Adult attention-deficit/hyperactivity disorder among alcohol use disorder inpatients is associated with food addiction and binge eating, but not BMI.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is associated with binge eating (BE), food addiction (FA), and obesity/higher BMI in individuals without alcohol use disorder (AUD). ADHD is highly prevalent in patients with AUD, but it is unknown whether the presence of comorbid AUD might change the nature of the association between ADHD, BE, FA and BMI (food and alcohol may either compete for the same brain neurocircuitry or share vulnerability risk factors). Here, we filled this gap by testing the association between ADHD and FA/BE in adult patients hospitalized for AUD, with the strength of simultaneously assessing childhood and adult ADHD. We also investigated the association between ADHD and BMI, and the other factors associated with BMI (FA/BE, AUD severity). METHODS: We included 149 AUD inpatients between November 2018 and April 2019. We assessed both childhood and adulthood ADHD (Wender Utah Render Scale and Adult ADHD Self-Report Scale), FA (modified Yale Food Addiction Scale 2.0), BE (Binge Eating Scale), and BMI and AUD (clinical assessment). RESULTS: In multivariable analyses adjusted for age, adult ADHD was associated with higher BE scores (p = .048), but not significant BE (9% vs. 7%; p = .70). ADHD was also associated with FA diagnosis and the number or FA symptoms, with larger effect size for adult (ORs: 9.45[95%CI: 2.82-31.74] and 1.38[1.13-1.69], respectively) than childhood ADHD (ORs: 4.45[1.37-14.46] and 1.40[1.13-1.75], respectively). In multivariable analysis, BMI was associated with both significant BE (p < .001) and FA diagnosis (p = .014), but not adult ADHD nor AUD severity. CONCLUSION: In patients hospitalized for AUD, self-reported adult ADHD was associated with FA and BE, but not BMI. Our results set the groundwork for longitudinal research on the link between ADHD, FA, BE, and BMI in AUD inpatients.

Evolution of circuits regulating pleasure and happiness with the habenula in control.

The habenula, which in humans is a small nuclear complex within the epithalamus, plays an essential role in regulating the intensity of reward-seeking and adversity-avoiding behavior in all vertebrate ancestors by regulating the activity of ascending midbrain monoaminergic tracts. In lampreys, considered to possess a brain comparable to humans' earliest evolutionary vertebrate ancestor, the activity of the lateral habenula is controlled by a subset of glutamatergic neurons of the animal's pallidum (habenula-projecting globus pallidus) that inhibit reward-seeking behavior when this conduct is not successful enough. The pathophysiological roles of the habenula and habenula-projecting globus pallidus in humans have hardly been studied, which is probably due to insufficient resolution of common neuroimaging techniques. Their dysregulation may, however, play an essential role in the pathogenesis of mood and stress disorders and addiction.

Posttraumatic Stress Disorder Is a Risk Factor for Multiple Addictions in Police Officers Hospitalized for Alcohol.

BACKGROUND: In police officers, posttraumatic stress disorder (PTSD) is associated with alcohol use disorder (AUD), but we lack data on the association between PTSD and other substance-related and addictive disorders. OBJECTIVES: We assessed whether PTSD could be a risk factor for different substance-related and addictive disorders in police officers, including alcohol, tobacco, cannabis, and gambling. METHOD: This cross-sectional study included all police officers admitted consecutively for alcohol to an inpatient ward dedicated to police officers (Le Courbat rehabilitation center, France; n= 133). Each patient completed self-administered questionnaires that assessed lifetime exposure to potentially traumatic events (Life Event Checklist for DSM-5), PTSD severity and diagnosis (PTSD Checklist for DSM-5), AUD severity (Alcohol Use Disorder Identification Test [AUDIT]), tobacco dependence (Fagerström test for Nicotine Dependence), cannabis dependence (Cannabis Abuse Screening test), and gambling disorder (Canadian Problem Gambling Index). RESULTS: Mean AUDIT score was 23.7 ± 8.0; 66.2% had an AUDIT score ≥20. Our sample comprised a high prevalence for PTSD (38.3%) and for substance-related and addictive disorders: tobacco dependence (68.4%), cannabis dependence (3.8%), and pathological gambling (3%). Patients with PTSD experienced higher lifetime exposure to traumatic experiences: physical assault, severe human suffering, sudden accidental death of another person, and other types of stressful events/experiences. In multiple linear regressions adjusted for age, sex, and marital status, PTSD was a significant predictor of the severity of AUD and tobacco use disorder, but not of the severity of cannabis use disorder nor gambling disorder. CONCLUSIONS: PTSD is common in police officers hospitalized for alcohol and associated with a higher severity of some addictive disorders (alcohol/tobacco). PTSD and its comorbid addictive disorders should be systematically screened and treated in this population.

