The role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications.

Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.

Lower Dopamine D2/3 Receptor Availability is Associated With Worse Verbal Learning and Memory in People Who Smoke Cigarettes.

INTRODUCTION: Tobacco smoking is a major public health burden. The mesocortical dopamine system-including the dorsolateral prefrontal cortex (dlPFC)-plays an important role in cognitive function. Dysregulated dopamine signaling in dlPFC is associated with cognitive deficits such as impairments in attention, learning, working memory, and inhibitory control. We recently showed that dlPFC dopamine D2/3-type receptor (D2R) availability was significantly lower in people who smoke than in healthy-controls and that dlPFC amphetamine-induced dopamine release was lower in females who smoke relative to males who smoke and female healthy-controls. However, we did not examine whether the smoking-related dopamine deficits were related to cognitive deficits. AIMS AND METHODS: The goal of this study was to relate dopamine metrics to cognitive performance in people who smoke and healthy-controls. In total 24 (12 female) people who smoke cigarettes and 25 sex- and age-matched healthy-controls participated in two same-day [11C]FLB457 positron emission tomography (PET) scans before and after amphetamine administration. Two outcome measures were calculated-D2R availability (non-displaceable binding potential; BPND) and amphetamine-induced dopamine release (%ΔBPND). Cognition (verbal learning and memory) was assessed with a computerized test from the CogState battery (International Shopping List). RESULTS: People who smoke had significantly worse immediate (p = .04) and delayed (p = .03) recall than healthy-controls. Multiple linear regression revealed that for people who smoke only, lower D2R availability was associated with worse immediate (p = .04) and delayed (p < .001) recall. %ΔBPND was not significantly related to task performance. CONCLUSION: This study demonstrated that lower dlPFC D2R availability in people who smoke is associated with disruptions in cognitive function that may underlie difficulty with resisting smoking. IMPLICATIONS: This is the first study to directly relate dopamine metrics in the prefrontal cortex to cognitive function in people who smoke cigarettes compared to healthy-controls. The current work included a well-characterized subject sample with regards to demographic and smoking variables, as well as a validated neurocognitive test of verbal learning and memory. The findings of this study extend previous literature by relating dopamine metrics to cognition in people who smoke, providing a better understanding of brain-behavior relationships.

Licit and illicit drug use across trimesters in pregnant women endorsing past-year substance use: Results from National Survey on Drug Use and Health (2009-2019).

PURPOSE: Given the health consequences, perinatal substance use is a significant public health concern, especially as substance use rates increase among women; ongoing data regarding the rates of substance use across trimesters of pregnancy is needed. METHODS: The present study utilized cross-sectional population-based data from the National Survey of Drug Use and Health (NSDUH) between 2009 and 2019. We aimed to explore both licit and illicit substance use assessed within each trimester among women endorsing past-year substance use. The NSDUH sample included 8,530 pregnant women. RESULTS: Perinatal substance use was less prevalent among women in later trimesters; however, past-month substance use was observed for all substances across trimesters. The prevalence of past-month licit substance use among pregnant women ranged from 5.77 to 22.50% and past-month illicit substance use ranged from 4.67 to 14.81%. In the second trimester, lower odds of past-month substance use were observed across tobacco, alcohol, and marijuana (odds ratios [ORs] ranging from 0.29 to 0.47), when compared to the first trimester. A similar lower rate of past-month substance use was observed in the third trimester compared to the first trimester, across tobacco, alcohol, and marijuana use, as well as cocaine, prescription pain medication, and tranquilizer use (ORs ranging from 0.02 to 0.42). The likelihood of polysubstance use was lower among women in the second and third trimesters compared to the first trimester (ORs ranging from 0.09 to 0.46). CONCLUSION: Findings indicate that a minority of women continue to use substances across all trimesters. This is especially true among women using licit substances and marijuana. These results highlight the need for improved interventions and improved access to treatment for these women.

Sex Differences across Retrospective Transitions in Posttraumatic Stress and Substance Use Disorders.

