Neural and Hormonal Influences on Sex Differences in Risk for AUD

Sex Differences in Risk for Alcohol Use Disorder: Neural and Hormonal Influences

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).

Study Overview

• Status: Recruiting
• Conditions: Alcohol Use Disorder
• Intervention / Treatment: Drug: Alcohol

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Study Coordinator; Phone Number: 8592575794; Email: psychresearch@uky.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40504
      • Recruiting
      • University Of Kentucky Psychology Research Lab
      • Principal Investigator: Jessica Weafer, PhD
      • Contact: Study Coordinator; Phone Number: 859-257-5794; Email: psychresearch@uky.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 26 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• consume 4/5 drinks per week
• fluent in English
• high school education
• right-handed
• regular menstrual cycles (women)

Exclusion Criteria:

• serious medical problems
• body weight <110 or >210 lbs
• current medical or psychiatric conditions requiring medication for which alcohol is contraindicated
• substance use disorder other than alcohol
• current or recent history of inpatient/intensive treatment for addictive behaviors
• pregnant, nursing, on hormonal contraception
• contraindications for fMRI
• smoking > 5 cigarettes per day

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Males; Participants in this group will be adult male drinkers.	Drug: Alcohol; Participants will complete three experimental sessions. In each session, participants will provide detailed reports of their alcohol consumption over the past five days, and they will provide a blood sample for hormone assays. They will perform tasks during fMRI to assess each of the neurofunctional addiction domains: inhibitory control, negative emotionality, and cue reactivity. Following the fMRI scan, subjects will self-administer intravenous alcohol to provide a controlled assessment of pharmacologically-driven alcohol consumption.
Experimental: Females; Participants in this group will be adult female drinkers. Data will be segregated by menstrual cycle phase.	Drug: Alcohol; Participants will complete three experimental sessions. In each session, participants will provide detailed reports of their alcohol consumption over the past five days, and they will provide a blood sample for hormone assays. They will perform tasks during fMRI to assess each of the neurofunctional addiction domains: inhibitory control, negative emotionality, and cue reactivity. Following the fMRI scan, subjects will self-administer intravenous alcohol to provide a controlled assessment of pharmacologically-driven alcohol consumption.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neural inhibitory function	One measure of neural inhibitory function during performance of the stop signal task will be activity (as measured by BOLD % signal change)	13 minutes
Neural inhibitory function	The other measure of neural inhibitory function during performance of the stop signal task will be functional connectivity for the StopInh>Go contrast.	13 minutes
Neural negative emotionality	One measure of neural negative emotionality during performance of the Emotional Pictures Task will be activity (as measured by BOLD % signal change)	14 minutes
Neural negative emotionality	The other measure of neural negative emotionality during performance of the Emotional Pictures Task will be functional connectivity for the Negative>Neutral contrast.	14 minutes
Neural alcohol cue reactivity	One measure of neural alcohol cue reactivity during performance of the Alcohol Cue Reactivity Task will be activity (as measured by BOLD % signal change)	12 minutes
Neural alcohol cue reactivity	The other measure of neural alcohol cue reactivity during performance of the Alcohol Cue Reactivity Task will be functional connectivity for the Alcohol>Neutral contrast.	12 minutes
Intravenous alcohol self-administration (IV-ASA)	One measure of IV-ASA will be peak BrAC (mg%; highest BrAC obtained during the IV-ASA period)	60 minutes
Intravenous alcohol self-administration (IV-ASA)	Another measure of IV-ASA will be whether or not a participant reached binge level of alcohol exposure (80mg%)	60 minutes
Intravenous alcohol self-administration (IV-ASA)	The final measure of IV-ASA will be time to reach binge level of alcohol exposure (80mg%)	60 minutes
Self-reported current alcohol consumption	One measure of current alcohol consumption will be number of binge days (4/5 or more drinks in a sitting for women/men) as determined by responses on the Timeline Followback.	20 minutes
Self-reported current alcohol consumption	The other measure of current alcohol consumption will be average peak BrAC obtained on drinking days over the past 5 days, as determined by responses on the Timeline Followback.	20 minutes
Prospective alcohol consumption	One measure of prospective alcohol consumption will be number of binge episodes as determined by responses on the 90-day Timeline Followback.	18 months
Prospective alcohol consumption	The other measure of prospective alcohol consumption will be drinking days per month, as determined by responses on the 90-day Timeline Followback.	18 months

Collaborators and Investigators

• Sponsor: Jessica Weafer
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: Jessica Weafer, PhD, University of Kentucky

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2021
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: November 11, 2020
• First Submitted That Met QC Criteria: June 9, 2021
• First Posted (Actual): June 18, 2021

Study Record Updates

• Last Update Posted (Actual): August 25, 2023
• Last Update Submitted That Met QC Criteria: August 23, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: menstrual cycle; fMRI; hormone; risk factor; inhibitory control; sex
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Alcohol Drinking; Alcoholism
• Other Study ID Numbers: 58758; R01AA028503 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No