Adulthood and childhood ADHD in patients consulting for obesity is associated with food addiction and binge eating, but not sleep apnea syndrome.

INTRODUCTION: The exact mechanisms underlying the established association between ADHD and obesity remain unclear. Food addiction and binge eating may contribute to this link. We examined for the first time the association between childhood/adult ADHD and food addiction/binge eating in patients with obesity, as well as the association between ADHD and sleep apnea syndrome. METHODS: We included 105 obese patients from the Nutrition Department of the University Hospital of Tours (France) between January and December 2014. We assessed categorical diagnoses of childhood/adulthood ADHD (semi-structured interview DIVA 2.0), food addiction (Yale Food Addiction Scale 2.0), binge eating (Binge Eating Scale), obstructive sleep apnea (clinical assessment), and BMI (clinical assessment). RESULTS: Patients with adult ADHD were at significantly higher risk of food addiction than patients without adult ADHD (28.6% vs. 9.1%; p = .016). Adult and childhood ADHD were significantly associated with self-reported food addiction, food addiction scores and binge eating scores, with a larger effect size for adult (ORs: 4.00 [1.29-12.40], 1.37 [1.14-1.65] and 1.08 [1.03-1.14], respectively) than childhood (ORs: 3.32 [1.08-10.23], 1.29 [1.08-1.55] and 1.06 [1.01-1.11], respectively) ADHD. ADHD diagnosis was not significantly correlated to obstructive sleep apnea. Mean age of onset of ADHD preceded mean age of onset of obesity. CONCLUSION: ADHD diagnosis is associated with food addiction and binge eating, with a larger effect size for adult than childhood ADHD. Our results provide a strong rationale for further longitudinal research on the link between ADHD, food addiction, binge eating and obesity, paving the way for evidence-based therapeutic interventions for these patients.

Trends in Prevalence of Cannabis Use Disorder Among U.S. Veterans With and Without Psychiatric Disorders Between 2005 and 2019.

OBJECTIVE: Cannabis use disorder diagnoses are increasing among U.S. adults and are more prevalent among people with comorbid psychiatric disorders. Recent changes in cannabis laws, increasing cannabis availability, and higher-potency cannabis may have placed people with cannabis use and psychiatric disorders at disproportionately increasing risk for cannabis use disorder. The authors used Veterans Health Administration (VHA) data to examine whether trends in cannabis use disorder prevalence among VHA patients differ by whether they have psychiatric disorders. METHODS: VHA electronic health records from 2005 to 2019 (N range, 4,332,165-5,657,277) were used to identify overall and age-group-specific (<35, 35-64, and ≥65 years) trends in prevalence of cannabis use disorder diagnoses among patients with depressive, anxiety, posttraumatic stress, bipolar, or psychotic spectrum disorders and to compare these to corresponding trends among patients without any of these disorders. Given transitions in ICD coding, differences in trends were tested within two periods: 2005-2014 (ICD-9-CM) and 2016-2019 (ICD-10-CM). RESULTS: Greater increases in prevalence of cannabis use disorder diagnoses were observed among patients with psychiatric disorders compared to those without (difference in prevalence change, 2005-2014: 1.91%, 95% CI=1.87-1.96; 2016-2019: 0.34%, 95% CI=0.29-0.38). Disproportionate increases in cannabis use disorder prevalence among patients with psychiatric disorders were greatest among those under age 35 between 2005 and 2014, and among those age 65 or older between 2016 and 2019. Among patients with psychiatric disorders, the greatest increases in cannabis use disorder prevalences were observed among those with bipolar and psychotic spectrum disorders. CONCLUSIONS: The findings highlight disproportionately increasing disparities in risk of cannabis use disorder among VHA patients with common psychiatric disorders. Greater public health and clinical efforts are needed to monitor, prevent, and treat cannabis use disorder in this population.

The Long-Term Relationship Between Cannabis and Heroin Use: An 18- to 20-year Follow-Up of the Australian Treatment Outcome Study (ATOS).

