Xanthohumol microbiome and signature in adults with Crohn's disease (the XMaS trial): a protocol for a phase II triple-masked, placebo-controlled clinical trial.

BACKGROUND: Xanthohumol (XN), a bioactive flavonoid from Humulus lupulus with anti-inflammatory properties, has potential benefits for patients with Crohn's disease (CD), a type of inflammatory bowel disease. We recently completed and published results of a placebo-controlled phase I clinical trial demonstrating the safety and tolerability of 24 mg XN daily for 8 weeks. The present study aims to evaluate the safety and tolerability of the same dose of XN adults with clinically active CD in a placebo-controlled phase II clinical trial. Additional aims will assess the impact of XN on inflammatory biomarkers, platelet function, CD clinical activity, and stool microbial composition. The metabolism of XN will also be evaluated. This article provides a model protocol for consideration in investigations of XN or other natural products in disease states. METHODS: A triple-masked, randomized, placebo-controlled trial will be conducted in adults with clinically active CD. Participants (n ≤ 32) will be randomized to either 24 mg encapsulated XN per day or placebo and followed for 8 weeks. Throughout the trial, participants will be queried for adverse events. Biomarkers of clinical safety, blood and stool markers of inflammation, platelet function, Crohn's Disease Activity Index score, stool microbial composition, and XN metabolite profiles in blood, urine, and stool will be assessed every 2 weeks. DISCUSSION: We describe the protocol for a phase II clinical trial that evaluates the safety and tolerability of XN in adults with active CD, as well as evaluate metabolism and mechanisms that are relevant to CD and other diseases with underlying inflammation and/or gut permeability. The effects of XN on inflammatory biomarkers, platelet function, the microbiota, and multi-omics biomarkers measured in this phase II trial of adults with CD will be compared to the effects of XN in healthy adults in our previous phase I trial. The results of the study will advance the evidence guiding the use of XN in patients with CD. TRIAL REGISTRATION: ClinialTrials.gov NCT04590508. Registered on October 19, 2020.

Mental health aspects of binge eating disorder: A cross-sectional mixed-methods study of binge eating disorder experts' perspectives.

Binge eating disorder has high comorbidity with a variety of mental health diagnoses and significantly impairs quality of life. This mixed-methods cross-sectional survey study aimed to collect information from experts in the field about mental health issues pertaining to adult binge eating disorder pathology. Fourteen expert binge eating disorder researchers and clinicians were identified based on history of NIH R01 funding, relevant PubMed-indexed publications, active practice in the field, leadership in related professional societies, and/or distinction in popular press. Semi-structured interviews were anonymously recorded and analyzed by ≥2 investigators using reflexive thematic analysis and quantification. The domains of depression, anxiety, attention deficit disorder (ADD)/attention deficit hyperactive disorder (ADHD), substance-related and addictive disorders (SRADs), obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) were addressed in relation to binge eating disorder pathology by 100, 100, 93, 79, 71, and 64% of participants, respectively. Depression and anxiety seem to be the most commonly recognized mental health comorbidities among experts participating in this study. These expert perceptions generally align with the most comprehensive and up-to-date information available on mental health comorbidity prevalence data in adult binge eating disorder, though updated surveys are warranted. The findings from this study highlight the importance of screening for binge eating disorder among individuals with Axis-I mental health diagnoses (e.g., depression and other mood disorders, anxiety disorders, ADD/ADHD, and SRADs). Research on underlying mechanisms that link various Axis-I disorders to binge eating disorder is also warranted and recommended by the experts.

Binge Eating Disorder Is a Social Justice Issue: A Cross-Sectional Mixed-Methods Study of Binge Eating Disorder Experts' Opinions.