Objectives: Concurrent substance use disorder (SUD) and posttraumatic stress disorder (PTSD) occur at high rates and are typically associated with poor treatment outcomes in both sexes. However, women have a propensity to cope with increased negative affect via substance use in comparison to men; thus, it is important to elucidate the sex-specific bidirectional relationships between SUD and PTSD to improve our understanding of concurrent SUD/PTSD in men and women. Methods: Using data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-Wave 3; n = 36,309), the present study evaluated the impact of sex on the relationship between past-year SUDs (new, remitted, ongoing), including alcohol and drug use, and retrospective transitions in new vs. absent and ongoing vs. remitted diagnoses of PTSD. Additionally, the impact of sex was explored in models examining past year PTSD (new, remitted, ongoing) and retrospective transitions in new vs. absent and ongoing vs. remitted diagnosis of SUDs. Diagnostic transitions were based on retrospective reporting. Results: Results indicated that new, remitted, and ongoing SUDs increase the likelihood of new PTSD diagnoses (OR range = 2.53-8.11; p < 0.05). Among individuals with ongoing drug use disorders (DUD), there were greater odds of ongoing PTSD (OR = 2.10, p < 0.01). When examining the relationship reciprocally, new, remitted, and ongoing PTSD increased the likelihood of new SUDs (OR range = 2.50-8.22; p < 0.05), and ongoing PTSD increased the likelihood of ongoing SUD and DUD (OR = 1.40, 1.70, respectively; p < 0.05). Sex-specific analyses revealed that the relationship between PTSD and SUDs varies between sexes, particularly among women. For instance, women with new PTSD had higher odds of SUDs, and women with ongoing PTSD were almost 2.5 times more likely to have an ongoing DUD. Women with a new PTSD diagnosis were more likely to be diagnosed with a new SUD (OR = 3.27) and an ongoing DUD (OR = 3.08). Conclusions: Results indicate a bidirectional relationship between PTSD and SUD that is in many instances larger in women. Thus, illustrating potential sex-specific differences in underlying mechanisms implicated in SUD/PTSD, warranting additional research.

Sex/gender differences in brain function and structure in alcohol use: A narrative review of neuroimaging findings over the last 10 years.

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.

A Critical Review of Alcohol Administration Guidelines in Laboratory Medication Screening Research: Is It Time to Include Treatment Seekers?

Human laboratory studies play an important role in alcohol use disorder (AUD) medication development. Medications that are found to be safe and effective during human laboratory screening will then move to more expensive clinical trials in patient populations. Given the gatekeeping role of human laboratory studies in the medication development pipeline, it is critical that these studies accurately forecast how pharmacotherapies will perform under true-to-life clinical conditions. On the other hand, the design of these studies also must adhere to ethical guidelines: certain aspects of clinical reality cannot be incorporated into screening studies because doing so might place the participant at risk for harm or breach other ethical guidelines. Conventions exist that guide the resolution of these conflicting ideals. This article considers the practice of recruiting non-treatment-seeking heavy drinkers to participate in laboratory screening studies. By convention, volunteers are excluded from laboratory screening studies that involve alcohol administration if they are deemed "treatment seeking," meaning that they recently stopped drinking or are motivated to do so. Although this common practice may reduce risk to participants, findings may not accurately predict medication effects on treatment seekers. Indeed, there is empirical evidence that treatment seekers differ from nontreatment seekers in their responses to medications (Neuropsychopharmacology 2017a; 42: 1776; Am J Drug Alcohol Abuse 2017b; 43: 703; J Psychiatr Res 2006; 40: 383). Here, we argue for the importance of recruiting treatment seekers for this research due to their qualitative difference from nontreatment seekers. We argue that these individuals should be the default population in human laboratory medication screening studies. We conclude by discussing 2 case examples of medication experiments led by our research groups that involved administering medications to treatment seekers.

Associations Between Nicotine Metabolite Ratio and Gender With Transitions in Cigarette Smoking Status and E-Cigarette Use: Findings Across Waves 1 and 2 of the Population Assessment of Tobacco and Health (PATH) Study.