OBJECTIVE: Cannabis use is common among individuals with opioid use disorder, but it remains unclear whether cannabis use is associated with an increase or a reduction in illicit opioid use. To overcome limitations identified in previous longitudinal studies with limited follow-ups, the authors examined a within-person reciprocal relationship between cannabis and heroin use at several follow-ups over 18 to 20 years. METHODS: The Australian Treatment Outcome Study (ATOS) recruited 615 people with heroin dependence in 2001 and 2002 and reinterviewed them at 3, 12, 24, and 36 months as well as 11 and 18-20 years after baseline. Heroin and cannabis use were assessed at each time point using the Opiate Treatment Index. A random-intercept cross-lagged panel model analysis was conducted to identify within-person relationships between cannabis use and heroin use at subsequent follow-ups. RESULTS: After accounting for a range of demographic variables, other substance use, and mental and physical health measures, an increase in cannabis use 24 months after baseline was significantly associated with an increase in heroin use at 36 months (estimate=0.21, SE=0.10). Additionally, an increase in heroin use at 3 months and 24 months was significantly associated with a decrease in cannabis use at 12 months (estimate=-0.27, SE=0.09) and 36 months (estimate=-0.22, SE=0.08). All other cross-lagged associations were not significant. CONCLUSIONS: Although there was some evidence of a significant relationship between cannabis and heroin use at earlier follow-ups, this was sparse and inconsistent across time points. Overall, there was insufficient evidence to suggest a unidirectional or bidirectional relationship between the use of these substances.

Association of Cortico-Striatal Engagement During Cue Reactivity, Reappraisal, and Savoring of Drug and Non-Drug Stimuli With Craving in Heroin Addiction.

OBJECTIVE: The authors investigated cortico-striatal reactivity to drug cues (as compared with neutral and food cues), drug cue reappraisal, food cue savoring, and their correlations with heroin craving in individuals with heroin use disorder compared with healthy control subjects. METHODS: Cross-sectional changes in functional MRI blood-oxygen-level-dependent signal during a novel cue reactivity task were assessed in 32 individuals with heroin use disorder (mean age, 40.3 years; seven women) and 21 age- and sex-matched healthy control subjects (mean age, 40.6 years; eight women). RESULTS: Drug cue reactivity (vs. neutral cues) was significantly higher in the nucleus accumbens in the heroin use disorder group compared with the control group and nominally significantly higher in the orbitofrontal cortex (OFC); ventromedial prefrontal cortex (vmPFC) activity positively correlated with drug craving. Drug cue reactivity (vs. salient food cues) was also higher in the inferior frontal gyrus (IFG) in the heroin use disorder group compared with the control group. Drug reappraisal and food savoring (vs. passive viewing) showed increased IFG and supplementary motor area activity in all participants; in the heroin use disorder group, higher IFG/dorsolateral PFC (dlPFC) activity during drug reappraisal and rostral anterior cingulate cortex (ACC) activity during food savoring were associated with lower drug cue-induced craving and longer treatment, respectively. A direct comparison of regulation of reactivity to both salient cues revealed widespread group differences such that drug reappraisal activity was higher in the heroin use disorder group and food savoring activity was higher in the control group in both cortical (e.g., OFC, IFG, ACC, vmPFC, and insula) and subcortical (e.g., dorsal striatum and hippocampus) regions. Higher drug reappraisal versus food savoring in the dlPFC was associated with higher self-reported methadone dosage in the heroin use disorder group. CONCLUSIONS: The results demonstrate cortico-striatal upregulation during drug cue exposure and impaired reactivity during processing of alternative non-drug rewards in the heroin use disorder group. Normalizing cortico-striatal function by reducing drug cue reactivity and enhancing natural reward valuation may inform therapeutic mechanisms for reducing drug craving and seeking in heroin addiction.

Understanding and Addressing Widening Racial Inequalities in Drug Overdose.

