Terril L. Verplaetse

Targeting the Noradrenergic System for Gender- Sensitive Medication Development for Tobacco Dependence

INTRODUCTION Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, and women often experience poorer smoking cessation outcomes than men. Preliminary evidence suggests there are sex differences in medication effectiveness for smoking cessation. However, current medications do not take into account gender-sensitive treatment development and efficacy, underscoring the importance of this underdeveloped area of research. METHODS We reviewed preclinical and clinical evidence for gender differences in the inability to quit smoking by examining (a) the effect of increased negative affect and stress reactivity on smoking outcomes in women and (b) smoking for nicotine reinforcement in men. We also reviewed the current literature targeting the noradrenergic system as a novel gender-sensitive treatment strategy for tobacco dependence. RESULTS We hypothesize that noradrenergic agents that normalize noradrenergic activity may differentially attenuate stress reactivity in women and nicotine-related reinforcement in men, indicating that targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through sex-specific mechanisms. CONCLUSIONS 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.

An overview of alcohol and tobacco/nicotine interactions in the human laboratory

ABSTRACT Background: 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. Objective: The aims of this review were to summarize the state of research examining alcohol-tobacco interactions in the human laboratory. Methods: We reviewed human laboratory evidence for alcohol and tobacco/nicotine interactions, 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 self-administration behaviors. The interactive effects of tobacco/nicotine with other drugs of abuse are also briefly discussed. Results: 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. Conclusion: 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.

Effect of Lowering the Dose of Varenicline on Alcohol Self-administration in Drinkers With Alcohol Use Disorders.

Objectives:Varenicline (2 mg/d) 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/d) on alcohol consumption in nontreatment-seeking adults meeting the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (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 1 mg/d dose reduced the frequency of insomnia compared with the 2 mg/d dose. The 2 mg/d 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/d varenicline dose versus placebo. Trough varenicline plasma levels greater than or equal to 3 ng/mL were associated with reduced drinking and levels greater than or equal to 5 ng/mL were associated with reduced heavy drinking. Conclusions:Overall, we found no evidence supporting an effect of 1 mg/d varenicline on craving or consumption, suggesting that doses of varenicline less than 2 mg/d may not be effective in reducing alcohol-related outcomes. Importantly, results suggest that higher plasma levels of varenicline may be needed to maximize the effect of varenicline on alcohol consumption and should be investigated in drinkers meeting criteria for alcohol use disorders.

Effects of varenicline on alcohol self-administration and craving in drinkers with depressive symptoms:

Varenicline (VAR) is approved to aid in smoking cessation and has been shown to be effective for reducing alcohol consumption in heavy drinkers. Little is known, however, about treatment moderators that may influence efficacy. The current study reanalyzed data from a human laboratory study (Verplaetse et al., 2016) to determine whether VAR was more effective at reducing alcohol use among drinkers reporting symptoms of depression. Participants were 60 adults meeting DSM-IV criteria for alcohol use disorders (n = 60) who were randomly assigned to receive VAR (1 mg/day, 2 mg/day) or placebo. Following 7 days of medication pretreatment, participants attended a laboratory testing session. They provided self-reported ratings of alcohol craving and performed an ad libitum alcohol consumption task after receiving a priming dose of alcohol (target blood alcohol concentration = 0.030 g/dL). Higher blood VAR plasma levels were associated with less alcohol craving and less drinking among participants with more depressive symptoms. Among participants with fewer depressive symptoms, VAR was associated with more drinking during the ad libitum drinking task. These findings show that depression symptoms may be a moderator of VAR efficacy in alcohol users and provides evidence for the role of nAChRs in depression and alcohol use.

Intersection of Stress and Gender in Association With Transitions in Past Year DSM-5 Substance Use Disorder Diagnoses in the United States

Background Stress contributes to the development and maintenance of substance use disorders, with some research suggesting that the impact of stress on substance use disorders is greater in women. However, this has yet to be evaluated in a national dataset, across major substances of abuse. Methods Using data from the newly available U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; Wave 3; n = 36,309), we evaluated relationships among past year stressful life events (0 or 1 vs. 2+ events, range 0–16) and gender, and their association with transitions (new vs. absent cases; ongoing vs. remitted cases) in Diagnostic and Statistical Manual of Mental Disorders Fifth Edition alcohol use disorder, tobacco use disorder, cannabis use disorder, and nonmedical prescription opioid use disorder diagnoses. Results Having two or more stressful life events in the past year increased the odds of having a new alcohol use disorder, tobacco use disorder, cannabis use disorder, and opioid use disorder (OR = 3.14, 2.15, 5.52, and 3.06, respectively) or ongoing alcohol use disorder, tobacco use disorder, and cannabis use disorder (OR = 2.39, 2.62, and 2.95, respectively) compared to zero or one stressful life event. A stress by gender interaction for new vs. absent alcohol use disorder demonstrated that having two or more stressful life events was associated with increased odds of new alcohol use disorder in men (OR = 2.51) and even greater odds of new alcohol use disorder in women (OR = 3.94). Conclusions Results highlight that stress is a robust factor in both men and women with new or ongoing substance use disorders, and that effective treatments for substance use should consider the role of stress in addiction etiology and maintenance. There was little evidence for gender differences in the role of stress on transitions in substance use disorders, except for the onset of alcohol use disorders. Given that rates of alcohol use disorders are increasing in women, the impact of stress needs to be considered.