INTRODUCTION: Nicotine metabolite ratio (NMR), the ratio of trans 3'-hydroxycotinine to cotinine, is a biomarker of nicotine metabolism. Discrepant findings among clinical trials and population-based studies warrant replication on whether higher NMR, or faster nicotine metabolism, is associated with quitting cigarette smoking. Associations of NMR and e-cigarette use are largely unknown, as well as the relationship between NMR and gender on quitting cigarette smoking or e-cigarette use. METHODS: The Population Assessment of Tobacco and Health (PATH) Study is a nationally representative, longitudinal cohort study assessing tobacco use in the US population. In the current study, the PATH (waves 1 and 2; adult interviews) was used to evaluate longitudinal predictions in relationships among NMR and gender and their association with transitions (quit vs. current stable) in cigarette smoking status and e-cigarette use status across waves 1 and 2 of the PATH study. RESULTS: NMR and gender were not significantly associated with quit behavior for combustible cigarettes. Regarding e-cigarettes, a significant two-way interaction demonstrated that women with higher NMR were less likely to quit e-cigarette use compared to women with lower NMR (odds ratio [OR] = 0.10, 95% confidence interval [CI] = 0.02-0.57; p = .01). CONCLUSIONS: Findings identify that women with faster nicotine metabolism were 10 times less likely to quit e-cigarettes compared to women with slower nicotine metabolism across waves 1 and 2 of the PATH study. Results suggest that NMR may be used as a biomarker for transitions in e-cigarette quit behavior for women. IMPLICATIONS: Findings identify that women with faster nicotine metabolism were 10 times less likely to quit e-cigarettes compared to women with slower nicotine metabolism. Results suggest that NMR may be used as a biomarker for transitions in e-cigarette quit behavior for women. Establishing parameters for NMR collection and for the use of NMR as a biomarker for cigarette smoking behavior and e-cigarette use is an important next step, and may have implications for early intervention and treatment for cessation.

Smoking Across the Menopausal Transition in a 10-Year Longitudinal Sample: The Role of Sex Hormones and Depressive Symptoms.

INTRODUCTION: Current cigarette smoking rates among older women remain problematic, especially given that this population experiences increased smoking-related health consequences. Despite these increased health concerns, little research to date has explored smoking patterns across the menopausal transition (pre-, early-peri-, late-peri-, and postmenopausal) or the effect of unique factors such as sex hormones and depression during this transition. METHODS: This study used 10 yearly waves of data from the Study of Women's Health Across the Nation, a longitudinal dataset. Data included 1397 women endorsing ever smoking regularly at baseline. Random-effects logistic regression models were used to examine smoking transitions. RESULTS: Although there were no associations between menopausal transition stage and smoking behavior, increased estradiol was associated with an increased likelihood of quitting regular smoking (eg, transitioning from regular smoking to non-regular or no smoking; odds ratio [OR] = 1.28), whereas increased testosterone was associated with an increased likelihood of relapsing to regular smoking (eg, transitioning from former or nonregular smoking to regular smoking OR = 2.56). Depression was associated with increased likelihood of continued smoking (OR = 0.97) and relapse (OR = 1.03). CONCLUSIONS: The results emphasize the need to develop interventions to target initiated or continued smoking among women across the menopausal transition and specifically highlight the importance of developing treatments that target depressive symptoms in this population. In addition, although singular hormone measures were associated with smoking behavior, there is a need for future study of dynamic changes in hormones, as well as the impact of progesterone on smoking behaviors across the menopausal transition. IMPLICATIONS: To date, no studies have examined smoking behaviors across the menopausal transition. In this study, although menopausal transition status was not significantly related to transitions in smoking behavior, important relationships between sex hormones and depression were observed. Increased estradiol was associated with an increased likelihood of quitting regular smoking, whereas increased testosterone was associated with an increased likelihood of relapsing to regular smoking behavior. Higher depression scores were related to continued smoking and relapse to regular smoking behavior. These results highlight the need to develop interventions to target smoking cessation among women across the menopausal transition.

The Prevalence of Substance Use Disorders among Community-based Adults with Legal Problems in the U.S.

BACKGROUND: Current national prevalence estimates of DSM-5 diagnosed substance use disorders (SUDs) among adults with justice system involvement are lacking. METHODS: This study drew from NESARC-III data (n = 36,309; 2012-2013), a nationally representative U.S. sample, to examine current and lifetime alcohol use disorder (AUD) and drug use disorder (DUD) diagnoses among adults reporting current or prior drug-related, alcohol-related, and general legal problems. RESULTS: Adults reporting current alcohol-related legal problems were 22 times more likely to have a current AUD diagnosis (AOR = 22.0, 95% CI = 12.1; 40.1) and 15 times more likely to have had a lifetime AUD diagnosis (AOR = 15.2, 95% CI = 7.5; 30.9) than adults without alcohol-related legal problems. Adults with lifetime drug-related legal problems were 3-5 times more likely to have a current (AOR = 2.6, 95% CI = 2.1; 3.2) and lifetime (AOR = 5.1, 95% CI = 4.3; 6.1) DUD diagnosis, with stimulant use disorder being the most prevalent (AOR = 5.4, 95% CI = 4.5; 6.5). Adults with general legal problems were around 3 times more likely to have a current AUD (AOR = 3.2, 95% CI = 2.6; 4.0) or DUD (AOR = 3.5, 95% CI = 2.8; 4.4). Women with any type of legal problem were more likely to have SUD diagnoses than men. CONCLUSIONS: SUD diagnoses are prevalent among adults reporting legal problems, particularly those involving alcohol. There is a continued need for community-based addiction prevention and intervention efforts, especially for women with justice system involvement.

