Neural and Hormonal Influences on Alcohol Use Disorder Risk
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Jessica Weafer
Must not be taking: Hormonal contraception
Disqualifiers: Serious medical problems, Substance use disorder, others
No Placebo Group
Trial Summary
What is the purpose of this trial?The sex gap in alcohol consumption is closing rapidly, due to alarming increases among women. From 2002-2013, Alcohol Use Disorder (AUD) increased 84% for women, compared to 35% for men. As such, there is an urgent need to determine the factors underlying sex differences in risk for AUD. Current addiction models propose three domains that drive problematic alcohol use and serve as candidate sex-specific risk factors: executive function, negative emotionality, and incentive salience. Data suggest that poor inhibitory control, a key component of executive function, is a stronger risk factor for women than for men. Moreover, there is have preliminary evidence that female drinkers show less engagement of neural inhibitory circuitry, and that this sex difference is influenced by estradiol. However, the degree to which hormonally-moderated sex differences in executive function extend to the negative emotionality and incentive salience domains, and how these sex differences influence current and future drinking is unknown.
The goal of this study is to identify the mechanisms underlying sex-specific risk for AUD, and ultimately to help develop sex-specific prevention and treatment efforts. The overall objective of this trial is to determine the neural and hormonal factors contributing to sex-specific risk for AUD in three addiction domains: inhibitory control (executive function), negative emotionality, and alcohol cue reactivity (incentive salience).
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot participate if you have medical or psychiatric conditions that require medication where alcohol is not allowed.
What evidence supports the effectiveness of the treatment 'Neural and Hormonal Influences on Sex Differences in Risk for AUD'?
Research suggests that sex hormones like testosterone and estrogen play a role in alcohol use and addiction, with testosterone linked to higher alcohol use in males and estrogen linked to higher use in females. Understanding these hormonal influences could help develop targeted treatments for alcohol use disorder (AUD) based on sex differences.
12345Is the treatment generally safe for humans?
The research does not provide specific safety data for humans, but it discusses the influence of hormones on alcohol use and the potential for different effects based on gender. Further studies would be needed to determine the safety of any treatment targeting these hormonal influences.
12567How does the treatment 'Neural and Hormonal Influences on Sex Differences in Risk for AUD' differ from other treatments for alcohol use disorder?
This treatment is unique because it focuses on the role of sex hormones and their influence on brain structure and function, which may contribute to differences in alcohol use disorder risk between males and females. It considers both the permanent and temporary effects of sex hormones on the brain, potentially offering a novel approach to understanding and treating alcohol addiction by targeting these hormonal influences.
12345Eligibility Criteria
This trial is for English-speaking, right-handed individuals with at least a high school education who regularly consume alcohol. Women must have regular menstrual cycles and not be pregnant, nursing, or on hormonal contraception. Participants should weigh between 110 and 210 lbs and not require medication that interacts badly with alcohol.Inclusion Criteria
fluent in English
I have regular menstrual cycles.
You drink around 4 to 5 alcoholic drinks every week.
+2 more
Exclusion Criteria
current or recent history of inpatient/intensive treatment for addictive behaviors
I take medication that shouldn't be mixed with alcohol due to my health condition.
My weight is either below 110 lbs or above 210 lbs.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Baseline Assessment
Participants undergo baseline assessments including neural inhibitory function, negative emotionality, and alcohol cue reactivity tasks
1-2 weeks
1 visit (in-person)
Experimental Sessions
Participants engage in tasks such as the stop signal task, Emotional Pictures Task, and Alcohol Cue Reactivity Task to measure neural responses
Varies per task
Multiple visits (in-person)
Follow-up
Participants are monitored for prospective alcohol consumption and self-reported current alcohol consumption
18 months
Participant Groups
The study aims to understand why women are increasingly at risk for Alcohol Use Disorder (AUD) by examining brain function and hormone levels related to self-control, emotional response, and reactions to alcohol cues.
2Treatment groups
Experimental Treatment
Group I: MalesExperimental Treatment1 Intervention
Participants in this group will be adult male drinkers.
Group II: FemalesExperimental Treatment1 Intervention
Participants in this group will be adult female drinkers. Data will be segregated by menstrual cycle phase.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The Ohio State UniversityColumbus, OH
University Of Kentucky Psychology Research LabLexington, KY
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Who Is Running the Clinical Trial?