Effect of doxazosin on stress reactivity and the ability to resist smoking

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, norepinephrine, epinephrine, and physiologic reactivity were assessed. Doxazosin (4 and 8 mg/day vs placebo) decreased cigarettes per day during the 21-day titration period. Following titration, doxazosin (4 and 8 mg/day vs placebo) decreased tobacco craving. During the laboratory session, doxazosin (8 mg/day vs 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.

Intersection of e-cigarette use and gender on transitions in cigarette smoking status: Findings across waves 1 and 2 of the Population Assessment of Tobacco and Health (PATH) study.

Introduction 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, and effects of gender are unknown. Methods The Population Assessment of Tobacco and Health (PATH; waves 1 & 2; adult interviews) was used to evaluate relationships among wave 1 e-cigarette use (daily, non-daily, never) and gender and their association with transitions (quit vs. current; relapse vs. former) in cigarette smoking status across waves 1 and 2 of the PATH study. Results Daily e-cigarette users had higher odds of quitting smoking (OR=1.56, 95% CI=1.12, 2.18) compared to never e-cigarette users. Conversely, daily and non-daily e-cigarette users were at greater risk of smoking relapse (OR=1.84, 95% CI=1.15, 2.94 and OR=1.85, 95% CI=0.99, 3.46 respectively) compared to never e-cigarette users. Women were less likely to quit smoking compared to men independent of e-cigarette use (OR=0.76, 95% CI=0.59, 0.99). In stratified analyses, daily or non-daily e-cigarette use did not increase the likelihood of quitting or relapse in women. In men, daily and non-daily e-cigarette users were at greater risk of smoking relapse (OR=2.96, 95% CI=1.49, 5.86 and OR=3.05, 95% CI=1.29, 7.17, respectively) compared to men who were never e-cigarette users. Conclusions Findings identify e-cigarettes as a potential aid for smoking cessation, but also as a potential risk for smoking relapse in men only. Overall, women were less likely to quit smoking, and e-cigarette use did not impact their ability to quit or to stay quit. Implications 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.

Tobacco use during a clinical trial of mecamylamine for alcohol dependence: Medication effects on smoking and associations with reductions in drinking

Mecamylamine is a nicotinic acetylcholine receptor (nAChR) antagonist that was recently used in a clinical trial to treat alcohol use disorder (AUD) in both smokers and non-smokers. The current manuscript reports a reanalysis of data from this clinical trial in which we examine changes in smoking that occurred over the course of the trial. We focused on examining the effects of mecamylamine on smoking and the association between reductions in alcohol use and smoking. Participants were the subgroup of smokers who participated in the clinical trial of mecamylamine (10 mg/day) to treat their AUD (n = 76). Smoking was assessed prior to randomization and tracked throughout the course of the 12-week medication treatment phase. Participants were categorized as treatment responders or non-responders based on their changes in drinking over the course of the clinical trial. Participants showed a reduction in smoking over the course of the clinical trial, but there were no significant differences in smoking outcomes between the mecamylamine and placebo groups. Among moderate/high dependence smokers, those who successfully reduced drinking showed a significant reduction in cigarettes smoked per day over the clinical trial. Mecamylamine had no detectable effect on smoking outcomes. Reductions in alcohol use predicted more favorable smoking outcomes among moderate/high tobacco dependence smokers irrespective of medication condition. The reduction in smoking among patients who decreased their alcohol use responders highlights an opportunity for patients being treated for AUD to reduce their smoking.

Pilot investigation of the effect of carvedilol on stress-precipitated smoking-lapse behavior:

Introduction: Separate α1- and β-adrenergic antagonists have shown efficacy in reducing nicotine-motivated behaviors in rodents and humans, supporting a role for the noradrenergic system in mediating the reinforcing properties of drugs of abuse. However, the effect of the combined α1- and β-adrenergic antagonist, carvedilol, on stress-related smoking is unknown. Methods: Using a well-established human laboratory model of stress-precipitated smoking-lapse behavior, we examined whether carvedilol (0 or 50 mg/day; between subject, n=17 per group), administered to steady-state, would attenuate the ability to resist smoking following stress imagery (vs. neutral imagery) and reduce subsequent smoking self-administration in nicotine-deprived smokers (n = 34 total). Tobacco craving, withdrawal, and physiologic reactivity were also assessed. Results: Latency to start smoking and number of cigarettes smoked during the self-administration period did not differ by medication condition. Counter to our hypothesis, tobacco craving demonstrated a medication × time effect, with greater craving in the carvedilol condition. Systolic blood pressure and heart rate demonstrated lower values in the carvedilol versus placebo group, consistent with known effects of carvedilol. Conclusion: While carvedilol attenuated physiologic reactivity consistent with its clinical indication, beneficial effects on smoking outcomes were absent in this preliminary investigation and may suggest possible worsening. Future work may benefit from discerning the single versus combined effects of α1- and β-adrenergic antagonism on smoking outcomes.

A preliminary investigation into the effects of doxazosin on cognitive functioning in tobacco-deprived and -satiated smokers

To test the effects of doxazosin, an α1 antagonist, on cognitive functioning during tobacco withdrawal in smokers.