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.

Lisdexamfetamine maintenance treatment for binge-eating disorder following successful treatments: randomized double-blind placebo-controlled trial.

BACKGROUND: Controlled research examining maintenance treatments for responders to acute interventions for binge-eating disorder (BED) is limited. This study tested efficacy of lisdexamfetamine (LDX) maintenance treatment amongst acute responders. METHODS: This prospective randomized double-blind placebo-controlled single-site trial, conducted March 2019 to September 2023, tested LDX as maintenance treatment for responders to acute treatments with LDX-alone or with cognitive-behavioral therapy (CBT + LDX) for BED with obesity. Sixty-one (83.6% women, mean age 44.3, mean BMI 36.1 kg/m2) acute responders were randomized to LDX (N = 32) or placebo (N = 29) for 12 weeks; 95.1% completed posttreatment assessments. Mixed-models and generalized-estimating equations comparing maintenance LDX v. placebo included main/interactive effects of acute (LDX or CBT + LDX) treatments to examine their predictive/moderating effects. RESULTS: Relapse rates (to diagnosis-level binge-eating frequency) following maintenance treatments were 10.0% (N = 3/30) for LDX and 17.9% (N = 5/28) for placebo; intention-to-treat binge-eating remission rates were 59.4% (N = 19/32) and 65.5% (N = 19/29), respectively. Maintenance LDX and placebo did not differ significantly in binge-eating but differed in weight-loss and eating-disorder psychopathology. Maintenance LDX was associated with significant weight-loss (-2.3%) whereas placebo had significant weight-gain (+2.2%); LDX and placebo differed significantly in weight-change throughout treatment and at posttreatment. Eating-disorder psychopathology remained unchanged with LDX but increased significantly with placebo. Acute treatments did not significantly predict/moderate maintenance-treatment outcomes. CONCLUSIONS: Adults with BED/obesity who respond to acute lisdexamfetamine treatment (regardless of additionally receiving CBT) had good maintenance during subsequent 12-weeks. Maintenance lisdexamfetamine, relative to placebo, did not provide further benefit for binge-eating but was associated with significantly better eating-disorder psychopathology outcomes and greater weight-loss.

Socioecological factors associated with multiple nicotine product use among U.S. youth: Findings from the population assessment of tobacco and health (PATH) study 2013-2018.

OBJECTIVE: This study utilized a socioecological approach to prospectively identify intrapersonal, familial, and environmental factors associated with single nicotine product use (NPU) and multiple NPU among U.S. youth. METHODS: Participants were 10,029 youths (ages 12-17 years) who had completed the Population Assessment of Tobacco Health study's Wave 1 (2013-2014) and Wave 4 (2016-2018) assessments and data on past 30-day nicotine product use. Multinomial logistic regression was fit for the 3-level outcome (no use, single NPU, multiple NPU) to estimate adjusted associations between the predictors and the outcome. RESULTS: The current study found that intrapersonal (sex, age, race/ethnicity, internalizing symptoms, sensation seeking, harm perceptions, lifetime history of using two or more tobacco products), familial (parental discussion about not using tobacco and living with someone who uses tobacco products) and environmental factors (exposure to tobacco advertising) commonly associated with tobacco use differentiated between individuals who later reported past 30-day NPU (either multiple or single NPU) from those who did not report past 30-day NPU. One familial factor only differentiated between lifetime users who were single NPUs from those who reported no NPU: non-combustible tobacco product use allowed anywhere in the home. Intrapersonal factors differentiated multiple NPU from single NPU: older age, being male, lifetime history of using nicotine product and less harm perceptions. CONCLUSIONS: This study identified factors that may be studied to prevent any NPU, along with factors that may be studied to promote harm reduction by preventing escalation of single NPU to problematic patterns of multiple NPU.

Associations Between Childhood Trauma and Tobacco Use Outcomes in Adults after Overnight Abstinence.

