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.

Weight change among patients engaged in medication treatment for opioid use disorder: a scoping review.

Background: Medication treatment for opioid use disorder (MOUD) is an instrumental tool in combatting opioid use and overdose. Excess weight gain associated with MOUD initiation is a potential barrier that is not well understood.Objectives: Conduct a scoping review of available studies investigating the effect of MOUD on weight.Methods: Included studies consisted of adults taking any type of MOUD (e.g. methadone, buprenorphine/naloxone, naltrexone) with data on weight or body mass index for at least two time points. Evidence was synthesized using qualitative and descriptive approaches, and predictors of weight gain including demographics, comorbid substance use, and medication dose were examined.Results: Twenty-one unique studies were identified. Most studies were uncontrolled cohort studies or retrospective chart reviews testing the association between methadone and weight gain (n = 16). Studies examining 6 months of methadone treatment reported weight gain ranging from 4.2 to 23.4 pounds. Women appear to gain more weight from methadone than men, while patients using cocaine may gain less. Racial and ethnic disparities were largely unexamined. Only three case reports and two nonrandomized studies examined the effects of either buprenorphine/naloxone or naltrexone, and potential associations with weight gain were not clear.Conclusion: The use of methadone as an MOUD appears to be associated with mild to moderate weight gain. In contrast, there is little data supporting or refuting weight gain with buprenorphine/naloxone or naltrexone. Providers should discuss the potential risk for weight gain with patients as well as prevention and intervention methods for excess weight gain.

Using machine learning to predict heavy drinking during outpatient alcohol treatment.

BACKGROUND: Accurate clinical prediction supports the effective treatment of alcohol use disorder (AUD) and other psychiatric disorders. Traditional statistical techniques have identified patient characteristics associated with treatment outcomes. However, less work has focused on systematically leveraging these associations to create optimal predictive models. The current study demonstrates how machine learning can be used to predict clinical outcomes in people completing outpatient AUD treatment. METHOD: We used data from the COMBINE multisite clinical trial (n = 1383) to develop and test predictive models. We identified three priority prediction targets, including (1) heavy drinking during the first month of treatment, (2) heavy drinking during the last month of treatment, and (3) heavy drinking between weekly/bi-weekly sessions. Models were generated using the random forest algorithm. We used "leave sites out" partitioning to externally validate the models in trial sites that were not included in the model training. Stratified model development was used to test for sex differences in the relative importance of predictive features. RESULTS: Models predicting heavy alcohol use during the first and last months of treatment showed internal cross-validation area under the curve (AUC) scores ranging from 0.67 to 0.74. AUC was comparable in the external validation using data from held-out sites (AUC range = 0.69 to 0.72). The model predicting between-session heavy drinking showed strong classification accuracy in internal cross-validation (AUC = 0.89) and external test samples (AUC range = 0.80 to 0.87). Stratified analyses showed substantial sex differences in optimal feature sets. CONCLUSION: Machine learning techniques can predict alcohol treatment outcomes using routinely collected clinical data. This technique has the potential to greatly improve clinical prediction accuracy without requiring expensive or invasive assessment methods. More research is needed to understand how best to deploy these models.

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 Differences in Opioid Use Disorder Prevalence and Multimorbidity Nationally in the Veterans Health Administration.

OBJECTIVE: Opioid use disorder (OUD) is a significant problem among US veterans with increasing rates of OUD and overdose, and thus has substantial importance for service delivery within the Veterans Health Administration (VHA). Among individuals with OUD, several sex- specific differences have begun to emerge regarding co-occurring medical, psychiatric and pain-related diagnoses. The rates of such multimorbidities are likely to vary between men and women with OUD and may have important implications for treatment within the VHA but have not yet been studied. Methods: The present study utilized a data set that included all veterans receiving VHA health care during Fiscal Year (FY) 2012 (October 1, 2011 through September 30, 2012), who were diagnosed during the year with opioid dependence or abuse. VHA patients diagnosed with OUD nationwide in FY 2012 were compared by sex on proportions with OUD, and among those with OUD, on sociodemographic characteristics, medical, psychiatric and pain-related diagnoses, as well as on service use, and psychotropic and opioid agonist prescription fills. Results: During FY 2012, 48,408 veterans were diagnosed with OUD, 5.77% of whom were women. Among those veterans with OUD, few sociodemographic differences were observed between sexes. Female veterans had a higher rate of psychiatric diagnoses, notably mood, anxiety and personality disorders, as well as higher rates of pain-related diagnoses, such as headaches and fibromyalgia, while male veterans were more likely to have concurrent, severe medical co-morbidities, including hepatic disease, HIV, cancers, peripheral vascular disease, diabetes and related complications, and renal disease. There were few differences in health service utilization, with women reporting greater receipt of prescriptions for anxiolytic/sedative/hypnotics, stimulants and lithium. Men and women did not differ in receipt of opioid agonist medications or mental health/substance use treatments. Conclusions: There are substantial sex-specific differences in patterns of multimorbidity among veterans with OUD, spanning medical, psychiatric and pain-related diagnoses. These results illustrate the need to view OUD as a multimorbid condition and design interventions to target such multimorbidities. The present study highlights the potential benefits of sex-specific treatment and prevention efforts among female veterans with OUD and related co-occurring disorders.