The fourth wave of the United States overdose crisis-driven by the polysubstance use of fentanyl with stimulants and other synthetic substances-has driven sharply escalating racial/ethnic inequalities in drug overdose death rates. Here the authors present a detailed portrait of the latest overdose trends and synthesize the literature to describe where, how, and why these inequalities are worsening. By 2022 overdose deaths among Native and Black Americans rose to 1.8 and 1.4 times the rate seen among White Americans, respectively. This reflects that Black and Native Americans have been disproportionately affected by fentanyl and the combination of fentanyl and stimulants at the national level and in virtually every state. The highest overdose deaths rates are currently seen among Black Americans 55-64 years of age as well as younger cohorts of Native Americans 25-44 years of age. In 2022-the latest year of data available-deaths among White Americans decreased relative to 2021, whereas rates among all other groups assessed continued to rise. Moving forward, Fundamental Cause Theory shows us a relevant universal truth of implementation science: in socially unequal societies, new technologies typically end up favoring more privileged groups first, thereby widening inequalities unless underlying social inequalities are addressed. Therefore, interventions designed to reduce addiction and overdose death rates that are not explicitly designed to also improve racial/ethnic inequalities will often unintentionally end up worsening them. Well-funded community-based programs, with Black and Native leadership, providing harm reduction resources, naloxone, and medications for opioid use disorder in the context of comprehensive, culturally appropriate healthcare and other services, represent the highest priority interventions to decrease inequalities.

The Psychiatrist's Role in Treating Perinatal Opioid Use Disorder and Reducing Maternal Mortality.

Drug overdose is a leading cause of maternal mortality. Psychiatrists can play a critical role in reducing these deaths by delivering effective evidence-based treatments for perinatal opioid use disorder (POUD), including the use of buprenorphine. Medications for POUD (i.e., buprenorphine, methadone) are life-saving treatments, but only half of those who are diagnosed as having POUD will receive this treatment, which can result in an increased risk for return to opioid use, overdose, and death. Psychiatrists are well positioned to prescribe buprenorphine given the Drug Enforcement Administration's (DEA) removal of the requirement to submit a Notice of Intent to prescribe buprenorphine for the treatment of opioid use disorders. Psychiatrists who have a current DEA registration that includes Schedule III authority may now prescribe buprenorphine for opioid use disorders; the training requirements to do so are outlined herein. This article reviews the standard of care for screening, diagnosis, and treatment of POUD, and prescribing buprenorphine for POUD, as well as shared decision-making for medication selection, induction, and maintenance of buprenorphine during pregnancy, labor and delivery, and the postpartum year.

Predictors of Substance Use Initiation by Early Adolescence.

OBJECTIVE: Substance use initiation during early adolescence is associated with later development of substance use and mental health disorders. This study used various domains to predict substance use initiation, defined as trying any nonprescribed substance (e.g., alcohol, tobacco, cannabis), by age 12, using a large longitudinal data set. METHODS: Substance-naive youths from the Adolescent Brain Cognitive Development Study (ages 9-10; N=6,829) were followed for 3 years. A total of 420 variables were examined as predictors of substance use initiation, using a penalized logistic regression with elastic net; domains spanned demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, culture and environment, hormones, neurocognitive functioning, and structural neuroimaging. RESULTS: By age 12, 982 (14.4%) children reported substance initiation, with alcohol being the most common. Models with only self-report predictors had similar prediction performance to models adding hormones, neurocognitive factors, and neuroimaging predictors (AUCtest=0.66). Sociodemographic factors were the most robust predictors, followed by cultural and environmental factors, physical health factors, and parenting behaviors. The top predictor was a religious preference of Mormon (coefficient=-0.87), followed by a religious preference for Jewish (coefficient=0.32), and by Black youths (coefficient=-0.32). CONCLUSIONS: Sociodemographic variables were the most robust predictors of substance use initiation. Adding resource-intensive measures, including hormones, neurocognitive assessment, and structural neuroimaging, did not improve prediction of substance use initiation. The application of these large-scale findings in clinical settings could help to streamline and tailor prevention and early intervention efforts.

Converging Evidence for Frontopolar Cortex as a Target for Neuromodulation in Addiction Treatment.

Noninvasive brain stimulation technologies such as transcranial electrical and magnetic stimulation (tES and TMS) are emerging neuromodulation therapies that are being used to target the neural substrates of substance use disorders. By the end of 2022, 205 trials of tES or TMS in the treatment of substance use disorders had been published, with heterogeneous results, and there is still no consensus on the optimal target brain region. Recent work may help clarify where and how to apply stimulation, owing to expanding databases of neuroimaging studies, new systematic reviews, and improved methods for causal brain mapping. Whereas most previous clinical trials targeted the dorsolateral prefrontal cortex, accumulating data highlight the frontopolar cortex as a promising therapeutic target for transcranial brain stimulation in substance use disorders. This approach is supported by converging multimodal evidence, including lesion-based maps, functional MRI-based maps, tES studies, TMS studies, and dose-response relationships. This review highlights the importance of targeting the frontopolar area and tailoring the treatment according to interindividual variations in brain state and trait and electric field distribution patterns. This converging evidence supports the potential for treatment optimization through context, target, dose, and timing dimensions to improve clinical outcomes of transcranial brain stimulation in people with substance use disorders in future clinical trials.