Jessica WeaferLead Sponsor
National Institute on Alcohol Abuse and Alcoholism (NIAAA)Collaborator
References
Sex hormone activity in alcohol addiction: integrating organizational and activational effects. [2015]There are well-known sex differences in the epidemiology and etiopathology of alcohol dependence. Male gender is a crucial risk factor for the onset of alcohol addiction. A directly modifying role of testosterone in alcohol addiction-related behavior is well established. Sex hormones exert both permanent (organizational) and transient (activational) effects on the human brain. The sensitive period for these effects lasts throughout life. In this article, we present a novel early sex hormone activity model of alcohol addiction. We propose that early exposure to sex hormones triggers structural (organizational) neuroadaptations. These neuroadaptations affect cellular and behavioral responses to adult sex hormones, sensitize the brain's reward system to the reinforcing properties of alcohol and modulate alcohol addictive behavior later in life. This review outlines clinical findings related to the early sex hormone activity model of alcohol addiction (handedness, the second-to-fourth-finger length ratio, and the androgen receptor and aromatase) and includes clinical and preclinical literature regarding the activational effects of sex hormones in alcohol drinking behavior. Furthermore, we discuss the role of the hypothalamic-pituitary-adrenal and -gonadal axes and the opioid system in mediating the relationship between sex hormone activity and alcohol dependence. We conclude that a combination of exposure to sex hormones in utero and during early development contributes to the risk of alcohol addiction later in life. The early sex hormone activity model of alcohol addiction may prove to be a valuable tool in the development of preventive and therapeutic strategies.
The Endocrine System and Alcohol Drinking in Females. [2021]Sexually dimorphic effects of alcohol exposure throughout life have been documented in clinical and preclinical studies. In the past, rates of alcohol use disorder (AUD) were higher in men than in women, but over the past 10 years, the difference between sexes in prevalence of AUD and binge drinking has narrowed. Recent evidence adds to historical data regarding the influence of sex steroids on alcohol drinking and the interaction with stress-related steroids. This review considers the contribution of the endocrine system to alcohol drinking in females, with a focus on the hypothalamic pituitary gonadal axis and the hypothalamic pituitary adrenal axis and their reciprocal interactions. Emphasis is given to preclinical studies that examined genomic and rapid membrane effects of estrogen, progesterone, glucocorticoids, and GABAergic neurosteroids for their effects on alcohol drinking and models of relapse. Pertinent comparisons to data in males highlight divergent effects of sex and stress steroids on alcohol drinking and emphasize the importance of considering sex in the development of novel pharmacotherapeutic targets for the treatment of AUD. For instance, pharmacological strategies targeting the corticotropin releasing factor and glucocorticoid receptor systems may be differentially effective in males and females, whereas strategies to enhance GABAergic neurosteroids may represent a biomarker of treatment efficacy in both sexes.
Sex/gender differences in brain function and structure in alcohol use: A narrative review of neuroimaging findings over the last 10 years. [2021]Over the last 10 years, rates of alcohol use disorder (AUD) have increased in women by 84% relative to a 35% increase in men. Rates of alcohol use and high-risk drinking have also increased in women by 16% and 58% relative to a 7% and 16% increase in men, respectively, over the last decade. This robust increase in drinking among women highlights the critical need to identify the underlying neural mechanisms that may contribute to problematic alcohol consumption across sex/gender (SG), especially given that many neuroimaging studies are underpowered to detect main or interactive effects of SG on imaging outcomes. This narrative review aims to explore the recent neuroimaging literature on SG differences in brain function and structure as it pertains to alcohol across positron emission tomography, magnetic resonance imaging, and functional magnetic resonance imaging modalities in humans. Additional work using magnetic resonance spectroscopy, diffusion tensor imaging, and event-related potentials to examine SG differences in AUD will be covered. Overall, current research on the neuroimaging of AUD, alcohol consumption, or risk of AUD is limited, and findings are mixed regarding the effect of SG on neurochemical, structural, and functional mechanisms associated with AUD. We address SG disparities in the neuroimaging of AUD and propose a call to action to include women in brain imaging research. Future studies are crucial to our understanding of the neurobiological underpinnings of AUD across neural systems and the vulnerability for AUD among women and men.
Sex hormones in alcohol consumption: a systematic review of evidence. [2022]Sex hormones play an important role in establishing sex-distinctive brain structural and functional variations that could contribute to the sex differences in alcohol consumption behavior. Here, we systematically reviewed articles that studied sex hormone impacts on alcohol consumption and alcohol use disorder (AUD). An extensive literature search conducted in MEDLINE, PubMed, Scopus and CINAHL databases identified 776 articles, which were then evaluated for pre-specified criteria for relevance and quality assurance. A total of 50 articles, including 19 human studies and 31 animal studies, were selected for this review. Existing evidence supports the association of increased testosterone level and increased risk for alcohol use and AUD in males but results are inconclusive in females. In contrast, the evidence supports the association of increased estrogen level and increased alcohol use in females, with mixed findings reported in males. Much less is known about the impact of progestins on alcohol use and misuse in human subjects. Future observational and experimental studies conducted in both sexes with a comprehensive hormone panel are needed to elucidate the impact of the interplay between various sex hormone levels during various developmental stages on alcohol use-related phenotypes and AUD.