BACKGROUND: Binge eating disorder is an autonomous DSM-V diagnosis characterized by discrete rapid consumption of objectively large amounts of food without compensation, associated with loss of control and distress. Environmental factors that contribute to binge eating disorder continue to evolve. This mixed-methods cross-sectional study assessed whether there is consensus among experts in the field about environmental factors that influence adult binge eating disorder pathology. METHODS: Fourteen expert binge eating disorder researchers, clinicians, and healthcare administrators were identified internationally based on federal funding, PubMed-indexed publications, active practice in the field, leadership in relevant societies, and/or clinical and popular press distinction. Semi-structured interviews were recorded anonymously and analyzed by ≥2 investigators using reflexive thematic analysis and quantification. RESULTS: Identified themes included: (1) systemic issues and systems of oppression (100%); (2) marginalized and under-represented populations (100%); (3) economic precarity and food/nutrition insecurity/scarcity (93%); (4) stigmatization and its psychological impacts (93%); (5) trauma and adversity (79%); (6) interpersonal factors (64%); (7) social messaging and social media (50%); (8) predatory food industry practices (29%); and (9) research/clinical gaps and directives (100%). CONCLUSIONS: Overall, experts call for policy changes around systemic factors that abet binge eating and for greater public education about who can have binge eating disorder. There is also a call to take and account for the narratives and life experiences of individuals with binge eating disorder to better inform our current understanding of the diagnosis and the environmental factors that impact it.

Clinical aspects of binge eating disorder: A cross-sectional mixed-methods study of binge eating disorder experts' perspectives.

Introduction: Research on binge eating disorder continues to evolve and advance our understanding of recurrent binge eating. Methods: This mixed-methods, cross-sectional survey aimed to collect information from experts in the field about clinical aspects of adult binge eating disorder pathology. Fourteen experts in binge eating disorder research and clinical care were identified based on receipt of relevant federal funding, PubMed-indexed publications, active practice in the field, leadership in relevant societies, and/or clinical and popular press distinction. Anonymously recorded semi-structured interviews were analyzed by ≥2 investigators using reflexive thematic analysis and quantification. Results: Identified themes included: (1) obesity (100%); (2) intentional/voluntary or unintentional/involuntary food/eating restriction (100%); (3) negative affect, emotional dysregulation, and negative urgency (100%); (4) diagnostic heterogeneity and validity (71%); (5) paradigm shifts in understanding binge eating disorder (29%); and (6) research gaps/future directives (29%). Discussion: Overall, experts call for a better understanding of the relationship between binge eating disorder and obesity, including a need for clarification around the extent to which the two health issues are separate vs. related/overlapping. Experts also commonly endorse food/eating restriction and emotion dysregulation as important components of binge eating disorder pathology, which aligns with two common models of binge eating disorder conceptualization (e.g., dietary restraint theory and emotion/affect regulation theory). A few experts spontaneously identified several paradigm shifts in our understanding of who can have an eating disorder (beyond the anorexi-centric "thin, White, affluent, cis-gendered neurotypical female" stereotype), and the various factors that can drive binge eating. Experts also identified several areas where classification issues may warrant future research. Overall, these results highlight the continual advancement of the field to better understand adult binge eating disorder as an autonomous eating disorder diagnosis.

Overeaters Anonymous: An Overlooked Intervention for Binge Eating Disorder.

The purpose of this communication is to provide an overview as well as the strengths and weaknesses of Overeaters Anonymous (OA) as an intervention for binge eating disorder treatment. Binge eating disorder is associated with low remission rates, high relapse rates, treatment dissatisfaction, and high rates of failure to receive treatment attributed to stigma, misconceptions, lack of diagnosis, access to care, and inadequate insurance coverage. New interventions are needed that can overcome these barriers. OA is a twelve-step program and established fellowship for individuals who self-identify as having problematic relationships with food or eating. OA can be referred clinically or sought out by an individual confidentially, without a diagnosis, and free of charge. OA's Nine Tools, Twelve Steps, and Twelve Traditions can provide structure, social support, and open, anonymous sharing that fosters a sense of connection and belonging. This may provide benefit to individuals who value structure and social support in their recovery. The tradition of anonymity may also create some challenges for conducting research and may explain the shortage of empirical support. This commentary reviews existing research findings on the effectiveness of twelve-step interventions and OA. Common misunderstandings about and within OA are also addressed and OA's limitations are discussed. Overall, OA provides a promising option for binge eating disorder treatment that warrants clinical research on its feasibility and efficacy in a way that respects and protects its tradition of anonymity.