INTRODUCTION: Childhood trauma is known to be associated with nicotine dependence, yet limited smoking outcomes have been examined and few studies have assessed associations between specific trauma subscales and smoking. Additionally, sex differences in trauma-smoking relations are understudied. This study examined associations between childhood trauma and several smoking-related outcomes in adults who smoke after overnight abstinence. AIMS AND METHODS: People who smoke (N = 205) completed self-report and biochemical assessments evaluating childhood trauma, affect, nicotine dependence, smoking urges, withdrawal, and plasma cortisol and cotinine levels. Smoking outcomes were compared between those with and without a history of moderate to severe childhood trauma among the total sample and by sex. RESULTS: Relative to those with no to minimal abuse, those with moderate to severe abuse had higher negative affect, withdrawal severity, and plasma cotinine levels. Exploratory analyses revealed that women were more likely than men to have urges to smoke for negative reinforcement and have higher withdrawal severity, but no interactions between abuse group and sex were observed. Examining specific trauma subscales, the moderate to severe emotional abuse group had more severe nicotine dependence, negative affect, and withdrawal compared to the no to minimal group. The moderate to severe sexual abuse group had more severe nicotine dependence and withdrawal compared to the no to minimal group. CONCLUSIONS: Exposure to childhood trauma is associated with more severe nicotine dependence, negative affect, withdrawal, and higher plasma cotinine levels. Findings also indicate that different types of trauma may differentially affect smoking behaviors. IMPLICATIONS: This study of adults who smoke finds that childhood trauma history may be a marker for smoking susceptibility and suggests that individuals with experiences of emotional and sexual abuse may require targeted forms of smoking cessation interventions. Moreover, findings suggest that smoking risks may differ for men and women. Findings inform public health interventions intended to reduce cigarette use in individuals with exposure to childhood trauma.

Lower Dorsal Putamen D2/3 Receptor Availability and Amphetamine-Induced Dopamine Release are Related to Poorer Cognitive Function in Recently Abstinent People Who Smoke and Healthy Controls.

INTRODUCTION: In the dopamine system, the mesolimbic pathway, including the dorsal striatum, underlies the reinforcing properties of tobacco smoking, and the mesocortical pathway, including the dorsolateral prefrontal cortex (dlPFC), is critical for cognitive functioning. Dysregulated dopamine signaling has been linked to drug-seeking behaviors and cognitive deficits. The dorsal striatum and dlPFC are structurally and functionally connected and are key regions for cognitive functioning. We recently showed that people who smoke have lower dlPFC dopamine (D2/3R) receptor availability than people who do not, which is related to poorer cognitive function. AIMS AND METHODS: The goal of this study was to examine the same brain-behavior relationship in the dorsal striatum. Twenty-nine (18 males) recently abstinent people who smoke and 29 sex-matched healthy controls participated in 2 same-day [11C]-(+)-PHNO positron emission tomography scans before and after amphetamine administration to provoke dopamine release. D2/3R availability (binding potential; BPND) and amphetamine-induced dopamine release (%ΔBPND) were calculated. Cognition (verbal learning and memory) was assessed with the CogState computerized battery. RESULTS: There were no group differences in baseline BPND. People who smoke have a smaller magnitude %ΔBPND in dorsal putamen than healthy controls (p = .022). People who smoke perform worse on immediate (p = .035) and delayed (p = .011) recall than healthy controls. In all people, lower dorsal putamen BPND was associated with worse immediate (p = .006) and delayed recall (p = .049), and lower %ΔBPND was related to worse delayed recall (p = .022). CONCLUSIONS: Lower dorsal putamen D2/3R availability and function are associated with disruptions in cognitive function that may underlie difficulty with resisting smoking. IMPLICATIONS: This study directly relates dopamine imaging outcomes in the dorsal striatum to cognitive function in recently abstinent people who smoke cigarettes and healthy controls. The current work included a well-characterized subject sample in terms of demographics, smoking characteristics, and a validated neurocognitive test of verbal learning and memory. The findings of this study extend previous literature relating dopamine imaging outcomes to cognition in recently abstinent people who smoke and people who do not smoke, expanding our understanding of brain-behavior relationships.

Overvaluation of shape/weight at posttreatment predicts relapse at 12-month follow-up after successful behaviorally-based treatment of binge-eating disorder.