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 association between problematic alcohol use, risk perceptions, and e-cigarette use.

Background: Use of e-cigarettes among college students has escalated, in part due to the perception that they are less harmful than traditional cigarettes and have other benefits such as circumventing smoking bans. College students also drink more heavily than other age groups, and e-cigarettes are associated with alcohol, especially among students who engage in problematic drinking.Objective: The present study sought to determine if an interaction between problematic alcohol use and increased perceptions of benefits and decreased perceptions of risks of e-cigarettes would predict whether participants had ever used an e-cigarette.Method: The present study included 1,133 undergraduate college students surveyed between November 2014 - November 2016. Participants were primarily Caucasian (82.3%) and female (78.1%). Participants completed questionnaires regarding demographics, smoking status/history, and expectancies.Results: Higher levels of problematic drinking and higher perceived benefits of e-cigarette use were both associated with having tried e-cigarettes. This relationship was significant even when controlling for several covariates such as cigarettes smoking status. However, there was not a significant interaction between problematic alcohol use and perceived benefits or risks of e-cigarettes. There was also no relationship between risk perceptions of e-cigarettes and e-cigarettes use.Conclusions: Both problematic alcohol use and perception of benefits of e-cigarettes were associated with having tried an e-cigarette. This finding is problematic as the use of e-cigarettes may influence further engagement in risky behaviors including problematic drinking or transitioning to regular cigarette use. Thus, it is important to develop interventions to help college students develop more accurate risk perceptions about e-cigarettes.

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.

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.

Do they see dead people? Cultural factors and sensitivity in screening for schizophrenia spectrum disorders.

OBJECTIVE: Schizophrenia spectrum disorders (SSDs), are diagnosed more frequently among African-Americans (AAs) than Caucasians. It has been suggested that cultural differences in symptom presentation and endorsement (including reporting spiritual/religious experiences) may influence this disparity. The current study investigated the relationship between endorsement of spiritual auditory and visual hallucinations and subsequent diagnosis of SSD among AA patients. DESIGN: Participants (N = 471 AAs) completed the Mini International Neuropsychiatric Interview-Plus (MINI-Plus) Screening Interview as part of their intake to a HIV outpatient clinic. Endorsement of auditory or visual (A/V) hallucinations was explored with the MINI-Plus Psychotic Disorder Module and questions regarding the content of the unusual experience. RESULTS: Logistic regression indicated that endorsement of A/V hallucinations significantly predicted a SSD (OR = 41.6, 95% CI 13.7-126.0, p < .001). However, when hallucinations were spiritual in nature, odds of an SSD fell dramatically (OR = 0.22, 95% CI 0.07-0.64, p < .001). CONCLUSIONS: The current study indicates that not all visual and auditory hallucinations are symptomatic of a psychotic disorder in AA patients. Many of these experiences may be related to spirituality. Clinicians assessing AA patients need to query content of, meaning attributed to, and distress associated with A/V unusual experiences.

Attenuated neural response to emotional cues in cocaine-dependence: a preliminary analysis of gender differences.

BACKGROUND: Cocaine users often report a loss of arousal for nondrug-related stimuli, which may contribute to their response to drug-related rewards. However, little is known about users' neural reactivity to emotional nondrug-related stimuli and the potential influence of gender. OBJECTIVES: Test the hypotheses that cocaine-dependent individuals have an attenuated neural response to arousing stimuli relative to controls and that this difference is amplified in women. METHODS: The brain response to typically arousing positive and negative images as well as neutral images from the International Affective Picture System was measured in 40 individuals (20 non-treatment seeking cocaine-dependent and 20 age- and gender-matched control participants; 50% of whom were women). Images were displayed for 4 s each in blocks of five across two 270-second runs. General linear models assessed within and between group activation differences for the emotional images. RESULTS: Cocaine-dependent individuals had a significantly lower response to typically arousing positive and negative images than controls, with attenuated neural activity present in the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). Analyses by gender revealed less mPFC/ACC activation among female users, but not males, for both positive and negative images. CONCLUSION: The dampened neural response to typically arousing stimuli among cocaine-dependent polydrug users suggests decreased salience processing for nondrug stimuli, particularly among female users. This decreased responding is consistent with data from other substance using populations and suggests that this may be a general feature of addiction. Amplifying the neural response to naturally arousing nondrug-related reinforcers may present an opportunity for unique behavioral and brain stimulation therapies.

An experimental laboratory-based minority stress paradigm for alcohol research among sexual minority women: A pilot study.