Gender differences in the brain: implications for the study of human alcoholism. [2019]Gender differences in alcohol intake and response to alcohol may be influenced by basic variations in the organization and modulation of male and female brains. Although a number of genetic, social, environmental, and metabolic factors have been proposed to explain the gender differences observed in risk for alcoholism, alcohol intake, and medical consequences of excessive alcohol intake, very little attention has been given to the role of gender differences in the brain regarding alcohol use. Recent evidence documents the influence of neurosteroids on neurotransmitter activity in the brain and the impact of alcohol on neurosteroid levels. Neurosteroids are found in different levels in males and females during development and throughout life, depending on factors such as age, stage of development, estrous and menstrual cycles, and stress. This study discusses the hypothesis that many of the gender differences observed concerning alcohol use and misuse are determined by gender differences in the brain, which in turn differentially influence the behavioral and neurochemical responses of males and females to alcohol.
Gender differences in ethanol preference and ingestion in rats. The role of the gonadal steroid environment. [2018]An ethanol oral self administration paradigm showed the existence of gender differences in alcohol preference in rats: whereas males and females initiated alcohol drinking at similar rates, females maintained their preference for ethanol over a longer duration. Neonatal estrogenization of females, which effectively confers a male phenotype on a genetically female brain, resulted in patterns of drinking that were similar to those displayed by intact male rats, indicating that gender differences in alcohol drinking patterns may be, at least partially, accounted for by sexual differentiation of the brain. To test whether gonadal steroids also exert activational effects on ethanol-seeking behavior, we also examined the effects of gonadectomy alone, or in combination with gonadal steroid replacement therapy. Castration did not significantly alter ethanol consumption in males, although treatment of castrated rats with dihydrotestosterone resulted in a significant inhibition of this parameter. As compared with the situation in intact female rats, ethanol ingestion was significantly reduced in ovariectomized female rats receiving estradiol (E2) and in ovariectomized female rats receiving combined E2 and progesterone replacement therapy. However, neither ovariectomy nor progesterone replacement in ovariectomized rats resulted in ethanol drinking patterns that were different compared to those observed in intact female controls. Thus, dihydrotestosterone and E2, respectively, appear to exert modulatory influences on the male and female rats' preference for ethanol, but further investigations are necessary to determine to what extent these effects result from activational actions on the brain.
Ovariectomy has minimal effects on neuroadaptations associated with ethanol dependence in female rats. [2019]We previously found gender selective alterations in gene expression for GABA(A) and NMDA receptors associated with the development of ethanol dependence. Males and females have a differing hormonal environment, including steroid hormone derivatives (neuroactive steroids) that exert effects at GABA(A) and NMDA receptors. Therefore, we explored whether the removal of ovarian steroids would alter gender differences in response to chronic ethanol exposure. We found that ovariectomy reduced ethanol drinking levels by 15%, comparable to earlier observations between intact female and male rats. However, investigation of the effects of chronic ethanol exposure on intact versus ovariectomized female rats uncovered few differences in chronic ethanol-induced alterations in selected GABA(A) or NMDA receptor subunit peptide levels. In general, findings for both groups of females were similar to previous observations. There was no reduction in GABA(A) receptor alpha1 subunit levels in cerebral cortex in either intact or ovariectomized female rats, in contrast to the significant reduction observed in male rats. In addition, both intact and ovariectomized female rats had increased levels of the NMDA NR1 subunit in cerebral cortex and hypothalamus, but not in hippocampus, whereas ethanol dependent male rats displayed significant increases in the NR1 subunit only in hippocampus. Radioligand binding analysis with [35S]TBPS found no differences in modulation of the GABA(A) receptor by neuroactive steroids between ethanol dependent male, intact female or ovariectomized female rats. Seizure susceptibility was not different between intact or ovariectomized female rats during ethanol withdrawal. We did observe differential effects on brain allopregnanolone and plasma corticosterone levels between ethanol dependent intact and ovariectomized female rats, suggesting that ovarian steroids influence HPA axis adaptations to prolonged ethanol exposure. Overall, these data suggest that ovarian steroids do not significantly impact the gender selective alterations of GABA(A) and NMDA receptors associated with ethanol dependence.