Corticosterone in the ventral hippocampus differentially alters accumbal dopamine output in drug-naïve and amphetamine-withdrawn rats.

Dysregulation in glucocorticoid stress and accumbal dopamine reward systems can alter reward salience to increase motivational drive in control conditions while contributing to relapse during drug withdrawal. Amphetamine withdrawal is associated with dysphoria and stress hypersensitivity that may be mediated, in part, by enhanced stress-induced corticosterone observed in the ventral hippocampus. Electrical stimulation of the ventral hippocampus enhances accumbal shell dopamine release, establishing a functional connection between these two regions. However, the effects of ventral hippocampal corticosterone on this system are unknown. To address this, a stress-relevant concentration of corticosterone (0.24ng/0.5 µL) or vehicle were infused into the ventral hippocampus of urethane-anesthetized adult male rats in control and amphetamine withdrawn conditions. Accumbal dopamine output was assessed with in vivo chronoamperometry. Corticosterone infused into the ventral hippocampus rapidly enhanced accumbal dopamine output in control conditions, but produced a biphasic reduction of accumbal dopamine output in amphetamine withdrawal. Selectively blocking glucocorticoid-, mineralocorticoid-, or cytosolic receptors prevented the effects of corticosterone. Overall, these results suggest that the ability of corticosterone to alter accumbal dopamine output requires cooperative activation of mineralocorticoid and glucocorticoid receptors in the cytosol, which is dysregulated during amphetamine withdrawal. These findings implicate ventral hippocampal corticosterone in playing an important role in driving neural systems involved in positive stress coping mechanisms in healthy conditions, whereas dysregulation of this system may contribute to relapse during withdrawal.

Amphetamine withdrawal differentially affects hippocampal and peripheral corticosterone levels in response to stress.

Amphetamine withdrawal is associated with heightened anxiety-like behavior, which is directly driven by blunted stress-induced glucocorticoid receptor-dependent serotonin release in the ventral hippocampus. This suggests that glucocorticoid availability in the ventral hippocampus during stress may be reduced during amphetamine withdrawal. Therefore, we tested whether amphetamine withdrawal alters either peripheral or hippocampal corticosterone stress responses. Adult male rats received amphetamine (2.5mg/kg, ip) or saline for 14 days followed by 2 weeks of withdrawal. Contrary to our prediction, microdialysis samples from freely-moving rats revealed that restraint stress-induced corticosterone levels in the ventral hippocampus are enhanced by amphetamine withdrawal relative to controls. In separate groups of rats, plasma corticosterone levels increased immediately after 20min of restraint and decreased to below stress-naïve levels after 1h, indicating negative feedback regulation of corticosterone following stress. However, plasma corticosterone responses were similar in amphetamine-withdrawn and control rats. Neither amphetamine nor stress exposure significantly altered protein expression or enzyme activity of the steroidogenic enzymes 11ß-hydroxysteroid dehydrogenase (11ß-HSD1) or hexose-6-phosphate dehydrogenase (H6PD) in the ventral hippocampus. Our findings demonstrate for the first time that amphetamine withdrawal potentiates stress-induced corticosterone in the ventral hippocampus, which may contribute to increased behavioral stress sensitivity previously observed during amphetamine withdrawal. However, this is not mediated by either changes in plasma corticosterone or hippocampal steroidogenic enzymes. Establishing enhanced ventral hippocampal corticosterone as a direct cause of greater stress sensitivity may identify the glucocorticoid system as a novel target for treating behavioral symptoms of amphetamine withdrawal.