Rates of alcohol use disorder (AUD) have increased in women by 84% over the past ten years relative to a 35% increase in men. This substantive increase in female drinking is alarming given that women experience greater alcohol-related health consequences compared to men. Stress is strongly associated with all phases of alcohol addiction, including drinking initiation, maintenance, and relapse for both women and men, but plays an especially critical role for women. The purpose of the present narrative review is to highlight what is known about sex differences in the relationship between stress and drinking. The critical role stress reactivity and negative affect play in initiating and maintaining alcohol use in women is addressed, and the available evidence for sex differences in drinking for negative reinforcement as it relates to brain stress systems is presented. This review discusses the critical structures and neurotransmitters that may underlie sex differences in stress-related alcohol use (e.g., prefrontal cortex, amygdala, norepinephrine, corticotropin releasing factor, and dynorphin), the involvement of sex and stress in alcohol-induced neurodegeneration, and the role of ovarian hormones in stress-related drinking. Finally, the potential avenues for the development of sex-appropriate pharmacological and behavioral treatments for AUD are identified. Overall, women are generally more likely to drink to regulate negative affect and stress reactivity. Sex differences in the onset and maintenance of alcohol use begin to develop during adolescence, coinciding with exposure to early life stress. These factors continue to affect alcohol use into adulthood, when reduced responsivity to stress, increased affect-related psychiatric comorbidities and alcohol-induced neurodegeneration contribute to chronic and problematic alcohol use, particularly for women. However, current research is limited regarding the examination of sex in the initiation and maintenance of alcohol use. Probing brain stress systems and associated brain regions is an important future direction for developing sex-appropriate treatments to address the role of stress in AUD.

Alcohol use disorders and tobacco use contribute significant risk to the global burden of disease, and each are major public health concerns. Together, alcohol and tobacco use are highly comorbid and have multiplicative health risks when used concurrently, underscoring the importance of examining alcohol-tobacco interactions in the human laboratory. The aims of this review were to summarize the state of research examining alcohol-tobacco interactions in the human laboratory, including 1) craving in drinkers and smokers exposed to smoking or drinking cues, 2) fixed-dosing of alcohol or nicotine in smokers and drinkers, and 3) smoking and alcohol influences on selfadministration behaviors. The interactive effects of tobacco/nicotine with other drugs of abuse are also briefly discussed. Overall, results identified that alcohol and tobacco have reciprocal influences on potentiating craving, subjective responses to fixed-dose alcohol or nicotine administration, and self-administration. The literature identified that alcohol increases craving to smoke, decreases time to initiate smoking, and increases smoking self-administration. Similarly, tobacco and nicotine increase alcohol craving, decrease subjective effects of alcohol, and increase alcohol consumption. Future studies should continue to focus on alcohol and tobacco/nicotine interactions in individuals with a wide scope of drinking and smoking histories, different states of alcohol and nicotine deprivation, and influences of either drug on craving, subjective responses, and consumption over the course of the blood alcohol curve. This work could have important implications for the impact of alcohol-tobacco interactions on guiding clinical practice, as well as in the changing landscape of addiction.

Objectives Varenicline (2mg/day) 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/day) on alcohol consumption in non-treatment seeking adults meeting 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 1mg/day dose reduced the frequency of insomnia compared to the 2mg/day dose. The 2 mg/day 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/day varenicline dose versus placebo. Trough varenicline plasma levels ≥ 3 ng/ml were associated with reduced drinking and levels ≥ 5ng/ml were associated with reduced heavy drinking. Conclusions Overall, we found no evidence supporting an effect of 1 mg/day varenicline on craving or consumption, suggesting that doses of varenicline less than 2mg/day may not be effective in reducing alcohol-related outcomes. Importantly, results suggest that higher plasma levels of varenicline may be needed in order to maximize the effect of varenicline on alcohol consumption and should be investigated in drinkers meeting criteria for alcohol use disorders.