Pharmacokinetics and Pharmacodynamics of Immediate-Release Versus Extended-Release Guanfacine in Adult Daily Smokers.

BACKGROUND: Guanfacine is Food and Drug Administration approved for hypertension and attention-deficit hyperactivity disorder and has been used off-label for migraine prophylaxis, heroin withdrawal, and more recently smoking cessation. Previous studies have shown positive effects of 3 mg/d of immediate-release (IR) guanfacine on smoking outcomes, but the dose equivalency of the IR and extended-release (ER) formulations is unknown. PROCEDURES: A within-subject design was used to compare the pharmacokinetics and pharmacodynamics of 3 mg/d of IR, 4 mg/d of ER, and 6 mg/d of ER guanfacine in adult daily smokers (n = 5). Plasma medication levels, vital signs, cigarettes per day, tobacco craving, and adverse events were assessed. Medication was titrated to stable dosing after each laboratory day (3 mg/d IR, then 4 mg/d ER, then 6 mg/d ER). RESULTS: Plasma medication levels did not differ between the 3 mg/d of IR and 4 mg/d of ER doses after 24 hours from last dose and were highest at the 6 mg/d of ER dose (3 mg/d IR: M = 3.40 ng/mL, SE = 0.34 vs 4 mg/d ER: M = 3.46 ng/mL, SE = 0.67 vs 6 mg/d ER: M = 5.92 ng/mL, SE = 1.02). All doses of guanfacine decreased heart rate and blood pressure from baseline. Absolute values of cigarettes per day (6 mg/d ER) and tobacco craving (4 and 6 mg/d ER) were lowest with the ER formulations. Treatment-emergent adverse events were subject rated as minimal to mild, except dry mouth. CONCLUSIONS: We demonstrated similar pharmacokinetic profiles between 3 mg/d of IR guanfacine and 4 mg/d of ER guanfacine, as hypothesized. All doses of guanfacine were well tolerated.

Alcohol Abstainer Status and Prazosin Treatment in Association with Changes in Posttraumatic Stress Disorder Symptoms in Veterans with Comorbid Alcohol Use Disorder and Posttraumatic Stress Disorder.

BACKGROUND: The noradrenergic system has been implicated in alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD), with adrenergic agents reducing drinking in individuals with AUD and improving sleep disturbances in individuals with PTSD. In a recent clinical trial, prazosin, an α1-adrenergic antagonist, was not superior to placebo in reducing PTSD symptoms, sleep problems, or alcohol consumption in a comorbid population; however, patients in both treatment conditions improved in all symptom domains over the course of treatment. It remains unknown whether alcohol abstinence is related to changes in PTSD symptoms and medication effects in individuals with this comorbidity. METHODS: Veterans with comorbid alcohol dependence and PTSD (n = 96) were randomized to prazosin (16 mg) or placebo in a 12-week outpatient, double-blind clinical trial. In this secondary data analysis, we examined main effects of alcohol abstainer status (abstainer vs. nonabstainer), treatment, and their interaction on changes in PTSD symptoms over time using linear mixed models. RESULTS: There was a main effect of alcohol abstainer status on symptoms of PTSD (p = 0.03), such that nonabstainers had lower total Clinician-Administered PTSD Scale (CAPS) scores than abstainers. There was a significant treatment by alcohol abstainer status interaction (p = 0.01); specifically, among placebo-treated individuals, those who did not abstain from alcohol had lower total CAPS scores compared to alcohol abstainers. Within the prazosin-treated group, abstainers and nonabstainers did not differ on total CAPS scores. Results were similar for the avoidance (p = 0.02), reexperiencing (p = 0.01), and hyperarousal (p = 0.04) subscales, such that placebo-treated nonabstainers had lower CAPS scores overall. CONCLUSIONS: Overall, prazosin treatment was not significantly related to changes in PTSD symptoms over the course of the 12-week clinical trial in a comorbid population. Interestingly, placebo-treated alcohol nonabstainers had a significant reduction in PTSD symptoms. Whether placebo-treated individuals continued to use alcohol because of ongoing symptoms of PTSD is not known.