OBJECTIVE: To test whether overvaluation of shape/weight at the end of treatment prospectively predicts relapse at 12-month follow-up in patients with binge-eating disorder (BED). METHOD: Participants were 129 patients with BED who achieved abstinence from binge eating after 6 months of behaviorally-based weight-loss treatments in a clinical trial. Independent assessments conducted at posttreatment and at 12-month follow-up included the Eating Disorder Examination interview, the Beck Depression Inventory, and weight measurements. RESULTS: Of the 129 participants who attained abstinence from binge-eating at posttreatment, 46 (36%) were categorized with clinical overvaluation and 83 (64%) with subclinical overvaluation; 115 (89%) were re-assessed at 12-month follow-up. Participants with overvaluation at posttreatment were significantly more likely than those without to relapse at 12-months to non-abstinence from binge eating (54% vs. 28%) and to diagnosis-level binge-eating frequency of once weekly or greater (31% vs. 13%). Overvaluation at posttreatment predicted significantly higher eating-disorder psychopathology and depression scores at 12-month follow-up but were unrelated to weight and weight changes. Treatment groups did not have main or interaction effects; posttreatment overvaluation effects were observed regardless of treatment and of covarying for posttreatment value of dependent variables. CONCLUSIONS: Our findings suggest that overvaluation of shape/weight at the end of treatment predicts relapse and heightened eating-disorder psychopathology and depression scores 1 year later in patients who achieved abstinence from binge eating with behaviorally-based treatments. Overvaluation of shape/weight has significant clinical implications and warrants consideration as a diagnostic specifier for BED as it provides important prospective prognostic information. PUBLIC SIGNIFICANCE: Although effective treatments are available for binge-eating disorder, relapse following successful treatments is not uncommon. Almost nothing is known about what predicts relapse following treatments for binge-eating disorder. Our study found that overvaluation of shape/weight (i.e., body image concerns that overly impact self-worth) at posttreatment prospectively predicted relapse and higher eating-disorder psychopathology and depression 1 year later in patients who achieved binge-eating abstinence with behaviorally based treatments. CLINICALTRIALS: gov registration: NCT00829283. (Treatment of obesity and binge eating: Behavioral weight loss vs. stepped care.).

A randomized controlled trial of potential tobacco policies prohibiting menthol flavor in cigarettes and e-cigarettes: a study protocol.

BACKGROUND: Menthol cigarette use remains a large public health problem and disproportionately affects Black adults in the United States. The Food and Drug Administration has proposed prohibiting menthol flavor in cigarettes to protect public health. However, e-cigarettes are available in menthol flavor and are a popular alternative product adults might switch to if menthol is prohibited in cigarettes. Research is needed to understand how availability of menthol (vs. tobacco) flavored e-cigarettes could impact cigarette use among adults who smoke menthol cigarettes. METHODS: We will recruit 150 adults who currently smoke menthol cigarettes and will randomize them to 1 of 3 conditions modeling different regulatory scenarios. We will recruit equal numbers of participants identifying as Black vs. non-Black and will stratify randomization by race. To promote standardization and adherence, cigarette and e-cigarette products will be provided for 8 weeks based on the assigned condition: (A) no menthol restriction (menthol cigarette and menthol flavored e-cigarette), (B) menthol prohibited in cigarettes only (non-menthol cigarette and menthol flavored e-cigarette), (C) menthol prohibited in both cigarettes and e-cigarettes (non-menthol cigarette and tobacco flavored e-cigarette). A follow-up visit will occur at week 12 to assess tobacco use status. The study aims are to (1) examine the impact of prohibiting menthol flavor in cigarettes and e-cigarettes on smoking behavior and (2) investigate whether outcomes differ by race to understand the impact of menthol policies on Black (vs. non-Black) individuals given high rates of menthol cigarette use in this population. The primary outcome will evaluate changes in the number of cigarettes smoked per day during the 8-week study period and will examine differences by regulatory scenario. Secondary outcomes will compare percent days smoke-free, changes in nicotine dependence, and motivation, confidence, and intentions to quit smoking by the regulatory scenarios. We will examine whether changes in the outcomes differ by Black vs. non-Black participants to compare the magnitude of the effect of the various menthol policy scenarios by race. DISCUSSION: Results will contribute critical information regarding menthol in cigarettes and e-cigarettes to inform regulatory policies that maximize reductions in cigarette smoking and reduce tobacco-related health disparities. TRIAL REGISTRATION: NCT05259566. Yale IRB protocol #2000032211, last approved 12/8/2023.

Naltrexone plus bupropion combination medication maintenance treatment for binge-eating disorder following successful acute treatments: randomized double-blind placebo-controlled trial.