Vaccines as Immunotherapies for Substance Use Disorders.

Substance use disorders (SUD) present a worldwide challenge with few effective therapies except for the relative efficacy of opioid pharmacotherapies, despite limited treatment access. However, the proliferation of illicit fentanyl use initiated a dramatic and cascading epidemic of lethal overdoses. This rise in fentanyl overdoses regenerated an interest in vaccine immunotherapy, which, despite an optimistic start in animal models over the past 50 years, yielded disappointing results in human clinical trials of vaccines against nicotine, stimulants (cocaine and methamphetamine), and opioids. After a brief review of clinical and selected preclinical vaccine studies, the "lessons learned" from the previous vaccine clinical trials are summarized, and then the newest challenge of a vaccine against fentanyl and its analogs is explored. Animal studies have made significant advances in vaccine technology for SUD treatment over the past 50 years, and the resulting anti-fentanyl vaccines show remarkable promise for ending this epidemic of fentanyl deaths.

Neural Correlates of Stress and Alcohol Cue-Induced Alcohol Craving and of Future Heavy Drinking: Evidence of Sex Differences.

OBJECTIVE: Stress and alcohol cue reactivity are associated with poor treatment outcomes in alcohol use disorder (AUD), but sex-specific neural correlates of stress and alcohol cue-induced craving compared with neutral cue-induced craving and of heavy drinking outcomes in AUD have not been examined. Thus, this study prospectively examined these associations and assessed sex differences. METHODS: Treatment-seeking adults with AUD (N=77; 46 men and 31 women) completed a functional MRI task involving stress, alcohol, and neutral cue exposure with repeated assessments of alcohol craving. Most of these participants (N=72; 43 men and 29 women) then participated in an 8-week standardized behavioral AUD treatment program, during which the percentage of heavy drinking days was assessed. RESULTS: Significant increases in both stress and alcohol cue-induced craving relative to neutral cue-induced craving were observed, with a greater alcohol-neutral contrast in craving relative to the stress-neutral contrast among men and equivalent stress-neutral and alcohol-neutral contrasts in craving among women. Whole-brain voxel-based regression analyses showed craving-associated hyperactivation in the neutral condition, but hypoactive prefrontal (ventromedial and lateral prefrontal, supplementary motor, and anterior cingulate regions) and striatal responses during exposure to stressful images (stress-neutral contrast) and alcohol cues (alcohol-neutral contrast), with significant sex differences. Additionally, a higher percentage of heavy drinking days was associated with hypoactivation of the subgenual anterior cingulate cortex and the bed nucleus of the stria terminalis in the stress-neutral contrast among women, hyperactivation of the hypothalamus in the stress-neutral contrast among men, and hyperactivation of the hippocampus in the alcohol-neutral contrast among men. CONCLUSIONS: Sex differences in stress- and alcohol cue-induced responses in the cortico-striatal-limbic network related to subjective alcohol craving and to heavy drinking indicated that distinct brain circuits underlie alcohol use outcomes in women and men. These findings underscore the need for sex-specific therapeutics to address this neural dysfunction effectively.

Effects of Bundling Medication for Opioid Use Disorder With an mHealth Intervention Targeting Addiction: A Randomized Clinical Trial.