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 Study.

INTRODUCTION: Cigarette smokers report using electronic cigarettes (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 and 2; adult interviews) was used to evaluate relationships among wave 1 e-cigarette use (daily, nondaily, 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 (odds ratio [OR] = 1.56, 95% confidence interval [CI] = 1.12 to 2.18) compared with never e-cigarette users. Conversely, daily and nondaily e-cigarette users were at greater risk of smoking relapse (OR = 1.84, 95% CI = 1.15 to 2.94 and OR = 1.85, 95% CI = 0.99 to 3.46, respectively) compared with never e-cigarette users. Women were less likely to quit smoking compared with men independent of e-cigarette use (OR = 0.76, 95% CI = 0.59 to 0.99). In stratified analyses, daily or nondaily e-cigarette use did not increase the likelihood of quitting or relapse in women. In men, daily and nondaily e-cigarette users were at greater risk of smoking relapse (OR = 2.96, 95% CI = 1.49 to 5.86 and OR = 3.05, 95% CI = 1.29 to 7.17, respectively) compared with 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 PATH (waves 1 and 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 Food and Drug Administration and the benefit-cost ratio of e-cigarette use in smokers.

Electronic Cigarette Use and Risk of Harmful Alcohol Consumption in the U.S. Population.

BACKGROUND: Electronic cigarette (e-cigarette) use is an increasingly common method of nicotine delivery in the general population. It is well-established that tobacco users are at increased risk to engage in hazardous drinking and meet criteria for alcohol use disorder (AUD) relative to nonusers. Less is known, however, about the risk of harmful alcohol use among people who use e-cigarettes. The current study reports on the association between e-cigarette and alcohol use in the U.S. population using a nationally representative sample. METHODS: Data from 36,309 adults who participated in the National Epidemiologic Survey on Alcohol and Related Conditions-Wave III were included in the study. The Alcohol Use Disorder and Associated Disabilities Interview Schedule (AUDADIS) measured past-year e-cigarette and alcohol use outcomes. Based on past-year e-cigarette use, respondents were categorized as nonusers, nondaily users, or daily users. Alcohol use outcomes were drinking quantity/frequency, binge drinking frequency, AUD diagnostic status, and National Institute on Alcohol Abuse and Alcoholism-defined hazardous drinking status. RESULTS: Controlling for demographic characteristics, daily and nondaily e-cigarette users showed increased risk of harmful alcohol use compared to e-cigarette nonusers, including hazardous drinking (adjusted odds ratios [AORs] = 1.69; 2.48), AUD (AORs = 1.89; 2.44), and binge drinking frequency (AORs = 1.30 to 3.30). Nondaily e-cigarette use was associated with higher levels of risk than was daily use. Secondary analyses examined alcohol use outcomes according to participants' patterns of dual tobacco cigarette/e-cigarette use. These analyses confirmed that e-cigarette use alongside tobacco cigarette use is associated with additive risk of harmful alcohol consumption, particularly among nondaily users. CONCLUSIONS: E-cigarette users, particularly those who engage in nondaily and dual use, show elevated rates of harmful alcohol use. Heavy drinking may constitute a source of health risk among e-cigarette users.

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

OBJECTIVE: To test the effects of doxazosin, an α1 antagonist, on cognitive functioning during tobacco withdrawal in smokers. METHODS: Participants (n = 35) were randomly assigned to receive placebo, 4-mg/day, or 8-mg/day doxazosin. They completed a continuous performance task and self-reported their withdrawal symptoms at baseline and twice following a medication titration period: once in a tobacco-deprived state and again in a nondeprived state. Ability to resist smoking was assessed using a laboratory smoking-lapse paradigm. RESULTS: Participants showed poorer cognitive performance on most measures taken from the continuous performance task when tobacco deprived. Eight-mg/day doxazosin improved inhibitory control during the nondeprivation session but did not affect sustained attention or reaction time. Participants receiving doxazosin reported fewer withdrawal symptoms during deprivation than those on placebo. Those showing the greatest improvement of inhibitory control under doxazosin were better able to resist smoking (i.e., latency to smoke) during a smoking lapse task. Self-reported withdrawal symptoms also were negatively associated with time to smoking. CONCLUSIONS: Doxazosin reduced symptoms of tobacco withdrawal according to self-report and cognitive assessment and improved inhibitory control above predrug levels. This research identifies potential mechanisms by which doxazosin might improve smoking outcomes.