BACKGROUND: Certain treatments have demonstrated acute efficacy for binge-eating disorder (BED) but there is a dearth of controlled research examining pharmacotherapies as maintenance treatments for responders to initial interventions. This gap in the literature is particularly critical for pharmacotherapy for BED which is associated with relapse following discontinuation. The current study tested the efficacy of naltrexone/bupropion maintenance treatment amongst responders to acute treatments for BED. METHODS: Prospective randomized double-blind placebo-controlled single-site trial, conducted August 2017-December 2021, tested naltrexone/bupropion as maintenance treatment for responders to acute treatments with naltrexone/bupropion and/or behavioral weight-loss therapy for BED with comorbid obesity. Sixty-six patients (84.8% women, mean age 46.9, mean BMI 34.9 kg/m2) who responded to acute treatments were re-randomized to placebo (N = 34) or naltrexone/bupropion (N = 32) for 16 weeks; 86.3% completed posttreatment assessments. Mixed models and generalized estimating equations comparing maintenance treatments (naltrexone/bupropion v. placebo) included main and interactive effects of acute treatments. RESULTS: Intention-to-treat binge-eating remission rates following maintenance treatments were 50.0% (N = 17/34) for placebo and 68.8% (N = 22/32) for naltrexone/bupropion. Placebo following response to acute treatment with naltrexone/bupropion was associated with significantly decreased probability of binge-eating remission, increased binge-eating frequency, and no weight loss. Naltrexone/bupropion following response to acute treatment with naltrexone/bupropion was associated with good maintenance of binge-eating remission, low binge-eating frequency, and significant additional weight loss. CONCLUSIONS: Adult patients with BED with co-occurring obesity who have good responses to acute treatment with naltrexone/bupropion should be offered maintenance treatment with naltrexone/bupropion.

Change in impulsivity is prospectively associated with treatment outcomes for binge-eating disorder.

BACKGROUND: Impulsivity may be a process underlying binge-eating disorder (BED) psychopathology and its treatment. This study examined change in impulsivity during cognitive-behavioral therapy (CBT) and/or pharmacological treatment for BED and associations with treatment outcomes. METHODS: In total, 108 patients with BED (NFEMALE = 84) in a randomized placebo-controlled clinical trial evaluating the efficacy of CBT and/or fluoxetine were assessed before treatment, monthly throughout treatment, at post-treatment (16 weeks), and at 12-month follow-up after completing treatment. Patients completed established measures of impulsivity, eating-disorder psychopathology, and depression, and were measured for height and weight [to calculate body mass index (BMI)] during repeated assessments by trained/monitored doctoral research-clinicians. Mixed-effects models using all available data examined changes in impulsivity and the association of rapid and overall changes in impulsivity on treatment outcomes. Exploratory analyses examined whether baseline impulsivity predicted/moderated outcomes. RESULTS: Impulsivity declined significantly throughout treatment and follow-up across treatment groups. Rapid change in impulsivity and overall change in impulsivity during treatment were significantly associated with reductions in eating-disorder psychopathology, depression scores, and BMI during treatment and at post-treatment. Overall change in impulsivity during treatment was associated with subsequent reductions in depression scores at 12-month follow-up. Baseline impulsivity did not moderate/predict eating-disorder outcomes or BMI but did predict change in depression scores. CONCLUSIONS: Rapid and overall reductions in impulsivity during treatment were associated with improvements in specific eating-disorder psychopathology and associated general outcomes. These effects were found for both CBT and pharmacological treatment for BED. Change in impulsivity may be an important process prospectively related to treatment outcome.

Does Symptom-Onset Treatment With Sertraline Improve Functional Impairment for Individuals With Premenstrual Dysphoric Disorder?: A Randomized Controlled Trial.

PURPOSE/BACKGROUND: Daily treatment with sertraline improves functional impairment among individuals with premenstrual dysphoric disorder (PMDD). We do not know whether treatment initiated at symptom onset also improves functional impairment. METHODS/PROCEDURES: This 3-site, double blind, randomized, clinical trial compared sertraline (25-100 mg) to similar appearing placebo, both administered at symptom onset, for reduction of PMDD symptoms. Ninety participants were allocated to sertraline and 94 participants to placebo. Functional outcomes from the Daily Ratings of the Severity of Problems included (1) reduced productivity or efficiency at work, school, home, or daily routine; (2) interference with hobbies or social activities; and (3) interference with relationships. Items were measured from 1 (no interference) to 6 (extreme interference) and averaged for the final 5 luteal phase days. This secondary analysis examined whether improvement in functional domains was greater for those allocated to sertraline compared with placebo. Second, we used causal mediation analyses to explore whether specific PMDD symptoms mediated functional improvement. RESULTS/FINDINGS: Only relationship functioning improved significantly with active treatment between baseline and the end of the second cycle (active group mean [SD] change, -1.39 [1.38]; placebo group mean change, -0.76 [1.20]; ß = -0.40; SE, 0.15; P = 0.009). The total effect of treatment on interference was -0.37 (95% confidence interval [CI], -0.66 to -0.09; P = 0.011). Given the nonsignificant direct effect (0.11; 95% CI, -0.07 to 0.29; P = 0.24) and significant indirect effect (-0.48; 95% CI, -0.71 to -0.24; P < 0.001), amelioration of anger/irritability likely mediated reductions in relationship interference. IMPLICATIONS/CONCLUSIONS: That anger/irritability mediates impairments in relationship functioning has face validity but should be replicated in other data sets. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00536198 .

