Non-invasive Vagal Nerve Stimulation as Novel Treatment to Improve Functional Outcomes in Veterans With Alcohol Use Disorder

Not Applicable

Recruiting

• Conditions: Alcohol Use Disorder
• Interventions: Device: Cervical transcutaneous vagus nerve stimulation (active comparator); Device: Cervical transcutaneous vagus nerve stimulation (sham comparator)

• Registration Number: NCT06399653
• Lead Sponsor: VA Office of Research and Development

Brief Summary

Alcohol use disorder (AUD) is a major health concern amongst Veterans as it causes functional impairments and decreased quality of life. Current AUD treatments show limited effectiveness in reducing withdrawal-related psychological and physical distress, which drives the urge to drink to relieve these symptoms. The investigators propose the vagus nerve, which is the primary nerve of the "rest and digest" branch of the autonomic nervous system via its bidirectional connections between the brain and the body, as a novel treatment target for AUD. The goal of this study is to assess treatment efficacy and mechanism of action. Noninvasive neuromodulation technologies offer the possibility for innovative, low risk treatments to support the rehabilitation and community reintegration of Veterans with AUD.

Detailed Description

Alcohol use disorder (AUD) is a serious mental health disorder that affects more than 40% of US military Veterans, presenting a major burden to this population and to the VA Healthcare System. Relapse rates of AUD are extremely high; over half of Veterans who complete treatment, relapse within 6 months, highlighting the need for improved treatments or different treatment targets. Long-term excessive drinking results in homeostatic dysregulation due to changes in the central and autonomic nervous system, which manifests in psychological and physical distress during abstinence and results in the urge to drink to relieve these symptoms. These symptoms, which can be equated to withdrawal, lead to continued harmful drinking and relapse, and are associated with significant functional impairment and reduced quality of life.

Current AUD treatments do not effectively mitigate this homeostatic dysregulation and have risks and side effects as well as other limitations. The investigators propose the vagus nerve, which is the main nerve of the parasympathetic branch of the autonomic nervous system and plays an important role in maintaining and restoring physiological homeostasis, as a novel treatment target for AUD. Noninvasive stimulation of the vagus nerve (nVNS) has been shown to alleviate anxiety, depression, and pain. The investigators hypothesize that nVNS can restore homeostasis and reduce withdrawal-related distress and craving, and consequently improve functional outcomes and quality of life in Veterans with AUD.

The goal of this study is to assess treatment efficacy and mechanism of action. The proposed study will include 80 Veterans with current AUD, who will be randomized to receive nVNS or sham stimulation prior to performing a well-validated heat pain task designed to assess neural and physiological correlates of distress. Subjects will then self-administer nVNS/sham at home twice a day for 7 days and return for a follow-up visit, during which all study components will be repeated. Behavioral assessments of psychological and physiological distress, craving, and functional outcomes will be administered at baseline and post-treatment, as well as at a 1-month follow-up visit.

Study Timeline

• Study First Submitted: 2024-04-30
• Study First Submitted QC: 2024-04-30
• Study First Posted: 2024-05-06
• Study Start: 2025-01-01
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-16
• Last Update Posted: 2025-04-18
• Primary Completion: 2028-08-31
• Study Completion: 2029-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

1. Veterans between 21 and 65 years, any race or ethnicity.
2. Meet current DSM-5 diagnosis of moderate or severe AUD (Structured Clinical Interview for DMS-5 (SCID) interview) with at least one functional disability due to alcohol use, current alcohol craving, and current heavy drinking (>= 5 drinks (men) / >= 4 drinks (women) on the same occasion, on 5 or more days in the past month) as defined by the Substance Abuse and Mental Health Services Administration (SAMHSA), and mild to moderate withdrawal symptoms during abstinence.
3. Able to forgo consumption of alcohol for 12-24 hours without any serious discomfort or complications.
4. Capable of complying with study schedule, procedures, and speaks English.
5. Able to provide voluntary written informed consent prior to initiation of visit 1.
6. Able and willing to self-administer nVNS/sham stimulation as instructed for the duration of the study, and willing to commit to the return visit at the end of the study.