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

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 Varenicline Combined with High-Dose Alcohol on Craving, Subjective Intoxication, Perceptual Motor Response, and Executive Cognitive Function in Adults with Alcohol Use Disorders: Preliminary Findings.

BACKGROUND: Varenicline has been found to decrease alcohol-motivated behaviors. Recent warnings regarding aversive events associated with varenicline used in conjunction with alcohol warrant further investigation into the safety of the drug when combined with alcohol. The purpose of this preliminary investigation was to examine the effect of combining varenicline with a high, fixed dose of alcohol on subjective reactivity and cognitive function in adults with alcohol use disorders (AUDs). METHODS: This double-blind, placebo-controlled preliminary investigation examined the effects of varenicline (0, 1, 2 mg/d) on subjective reactivity, cognition, perceptual motor function, and physiologic reactivity to a fixed dose of alcohol (vs. nonalcohol control beverage) using an established laboratory paradigm in smokers and nonsmokers meeting criteria for AUDs (n = 44). All participants had completed a parent varenicline study evaluating alcohol self-administration. Each subject completed 2 fixed-dose laboratory sessions assessing reactivity to a high-dose alcohol (0.08 g/dl) or a nonalcoholic control beverage, order counterbalanced. RESULTS: Varenicline attenuated alcohol-related increases in subjective intoxication and alcohol-related decreases in executive cognitive function. At baseline, varenicline reduced alcohol craving and diastolic blood pressure, and increased associative learning, working memory, and perceptual motor function. Varenicline produced nonspecific effects on diastolic blood pressure and heart rate. Overall, there were few differences in effects between 1 and 2 mg/d varenicline versus placebo. CONCLUSIONS: These preliminary results continue to support the safety and use of varenicline in combination with alcohol in individuals meeting criteria for AUDs.

Associations of Gender, Smoking, and Stress with Transitions in Major Depression Diagnoses.

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 gender, cigarette smoking status (current, former, non-smoker), life event stress (0-1 vs. 2+ events), and their impact on transitions in major depression diagnosis (MDD; new vs. absent cases; ongoing vs. remit cases). Women who were both current and former cigarette smokers with more than two stressful events had higher rates of new MDD diagnosis compared to men who were current or former smokers with two or more stressful events. Current smoking and experiencing two or more stressful events increased the odds of having an ongoing MDD diagnosis, while being a former smoker decreased these odds. Results suggest that smoking and stress are markers for depression risk in women and should help guide clinical assessment as well as gender-difference research on the biological underpinnings of these conditions.

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.

Imaging a putative marker of brain cortisol regulation in alcohol use disorder.

Background: Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [18F]AS2471907 to measure 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls. Methods: We imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11ß-HSD1 inhibitor radiotracer [18F]AS2471907 as a bolus injection and were imaged for 150-180 min on the High-Resolution Research Tomograph. 11ß-HSD1 availability was quantified by [18F]AS2471907 volume of distribution (VT; mL/cm3). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate. Results: Individuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [18F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [18F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02). Conclusions: This is the first in vivo examination of 11ß-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11ß-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11ß-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.

Liquor consumption is associated with other medical conditions in females who consume alcohol.

Background: Our group previously identified that females with AUD and females engaging in heavy or extreme binge drinking were more likely to report cancers and other medical conditions compared to their male counterparts. This analysis aimed to extend our previous findings to examine relationships between sex and consumption of alcohol by type on past year medical condition diagnoses. Methods: Data from the U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III; n = 36,309) was used to evaluate associations between sex (female vs. male) and alcohol type (liquor, wine, beer, coolers) on past year self-reported doctor-confirmed medical conditions, controlling for frequency of alcohol consumption. Results: A significant interaction demonstrated that females who consumed liquor were more likely to have other medical conditions (OR=1.95) compared to males who consumed liquor. Females who consumed wine in the past year were less likely to have cardiovascular conditions (OR=0.81) compared to males who consumed wine. Those who consumed liquor had increased odds of pain, respiratory, and other conditions (OR=1.11 - 1.21). Females were 1.5 times more likely to have cancers or pain, respiratory, and other medical conditions compared to males (OR=1.36 - 1.81). Conclusions: Results identify that consumption of higher alcohol content drinks (i.e., liquor) is associated with past year self-reported doctor- or health-professional confirmed medical conditions in females compared to males consuming the same high alcohol content beverage. Not only should AUD status and risky drinking be considered in the clinical care of individuals with poorer health but also alcohol type, especially higher alcohol content beverages.