The first nicotine product tried is associated with current multiple nicotine product use and nicotine dependence among a nationally representative sample of U.S. youths.

This study examines the demographic factors associated with youths' first product tried (i.e., cigarettes, e-cigarettes, cigars, hookah, or smokeless tobacco). This study also evaluates whether the first product tried is associated with future nicotine product use (i.e., no use, single product use, and multiple product use) and nicotine dependence. Participants were 1999 youths (ages 12-17 years) who had ever tried a nicotine product and completed the Population Assessment of Tobacco Health study's Wave 1 (2013-2014) and Wave 4 (2016-2018) assessments. Two separate multinomial logistic regression models examined the association between 1) demographic factors and the first product tried at Wave 1 and 2) the first product tried at Wave 1 and past-30-day product use status at Wave 4. A two-part multivariable model examined the association between the first product tried and nicotine dependence, with part 1 modeling the presence (or absence) of any symptom of dependence and part 2 modeling the degree of dependence among those with any symptom of dependence. The first product tried was associated with sex, race, urbanicity, and parent education. First trying smokeless tobacco (vs. e-cigarettes) was associated with a greater likelihood of multiple product use (vs. no use and vs. single product use). Regarding the degree of nicotine dependence (n = 713), first trying smokeless tobacco (vs. e-cigarettes) was associated with higher nicotine dependence scores among those with any symptom of dependence. Youths who first try smokeless tobacco (vs. e-cigarettes) may be at higher risk for future multiple product use and more symptoms nicotine dependence. Research should explore tailored interventions for smokeless tobacco users.

Models for Zero-Inflated and Overdispersed Correlated Count Data: An Application to Cigarette Use.

INTRODUCTION: Count outcomes in tobacco research are often analyzed with the Poisson distribution. However, they often exhibit features such as overdispersion (variance larger than expected) and zero inflation (extra zeros) that violate model assumptions. Furthermore, longitudinal studies have repeated measures that generate correlated counts. Failure to account for overdispersion, zero inflation, and correlation can yield incorrect statistical inferences. Thus, it is important to familiarize researchers with proper models for such data. AIMS AND METHODS: Poisson and Negative Binomial models with correlated random effects with and without zero inflation are presented. The illustrative data comes from a study comparing a mindfulness training app (Craving to Quit [C2Q], n = 60) with a control app (experience sampling-only app, n = 66) on smoking frequency at 1, 3, and 6 months. Predictors include app, time, the app-by-time interaction, and baseline smoking. Each model is evaluated in terms of accounting for zero inflation, overdispersion, and correlation in the data. Emphasis is placed on evaluating model fit, subject-specific interpretation of effects, and choosing an appropriate model. RESULTS: The hurdle Poisson model provided the best fit to the data. Smoking abstinence rates were 33%, 32%, and 28% at 1, 3, and 6 months, respectively, with variance larger than expected by a factor >7 at each follow-up. Individuals on C2Q were less likely to achieve abstinence across time but likely to smoke fewer cigarettes if smoking. CONCLUSIONS: The models presented are specifically suited for analyzing correlated count outcomes and account for zero inflation and overdispersion. We provide guidance to researchers on the use of these models to better inform nicotine and tobacco research. IMPLICATIONS: In tobacco research, count outcomes are often measured repeatedly on the same subject and thus correlated. Such outcomes often have many zeros and exhibit large variances relative to the mean. Analyzing such data require models specifically suited for correlated counts. The presented models and guidelines could improve the rigor of the analysis of correlated count data and thus increase the impact of studies in nicotine and tobacco research using such outcomes.

A Network Analysis of Cigarette Craving.