Background Previous studies show that prazosin, an α1-adrenergic receptor antagonist, decreases alcohol drinking in animal models of alcohol use and dependence (Walker et al., 2008, Rasmussen et al., 2009) and in alcohol-dependent men (Simpson et al., 2009). This study extended these findings by using a paradigm that allows for separate assessment of prazosin on motivation to seek versus consume alcohol or sucrose in selectively bred rats. Methods Alcohol-preferring P rats were trained to complete an operant response that resulted in access to either 2% sucrose or 10% alcohol. A 4-week Seeking Test Phase examined responding in single, weekly extinction sessions when no reinforcer could be obtained. A 4-week Drinking Test Phase consisted of rats lever-pressing to “pay” a specified amount up front to gain access to unlimited alcohol (or sucrose) for a 20-minute period. On Seeking and Drinking test days, prazosin (0.0, 0.5, 1.0, 1.5 mg/kg) was administered (IP) 30 min prior to behavioral sessions. Results Rats were self-administering an average of 0.9 (±0.09) g/kg alcohol on vehicle test day, and had pharmacologically relevant BECs. Prazosin significantly decreased alcohol-seeking at all doses tested. The highest dose of prazosin also increased the latency to first response for alcohol and decreased alcohol intake. While sucrose-seeking and intake were similarly affected by prazosin, the high dose of prazosin did not increase response latency. Conclusions These findings are consistent with and extend previous research and suggest that prazosin decreases motivation to initiate and engage in alcohol consumption. The specificity of prazosin in attenuating the initiation of alcohol- but not sucrose-seeking suggests that this effect is not due to prazosin-induced motor-impairment or malaise. Together with previous findings, these data suggest that prazosin may be an effective pharmacotherapy, with specific application in people that drink excessively or have a genetic predisposition to alcohol abuse.

Cigarette smokers report using e-cigarettes to reduce or quit smoking but findings are mixed regarding the benefit and risk of e-cigarettes in this population. Using data from the newly available Population Assessment of Tobacco and Health (PATH; waves 1 & 2; adult interviews), our findings identify e-cigarettes as a potential aid for smoking cessation, but also identify e-cigarettes as a potential risk for smoking relapse in men only. These findings may have implications for the regulation of e-cigarettes by the FDA and the benefit-cost ratio of e-cigarette use in smokers.

Preclinical findings support a role for α1-adrenergic antagonists in reducing nicotine motivated behaviors, but these findings have yet to be translated to humans. The current study evaluated whether doxazosin would attenuate stress-precipitated smoking in the human laboratory. Using a well-validated laboratory analogue of smoking-lapse behavior, this pilot study evaluated whether doxazosin (4 and 8 mg/day) versus placebo attenuated the effect of stress (vs. neutral imagery) on tobacco craving, the ability to resist smoking and subsequent ad-libitum smoking in nicotine-deprived smokers (n=35). Cortisol, adrenocorticotropin (ACTH), norepinephrine, epinephrine, and physiologic reactivity were assessed. Doxazosin (4 and 8 mg/day versus placebo) decreased cigarettes per day during the 21-day titration period. Following titration, doxazosin (4 and 8 mg/day versus placebo) decreased tobacco craving. During the laboratory session, doxazosin (8 mg/day versus placebo) further decreased tobacco craving following stress versus neutral imagery. Doxazosin increased the latency to start smoking following stress, and reduced the number of cigarettes smoked. Dosage of 8 mg/day doxazosin increased or normalized cortisol levels following stress imagery and decreased cortisol levels following neutral imagery. These preliminary findings support a role for the noradrenergic system in stress-precipitated smoking behavior, and support further development of doxazosin as a novel pharmacotherapeutic treatment strategy for smoking cessation.

Converging lines of preclinical and clinical evidence suggest that gender-sensitive approaches to medication development for smoking cessation are a critical next step for addressing low quit rates and exacerbated health risks among women. Evidence reviewed indicates that smoking activates different brain systems modulated by noradrenergic activity in women versus men, and noradrenergic compounds may preferentially target these gender-sensitive systems.

Over the last 10 years, rates of alcohol use disorder (AUD) have increased in women by 84% relative to a 35% increase in men. Rates of alcohol use and high‐risk drinking have also increased in women by 16% and 58% relative to a 7% and 16% increase in men, respectively, over the last decade. This robust increase in drinking among women highlights the critical need to identify the underlying neural mechanisms that may contribute to problematic alcohol consumption across sex/gender (SG), especially given that many neuroimaging studies are underpowered to detect main or interactive effects of SG on imaging outcomes. This narrative review aims to explore the recent neuroimaging literature on SG differences in brain function and structure as it pertains to alcohol across positron emission tomography, magnetic resonance imaging, and functional magnetic resonance imaging modalities in humans. Additional work using magnetic resonance spectroscopy, diffusion tensor imaging, and event‐related potentials to examine SG differences in AUD will be covered. Overall, current research on the neuroimaging of AUD, alcohol consumption, or risk of AUD is limited, and findings are mixed regarding the effect of SG on neurochemical, structural, and functional mechanisms associated with AUD. We address SG disparities in the neuroimaging of AUD and propose a call to action to include women in brain imaging research. Future studies are crucial to our understanding of the neurobiological underpinnings of AUD across neural systems and the vulnerability for AUD among women and men.