking smokers. It has been suggested that medications aiming to block the addictive rewarding effects, increase the aversive effects, and/or reduce drug-conditioned reactivity to cues may serve as effective treatment options for heavy drinking smokers . As varenicline and naltrexone have both exerted effects on smoking outcomes as detailed above, these two medications in combination may serve as a promising treatment combination. Previous work from our laboratory has shown initial promising evidence for the combination of these two medications for smoking cessation outcomes . Ray and colleagues randomized 130 heavy drinking smokers to varenicline , low dose naltrexone , varenicline plus low dose naltrexone , and placebo to examine differences in these medications on subjective response to alcohol and cigarettes craving in the human laboratory. Following nine days on study medication, participants received a priming dose of alcohol to raise their breath alcohol concentration to 0.06g/dl then smoked their first cigarette of the day in laboratory .