INTRODUCTION: Craving is considered a central process to addictive behavior including cigarette smoking, although the clinical utility of craving relies on how it is defined and measured. Network analysis enables examining the network structure of craving symptoms, identifying the most central symptoms of cigarette craving, and improving our understanding of craving and its measurement. AIMS AND METHODS: This study used network analysis to identify the central symptoms of self-reported cigarette craving as measured by the Craving Experience Questionnaire, which assesses both craving strength and craving frequency. Data were obtained from baseline of a randomized controlled trial of mindfulness training for smoking cessation. RESULTS: The most central symptoms in an overall cigarette craving network were the frequency of imagining its smell, imagining its taste, and intrusive thoughts. The most central symptoms of both craving frequency and craving strength sub-networks were imagining its taste, the urge to have it, and intrusive thoughts. CONCLUSIONS: The most central craving symptoms reported by individuals in treatment for cigarette smoking were from the frequency domain, demonstrating the value of assessing craving frequency along with craving strength. Central craving symptoms included multisensory imagery (taste, smell), intrusive thoughts, and urge, providing additional evidence that these symptoms may be important to consider in craving measurement and intervention. Findings provide insight into the symptoms that are central to craving, contributing to a better understanding of cigarette cravings, and suggesting potential targets for clinical interventions. IMPLICATIONS: This study used network analysis to identify central symptoms of cigarette craving. Both craving frequency and strength were assessed. The most central symptoms of cigarette craving were related to craving frequency. Central symptoms included multisensory imagery, intrusive thoughts, and urge. Central symptoms might be targeted by smoking cessation treatment.

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.

Cognitive-behavioral therapy for binge-eating disorder for non-responders to initial acute treatments: Randomized controlled trial.

OBJECTIVE: Certain treatments have demonstrated acute efficacy for binge-eating disorder (BED) but many patients who receive "evidence-based" interventions do not derive sufficient benefit. Given the dearth of controlled research examining treatments for patients who fail to respond to initial interventions, this study tested the efficacy of cognitive-behavioral therapy (CBT) for patients with BED who do not respond to initial acute treatments. METHODS: Prospective randomized double-blind placebo-controlled single-site trial, conducted August 2017-December 2021, tested 16-weeks of therapist-led CBT for non-responders to initial treatment (naltrexone/bupropion and/or behavioral therapy) for BED with obesity. Thirty-one patients (mean age 46.3 years, 77.4% women, 80.6% White, mean BMI 38.99 kg/m2 ) who were non-responders to initial acute treatments were randomized to CBT (N = 18) or no-CBT (N = 13), in addition to continuing double-blinded pharmacotherapy. Independent assessments were performed at baseline, throughout treatment, and posttreatment; 83.9% completed posttreatment assessments. RESULTS: Intention-to-treat remission rates were significantly higher for CBT (61.1%; N = 11/18) than no-CBT (7.7%; N = 1/13). Mixed models of binge-eating frequency (assessed using complementary methods) converged revealing a significant interaction between CBT and time and a significant main effect of CBT. Binge-eating frequency decreased significantly with CBT but did not change significantly with no-CBT. Since only four patients received behavioral treatment during the acute treatments, we performed "sensitivity-type" analyses restricted to the 27 patients who received pharmacotherapy during the acute treatment and found the same pattern of findings for CBT versus no-CBT. CONCLUSIONS: Adult patients with BED who fail to respond to initial pharmacological treatments should be offered CBT. PUBLIC SIGNIFICANCE: Even with leading evidence-based treatments for binge-eating disorder, many patients do not derive sufficient benefit. Almost no controlled research has examined treatments for patients who fail to respond to initial interventions. This study found that that cognitive-behavioral therapy was effective for patients with binge-eating disorder who did not respond to initial interventions, with 61% achieving abstinence.

Including the term 'tobacco-free nicotine' in the nicotine addiction warning label mandated by the US Food and Drug Administration alters risk perceptions and use intentions.