OBJECTIVE: Medication for opioid use disorder (MOUD) improves treatment retention and reduces illicit opioid use. A-CHESS is an evidence-based smartphone intervention shown to improve addiction-related behaviors. The authors tested the efficacy of MOUD alone versus MOUD plus A-CHESS to determine whether the combination further improved outcomes. METHODS: In an unblinded parallel-group randomized controlled trial, 414 participants recruited from outpatient programs were assigned in a 1:1 ratio to receive either MOUD alone or MOUD+A-CHESS for 16 months and were followed for an additional 8 months. All participants were on methadone, buprenorphine, or injectable naltrexone. The primary outcome was abstinence from illicit opioid use; secondary outcomes were treatment retention, health services use, other substance use, and quality of life; moderators were MOUD type, gender, withdrawal symptom severity, pain severity, and loneliness. Data sources were surveys comprising multiple validated scales, as well as urine screens, every 4 months. RESULTS: There was no difference in abstinence between participants in the MOUD+A-CHESS and MOUD-alone arms across time (odds ratio=1.10, 95% CI=0.90-1.33). However, abstinence was moderated by withdrawal symptom severity (odds ratio=0.95, 95% CI=0.91-1.00) and MOUD type (odds ratio=0.57, 95% CI=0.34-0.97). Among participants without withdrawal symptoms, abstinence rates were higher over time for those in the MOUD+A-CHESS arm than for those in the MOUD-alone arm (odds ratio=1.30, 95% CI=1.01-1.67). Among participants taking methadone, those in the MOUD+A-CHESS arm were more likely to be abstinent over time (b=0.28, SE=0.09) than those in the MOUD-alone arm (b=0.06, SE=0.08), although the two groups did not differ significantly from each other (∆b=0.22, SE=0.11). MOUD+A-CHESS was also associated with greater meeting attendance (odds ratio=1.25, 95% CI=1.05-1.49) and decreased emergency department and urgent care use (odds ratio=0.88, 95% CI=0.78-0.99). CONCLUSIONS: Overall, MOUD+A-CHESS did not improve abstinence relative to MOUD alone. However, MOUD+A-CHESS may provide benefits for subsets of patients and may impact treatment utilization.

Harm Reduction for Opioid Use Disorder: Strategies and Outcome Metrics.

Tweet: The authors discuss harm reduction strategies and associated outcome metrics in relation to the ongoing opioid crisis.

Associations Between a Primary Care-Delivered Alcohol-Related Brief Intervention and Subsequent Opioid-Related Outcomes.

OBJECTIVE: The co-occurrence of unhealthy alcohol use and opioid misuse is high and associated with increased rates of overdose, emergency health care utilization, and death. The current study examined whether receipt of an alcohol-related brief intervention is associated with reduced risk of negative downstream opioid-related outcomes. METHODS: This retrospective cohort study included all VISN-6 Veterans Affairs (VA) patients with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) screening results (N=492,748) from 2014 to 2019. Logistic regression was used to examine the association between documentation of an alcohol-related brief intervention and probability of a new 1) opioid prescription, 2) opioid use disorder (OUD) diagnosis, or 3) opioid-related hospitalization in the following year, controlling for demographic and clinical covariates. RESULTS: Of the veterans, 13% (N=63,804) had "positive" AUDIT-C screen results. Of those, 72% (N=46,216) had a documented alcohol-related brief intervention. Within 1 year, 8.5% (N=5,430) had a new opioid prescription, 1.1% (N=698) had a new OUD diagnosis, and 0.8% (N=499) had a new opioid-related hospitalization. In adjusted models, veterans with positive AUDIT-C screen results who did not receive an alcohol-related brief intervention had higher odds of new opioid prescriptions (adjusted odds ratio [OR]=1.10, 95% CI=1.03-1.17) and new OUD diagnoses (adjusted OR=1.19, 95% CI=1.02-1.40), while new opioid-related hospitalizations (adjusted OR=1.19, 95% CI=0.99-1.44) were higher although not statistically significant. Removal of medications for OUD (MOUD) did not impact associations. All outcomes were significantly associated with an alcohol-related brief intervention in unadjusted models. CONCLUSIONS: The VA's standard alcohol-related brief intervention is associated with subsequent lower odds of a new opioid prescription or a new OUD diagnosis. Results suggest a reduction in a cascade of new opioid-related outcomes from prescriptions through hospitalizations.

Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study.

OBJECTIVE: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD. METHODS: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling. RESULTS: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively. CONCLUSIONS: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

Peer Social Genetic Effects and the Etiology of Substance Use Disorders, Major Depression, and Anxiety Disorder in a Swedish National Sample.