BACKGROUND: Sexual minority women (SMW) use alcohol at higher rates and experience greater alcohol-related harms than their heterosexual counterparts. Evidence from observational studies suggests that minority stress (i.e., stress experienced due to marginalization in society) is an important risk factor among SMW, yet there is a lack of experimental evidence to establish a direct causal role of minority stress on alcohol use in this population. We adapted the preexisting personalized guided stress induction paradigm to conduct a pilot study of how minority stress is related to stress response (assessed via subjective measures and salivary cortisol) and mechanisms of alcohol use (craving, demand, and risky decision making) in SMW. METHODS: Using a within-subjects design (N = 8) cisgender SMW who endorsed high-risk drinking (≥1 heavy drinking episode in the past 30 days) completed three study visits: a script development session and two in-person imagery induction appointments (minority stress and neutral). Analyses examined feasibility and acceptability, stress response, and mechanisms of alcohol use. RESULTS: The paradigm significantly increased subjective stress response (g = 1.32). Data supported the feasibility, acceptability, and appropriateness of the paradigm for use with SMW. While the paradigm did not significantly change scores on minority stress and alcohol outcomes measures, effect sizes for craving and minority stress outcomes were in the small-to-medium range (gs = 0.24-0.54). CONCLUSIONS: The adapted minority stress paradigm appears to be feasible and appropriate for use with SMW to induce stress in laboratory settings. Future research can use this paradigm to understand the causal effects of minority stress on alcohol use and related outcomes.

The role of sex hormones in targeting stress-induced tobacco craving, stress-reactivity, and smoking with guanfacine among women who smoke.

Women who smoke are particularly vulnerable to tobacco craving, smoking behaviors, and relapse in the context of stress when compared to men who smoke. One factor in this sex difference may be sex hormones, including estradiol and progesterone; however, smoking cessation medication trials often do not explore the impact of sex hormones on drug effects. This secondary analysis of a double-blind, placebo-controlled study explored the impact of levels of actual estradiol and progesterone on guanfacine, a noradrenergic α2a agonist, which attenuates stress-induced smoking behaviors in women. Women who smoke (n = 43) completed a stress induction laboratory paradigm followed by an ad-libitum smoking period. Assessment of tobacco craving, and stress-reactivity (via cortisol response) occurred pre- and post-stress induction. Results indicated that guanfacine attenuated stress-induced tobacco craving (F = 10.94, p = 0.02) and cortisol response (F = 14.23, p < 0.001); however, high levels of estradiol overrode guanfacine's effect on craving (F = 4.00, p = 0.05), cortisol response (F = 14.23, p < 0.001), and smoking during the ad-libitum period (F = 12.23, p = 0.001). Additionally, progesterone proved to be protective against tobacco craving and enhanced guanfacine's medication effect on craving (F = 5.57, p = 0.02). The present study found that sex hormones had a significant impact on medication effects in a smoking cessation trial and thus underscore the importance of examining the role of sex hormones in future medication trials.

Developing Researchers with Expertise in Sex as a Biological Variable through SCORE Career Enhancement Core Center Programs.

There is a critical need for interdisciplinary and translational scientists to apply sex as a biological variable (SABV) research to address knowledge gaps in the health of women. In 2018, the Office of Research on Women's Health (ORWH) partnered with several National Institute of Health (NIH) Institutes and Centers to expand the Specialized Centers of Research (SCOR) Excellence (SCORE) Programs (together referred to as SCOR/E) with an important feature-the Career Enhancement Core (CEC). The SCORE CEC mentors early career investigators to become the next generation of biomedical and behavioral researchers focused on SABV and women's health. In this article, we outline our approach at the Yale University SCORE to support early career trajectories through the provision of salary support, educational curricula, translational mentorship, pilot project funding, and professional development. Using the Yale-SCOR/E CEC Programs as instructional models, we highlight critical measures of academic success, namely grant funding and publications, among early career investigators. At Yale University, 12 pilot projects funded by the SCOR/E Programs resulted in 14 extramural grants, amounting to an $80 return on every $1 invested in "seed" funding. So far, our SCOR/E Programs have resulted in 129 publications, 83% of which were first-authored by trainees, and 100% of trainees continued research careers with an emphasis on SABV. Finally, we provide recommendations on how biomedical scientists can apply SABV in their studies of major medical conditions in an interdisciplinary and integrative way.

Adverse Childhood Experiences and Pathways to Violent Behavior for Women and Men.

Childhood maltreatment is associated with risk for committing future violence, but the relationship between subgroups and biological sex is unknown. The relationship between adverse childhood experiences (ACEs), violence, and sex was examined using a nationally representative sample. Results from a latent class analysis suggested a four-class model (low adversity; moderate maltreatment with high household dysfunction; severe maltreatment with moderate household dysfunction; severe multi-type adversities). When compared to low adversity, all typology groups were at significantly higher risk to engage in violence (odds ratio > 2.10, ps < .013). The data supported a linear trajectory, meaning increased childhood trauma was associated with increased risk for violence. Although men endorsed more violent behavior, the relationship between ACEs and violence was significantly stronger among women. Prior findings identify that women are more negatively impacted by ACEs and the current findings newly identify that this extends to violent crime.

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.