BACKGROUND: The US Food and Drug Administration (FDA) requires a warning label on nicotine e-cigarettes and pouches: 'This product contains nicotine. Nicotine is an addictive chemical'. Some brands marketing synthetic nicotine products have modified the warning ('This product contains tobacco-free nicotine (TFN)…'). The public health impact of altering the warning is unknown, so we examined its impact on risk perceptions and use intentions. METHODS: 1000 participants completed an anonymous online survey. Participants viewed the black-and-white FDA and TFN-modified warning labels in isolation, in a randomised order and reported on perceived addictiveness and, secondarily, use intentions. Participants then selected which label conveyed the most harm overall. Generalised estimating equations (GEEs) were used to evaluate the impact of label type and participant characteristics on perceived addictiveness and, secondarily, use intentions. Multivariable logistic regression was used to evaluate relationships between participant characteristics and choosing which label conveyed the most harm. RESULTS: Overall, the TFN-modified label was associated with lower addictiveness ratings but not increased use intentions. Where significant interactions between label type and participant characteristics emerged, TFN-modified labelling was associated with disproportionately reduced risk perceptions or increased use intentions among vulnerable populations (eg, underage individuals, racially minoritised groups). 25.5% of participants selected the TFN-modified label as conveying the most harm, with younger individuals (<21 years) significantly less likely to choose the TFN-modified label. CONCLUSIONS: Modifying the FDA-mandated nicotine warning label to include 'tobacco-free nicotine' may negatively impact public health, so the FDA should enforce inclusion of its original required warning label.

Predictors of abstinence, no heavy drinking days, and a 2-level reduction in World Health Organization drinking levels during treatment for alcohol use disorder in the COMBINE study.

BACKGROUND: Data from trials of medications for alcohol use disorder (AUD) can be used to identify predictors of drinking outcomes regardless of treatment, which can inform the design of future trials with heterogeneous populations. Here, we identified predictors of abstinence, no heavy drinking days, and a 2-level reduction in World Health Organization (WHO) drinking levels during treatment for AUD in the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study. METHODS: We utilized data from the COMBINE Study, a randomized placebo-controlled trial evaluating the efficacy of naltrexone and acamprosate, both alone and in combination, for AUD (n = 1168). A tree-based machine learning algorithm was used to construct classification trees predicting abstinence, no heavy drinking days, and a 2-level reduction in WHO drinking levels in the last 4 weeks of treatment, based on 89 baseline variables. RESULTS: The final tree for predicting abstinence had one split based on consecutive days abstinent prior to randomization, with a higher proportion of subjects achieving abstinence among those classified as abstinent for >2 versus ≤2 consecutive weeks prior to randomization (66% vs. 29%). The final tree for predicting no heavy drinking days in the last 4 weeks of treatment had three splits based on consecutive days abstinent, age, and total Alcohol Dependence Scale score at baseline. Seventy-three percent of the subjects classified as abstinent for >2 consecutive weeks prior to randomization had no heavy drinking days in the last 4 weeks of treatment. Among those classified as abstinent ≤2 consecutive weeks prior, three additional splits showed that younger subjects (age ≤44 years; 37%), and older subjects (age >44) with a total Alcohol Dependence Scale score >13 and complete abstinence (56%) or other drinking goals (35%), were less likely to have no heavy drinking days than older subjects with a total Alcohol Dependence Scale score ≤13 (67%). The final tree for predicting a 2-level reduction in WHO levels had no splits. CONCLUSIONS: Consecutive days abstinent prior to randomization may predict abstinence and no heavy drinking days and total Alcohol Dependence Scale score and age may predict no heavy drinking days. The 2-level reduction in WHO levels outcome may be less likely to discriminate based on multiple patient characteristics.

Sensitivity, specificity, and tolerability of the BACTrack Skyn compared to other alcohol monitoring approaches among young adults in a field-based setting.

BACKGROUND: There is a need for novel alcohol biosensors that are accurate, able to detect alcohol concentration close in time to consumption, and feasible and acceptable for many clinical and research applications. We evaluated the field accuracy and tolerability of novel (BACTrack Skyn) and established (Alcohol Monitoring Systems SCRAM CAM) alcohol biosensors. METHODS: The sensor and diary data were collected in a larger study of a biofeedback intervention and compared observationally in the present sub-study. Participants (high-risk drinkers, 40% female; median age 21) wore both Skyn and SCRAM CAM sensors for 1-6 days and were instructed to drink as usual. Data from the first cohort of participants (N = 27; 101 person-days) were used to find threshold values of transdermal alcohol that classified each day as meeting or not meeting defined levels of drinking (heavy, above-moderate, any). These values were used to develop scoring metrics that were subsequently tested using the second cohort (N = 20; 57 person-days). Data from both biosensors were compared to mobile diary self-report to evaluate sensitivity and specificity in relation to a priori standards established in the literature. RESULTS: Skyn classification rules for Cohort #1 within 3 months of device shipment showed excellent sensitivity for heavy drinking (94%) and exceeded expectations for above-moderate and any drinking (78% and 69%, respectively), while specificity met expectations (91%). However, classification worsened when Cohort #1 devices ≥3 months from shipment were tested (area under curve for receiver operator characteristic 0.87 vs. 0.79) and the derived classification threshold when applied to Cohort #2 was inadequately specific (70%). Skyn tolerability metrics were excellent and exceeded the SCRAM CAM (p ≤ 0.001). CONCLUSIONS: Skyn tolerability was favorable and accuracy rules were internally derivable but did not yield useful scoring metrics going forward across device lots and months of usage.