Exclusion Criteria

1. Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar) score >10 on the day of the scan (symptoms judged to be due to co-existing anxiety or headache disorders will not be counted toward the total).
2. Recent history past 6 months) of severe complications due to alcohol withdrawal (alcohol withdrawal seizures, hallucinations/illusions, delirium tremens).
3. Currently or recently (within last 90 days) enrolled in abstinence-based treatment program.
4. Evidence of a maladaptive pattern of substance use or abuse other than alcohol one month prior to screening visit.
5. Uncontrolled severe psychiatric disorder with psychotic symptoms or cognitive impairment. We will not exclude for PTSD.
6. At risk for suicide requiring urgent higher-level care or homicide (based on the Columbia-Suicide Severity Rating Scale and follow-up clinical interview).
7. History of neurological disorder that might be associated with cognitive dysfunction.
8. History of head trauma involving loss of consciousness >24 hours
9. Clinically significant uncontrolled/unstable medical illness or clinically significant surgery within 1 month of the screening visit.
10. MRI-related exclusion criteria: cardiac pacemaker, metal fragments in eyes/skin/body, aortic/aneurysm clips, heart-valve replacement, copper intrauterine device, shunt (ventricular or spinal), neuro/bio-stimulators, (for females) pregnant or nursing. Any implants will be reviewed for safety.
11. Vagus nerve stimulation related criteria: active implantable medical device, metallic device implanted at or near the neck, carotid atherosclerosis (narrowing of arteries), cervical vagotomy, clinically significant hypertension, hypotension, bradycardia, or tachycardia, cardiac disease and atherosclerotic cardiovascular disease (severe carotid artery disease (e.g., history of transient ischemic attack (TIA) or stroke), congestive heart failure, severe coronary artery disease or recent myocardial infarction (within 5 years)).
12. Pharmacotherapy for AUD: >= 2 weeks stability is required to ensure a steady state of medication effects prior to nVNS administration.
13. Currently taking opioids or benzodiazepines.
14. In case it is determined by the investigator during the course of the study, that a subject needs a higher level or care, study participation will be discontinued, and the subject will be excluded from the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active cervical transcutaneous vagus nerve stimulation	Cervical transcutaneous vagus nerve stimulation (active comparator)	Participants will be assigned to active transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week.
Sham cervical transcutaneous vagus nerve stimulation	Cervical transcutaneous vagus nerve stimulation (sham comparator)	Participants will be assigned to sham transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week.

Primary Outcome Measures

Name	Time	Method
WHO Quality of Life assessment (WHOQOL-BREF)	Baseline to week 1 and 1 month post baseline of 2x daily intervention	The WHOQOL-BREF assesses quality of life across four domains (physical health, psychological, social relationships, and environment) with a total of 26 questions. The WHOQOL-BREF is a widely used instrument with strong psychometric properties.
Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)	Baseline to week 1 and 1 month post baseline of 2x daily intervention	The Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) is a short form (5 min.) to assess symptoms of acute alcohol withdrawal and physical discomfort. The CIWA-Ar includes 8 items, 7 of which are rated from 1 to 7 (higher score indicating higher severity) and 1 of which is rated from 0 to 4 (higher score indication less orientation to place/or person)
Alcohol Urge Questionnaire (AUQ)	Baseline to week 1 and 1 month post baseline of 2x daily intervention	The Alcohol Urge Questionnaire (AUQ) is 8-item scale that measures cognitive preoccupation with alcohol on a 7-point rating scale ranging from "strongly disagree" to "strongly agree". Two items are reverse scored. Higher scores reflect greater craving.
Hamilton Anxiety Rating Scale (HAM-A)	Baseline to week 1 and 1 month post baseline of 2x daily intervention	The HAM-A is a 14-item scale that assesses the presence and severity of psychological distress and negative emotional states. Completion takes 10 minutes. This instrument is widely used in clinical trials and alcohol studies and is sensitive to both nVNS and AUD treatment. Items are rated on a scale ranging from 0 (not present) to 4 (very severe).

Secondary Outcome Measures

Name	Time	Method
Neural response to heat pain fMRI task	Baseline to week 1 of 2x daily intervention	During this task, participants receive brief thermal stimuli (experienced temperature ranging from warm to hot) applied to the leg via a thermode. Neural activation will be measured using percent signal change with higher scores indicating greater activation.

Trial Locations

Locations (1)

VA San Diego Healthcare System, San Diego, CA; 🇺🇸 San Diego, California, United States