Sex Differences in Trauma, Inflammation and Brain Function and the Implications for Treatment Efficacy in Alcohol Use Disorder

Overview

The goal of this clinical trial is to identify sex-specific biomarkers that confer greater susceptibility for Alcohol Use Disorder (AUD) and differentiate how treatment response varies by sex in people with Alcohol Use Disorder. The main questions it aims to answer are: * How does trauma affect emotion regulation, inflammation, and limbic function, and what are the sex-dependent effects of NTX (Naltrexone) on these aspects? * What is the mechanism of Naltrexone (NTX), and how does it potentially moderate reductions in alcohol use through changes in or interactions between emotion regulation, inflammation, or limbic system function? Participants will * Be consented and will undergo comprehensive screening for eligibility criteria * Complete behavioral assessments and neuropsychological assessments, as well as neurocognitive assessments and neuroimaging measures * Provide urine samples for a urine drug screen (UDS) and urine pregnancy test (for women), and have blood and a cheek swab collected and stored in the repository * Take a study drug once daily for 12 weeks and track drug usage and effects in a study journal * Undergo weekly assessment calls and bi-weekly medical follow-up safety exams Researchers will compare naltrexone to placebo in AUD to see if naltrexone is effective in reducing alcohol cravings and promoting abstinence. Researchers will also compare baseline measures between AUD and Healthy Controls.

Detailed description

A twelve-week randomized placebo-controlled trial of naltrexone (NTX) will be conducted in one hundred people with alcohol use disorder (AUD), fifty of which will be women. Fifty healthy participants will serve as controls for baseline measures. We will use validated measures to comprehensively assess trauma exposure including: military sexual trauma (MST), physical or sexual assault, combat exposure, intimate partner violence, and other traumatic events. Emotion regulation will be assessed with the Cognitive Emotion Regulation questionnaire and Difficulty in Emotion Regulation scale. Functional magnetic resonance imaging at rest and during an emotion regulation task will assess limbic system connectivity and reactivity. Inflammation will be indexed with a multiplex panel assay of peripheral inflammatory markers. Days of alcohol use and average weekly standard drinks will be assessed at each time-point.

Interventions

• Drug Naltrexone
  12-week randomized double blinded placebo-controlled drug trial titrating drug/placebo dose after 1 week.

Primary outcome measures

• Change from baseline in alcohol use (number of drinking days, amount used per day) [Time frame: Baseline and Week 12]
• Changes from baseline in peripheral immune biomarkers associated with inflammation [Time frame: Baseline and Week 12]
• Changes in limbic functional connectivity [Time frame: Baseline and Week 12]
• Changes from baseline in BOLD signal brain activation during an emotion regulation fMRI task [Time frame: Baseline and Week 12]
• Changes from baseline in emotion regulation assessed with the Difficulty in Emotion Regulation Scale (DERS) [Time frame: Baseline and Week 12]
• Changes from baseline in emotion regulation assessed with the Cognitive Emotion Regulation Questionnaire (CERQ) [Time frame: Baseline and Week 12]

Secondary outcome measures (3)

• Change from baseline in craving (include craving measures/questionnaires) [Time frame: Baseline and Week 12]
• Differences in baseline trauma exposure (composite score) [Time frame: Baseline and Week 12]
• Change from baseline in neuropsychological testing scores [Time frame: Baseline and Week 12]

Eligibility criteria

Inclusion criteria

• 18-60 years old
• Veteran enrolled in VHA healthcare

Alcohol Group:

• must meet diagnosis for recent alcohol-use disorder (DSM-V)
• willing to return for follow-up visits and can participate for 12-weeks

Control Group:

• must not meet DSM-V criteria for a use disorder other than nicotine

Exclusion criteria

• Clinically significant neurological, endocrine, hepatic, or systemic disease that would compromise safe participation or confound outcomes
• Left-handedness
• Axis-1 psychiatric diagnoses other than anxiety, depression or post-traumatic stress disorder
• Recreational or prescriptive use of psychotropic medications
• Recreational or prescriptive use of opioid medications or have a past or current history of abuse or dependence on opioids
• MRI contraindications (e.g. metal in body)
• Positive urine drug screen, except for nicotine and marijuana, on test days
• Women who are pregnant or breastfeeding
• Participants on hormonal therapy or treatments other than pregnancy contraceptives
• Autoimmune or neurodegenerative diseases that present with neuroinflammation (multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, Parkinson's)
• Current participation in an investigational drug study
• Alcohol group: < 5 days and > 3 weeks of abstinence from alcohol
• Alcohol group: Liver disease requiring medication or medical treatment, and/or aspartate or alanine aminotransferase levels greater than 3 times the upper limit of normal, gastrointestinal or renal disease that would significantly impair absorption, metabolism or excretion of study drug, or require medical treatment.
• Non-english speaker

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Basic science

Study locations

United States · 1 center

• VA Portland Health Care System — Portland

Identifiers

NCT: NCT06426303 · 25536

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