Novel Nicotine Concentration Labels Improve Adolescents' and Young Adults' Understanding of the Nicotine Strength of Electronic Nicotine Delivery System Products.

INTRODUCTION: E-cigarette liquid nicotine concentrations typically are labeled as mg/mL or percent, which poorly convey nicotine strength to users. We evaluated whether four novel nicotine concentration labels better convey information about nicotine strength and addictiveness. METHODS: Adolescents and young adults (N = 826) completed an online survey in 2020. Participants rated nicotine concentrations (3, 6, 18, 30, 40, and 50 mg/mL) from "no nicotine" to "very high nicotine" communicated using current market labels (mg/mL, percent) and four new labels (text-based, caution sign-shaped, horizonal stoplight, vertical thermometer) which used color, symbols, and verbal strength descriptors. Participants reported on perceived addictiveness for all labels viewed and rank-ordered labels on perceived ability to convey information accurately. RESULTS: Participants ranked the vertical (77%) and horizontal (70%) labels in first or second place and mg/mL (59.1%) and percent (47.2%) in last or second-to-last place. All new labels conveyed nicotine strength more accurately than did market labels (M[SD] correct of 6: percent = 1.50[1.08]; mg/mL = 2.14[1.52]; caution = 5.23[1.37]; vertical thermometer = 5.28[1.51]; text = 5.33[1.36]; horizontal stoplight = 5.47[1.14]), with the horizontal label also outperforming the thermometer and caution labels. Underestimating nicotine strength was uncommon among all new labels (4.7-6.8%). The new labels also were associated with increased perceived addictiveness at higher concentrations (30, 40, and 50 mg/mL), although the thermometer label underperformed the others. When considering perceived nicotine strength, rates of strength underestimates, perceived addictiveness, and rank ordering, the horizontal stoplight label performed best. CONCLUSIONS: Novel labeling could improve understanding of nicotine strength and e-cigarette-related risk. IMPLICATIONS: Extending prior research showing that adolescents and young adults who use Electronic Nicotine Delivery Systems (ENDS) have difficulty understanding nicotine concentrations labeled using mg/mL and percent nicotine, the current study demonstrates that novel nicotine concentration labels can improve understanding of nicotine strength and influence perceptions of addictiveness among young ENDS users. While four novel labels were tested, each outperforming current market labeling, the novel label that resembles a horizontal stoplight performed best. The study provides proof-of-concept that creating an easy-to-understand nicotine concentration label is possible and that new labeling better conveys information about nicotine strength and addictiveness.

Joint longitudinal trajectories of pain intensity and opioid prescription in veterans with back pain.

PURPOSE: We describe pain intensity and opioid prescription jointly over time in Veterans with back pain to better understand their relationship. METHODS: We performed a retrospective cohort study on electronic health record data from 117 126 Veterans (mean age 49.2 years) diagnosed with back pain in 2015. We used latent class growth analysis to jointly model pain intensity (0-10 scores) and opioid prescriptions over 2 years to identify classes of individuals similar in their trajectory of pain and opioid over time. Multivariable multinomial logit models assessed sociodemographic and clinical predictors of class membership. RESULTS: We identified six trajectory classes: a "no pain/no opioid" class (22.2%), a "mild pain/no opioid" class (45.0%), a "moderate pain/no opioid" class (24.6%), a "moderate, decreasing pain/decreasing opioid" class (3.3%), a "moderate pain/high opioid" class (2.6%), and a "moderate, increasing pain/increasing opioid" class (2.3%). Among those in moderate pain classes, being white (vs. non-white) and older were associated with higher odds of being prescribed opioids. Veterans with mental health diagnoses had increased odds of being in the painful classes versus "no pain/no opioid" class. CONCLUSION: We found distinct patterns in the long-term joint course of pain and opioid prescription in Veterans with back pain. Understanding these patterns and associated predictors may help with development of targeted interventions for patients with back pain.