OBJECTIVE: There is growing interest in how peers' genotypes may influence health (i.e., peer social genetic effects). The authors sought to clarify the nature of peer social genetic effects on risk for drug use disorder, alcohol use disorder (AUD), major depression, and anxiety disorder. METHOD: Cox models were used with data from a population-based Swedish cohort (N=655,327). Outcomes were drug use disorder, AUD, major depression, and anxiety disorder registrations between ages 17 and 30 from medical, criminal, and pharmacy registries. The authors indexed peer social genetic effects with peers' family genetic risk scores (FGRSs) for the same disorders, which are personalized measures of genetic risk inferred from diagnoses in first- to fifth-degree relatives. RESULTS: Across disorders, peer FGRSs predicted increased risks of proband registration (hazard ratio range, 1.01-1.59), with stronger effects for drug use disorder and AUD than for major depression and anxiety disorder. Peer social genetic effects were stronger for school classmates than for geographically proximal peers, and for peers from upper secondary school (ages 16-19) versus peers from lower secondary school (ages 7-16). Peer social genetic effects remained significant following statistical control for sociodemographic confounders, whether peers were affected, and peers' FGRS for educational attainment. Peer social genetic effects were more pronounced for probands at higher genetic risk. CONCLUSIONS: The genetic makeup of adolescents' peers has long-reaching consequences on risks for drug use disorder, AUD, major depression, and anxiety disorder. Individuals at high genetic risk are more sensitive to social genetic effects. Alternative hypotheses such as sociodemographic stratification, exposure to affected peers, and genetic predispositions for educational attainment did not explain the risk associated with peer social genetic effects for substance use and psychiatric disorders.

Alcohol Use Disorder and Chronic Pain: An Overlooked Epidemic.

Alcohol use disorder (AUD) and chronic pain disorders are pervasive, multifaceted medical conditions that often co-occur. However, their comorbidity is often overlooked, despite its prevalence and clinical relevance. Individuals with AUD are more likely to experience chronic pain than the general population. Conversely, individuals with chronic pain commonly alleviate their pain with alcohol, which may escalate into AUD. This narrative review discusses the intricate relationship between AUD and chronic pain. Based on the literature available, the authors present a theoretical model explaining the reciprocal relationship between AUD and chronic pain across alcohol intoxication and withdrawal. They propose that the use of alcohol for analgesia rapidly gives way to acute tolerance, triggering the need for higher levels of alcohol consumption. Attempts at abstinence lead to alcohol withdrawal syndrome and hyperalgesia, increasing the risk of relapse. Chronic neurobiological changes lead to preoccupation with pain and cravings for alcohol, further entrenching both conditions. To stimulate research in this area, the authors review methodologies to improve the assessment of pain in AUD studies, including self-report and psychophysical methods. Further, they discuss pharmacotherapies and psychotherapies that may target both conditions, potentially improving both AUD and chronic pain outcomes simultaneously. Finally, the authors emphasize the need to manage both conditions concurrently, and encourage both the scientific community and clinicians to ensure that these intertwined conditions are not overlooked given their clinical significance.

Moderate Alcohol Consumption and Depression: A Marginal Structural Model Approach Promoting Causal Inference.

OBJECTIVE: Moderate alcohol consumption is associated with decreased risk for depression, but it remains unclear whether this is a causal relationship or a methodological artifact. To compare the effects of consistent abstinence and occasional, moderate, and above-guideline alcohol consumption throughout early to middle adulthood on depression at age 50, the authors conducted a secondary analysis of the National Longitudinal Survey of Youth 1979 cohort and employed a marginal structural model (MSM) approach. METHODS: Baseline was set at 1994, when individuals were ages 29-37. The MSM incorporated measurements of alcohol consumption in 1994, 2002, and 2006, baseline and time-varying covariates, and repeated measurements with the Center for Epidemiologic Studies Depression Scale-Short Form (CES-D-SF). A total of 5,667 eligible participants provided valid data at baseline, 3,593 of whom provided valid outcome data. The authors used all observed data to predict CES-D-SF means and rates of probable depression for hypothetical trajectories of consistent alcohol consumption. RESULTS: The results approximated J-curve relationships. Specifically, both consistent occasional and consistent moderate drinkers were predicted to have reduced CES-D-SF scores and rates of probable depression at age 50 compared with consistent abstainers (CES-D-SF scores: b=-0.84, 95% CI=-1.47, -0.11; probable depression: odds ratio=0.58, 95% CI=0.36, 0.88 for consistent occasional drinkers vs. abstainers; CES-D-SF scores: b=-1.08, 95% CI=-1.88, -0.20; probable depression: odds ratio=0.59, 95% CI=0.26, 1.13 for consistent moderate drinkers vs. consistent abstainers). Consistent above-guideline drinkers were predicted to have slightly increased risk compared with consistent abstainers, but this was not significant. In sex-stratified analyses, results were similar for females and males. CONCLUSIONS: This study contributes preliminary evidence that associations between moderate alcohol consumption and reduced risk for depression may reflect genuine causal effects. Further research using diverse methodologies that promote causal inference is required.