Neuroimmune Dysfunction in Alcohol Use Disorder

NCT ID: NCT04210713

Last Updated: 2023-12-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 142 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-03
• Study Completion Date: 2023-09-20

Brief Summary

The objective of this proposal is to advance medication development for alcohol use disorder by examining the efficacy and mechanisms of action of minocycline, a neuroimmune modulator, as a potential treatment. This study has important clinical implications, as the available treatments for alcohol use disorder are only modestly effective and testing novel medications is a high research priority.

Detailed Description

The research objective of this project is to characterize the role of the neuroimmune system in alcohol use disorder (AUD). The proposed study employs a randomized, double-blind, and placebo-controlled design to examine how neuroinflammation, as measured via neuroimaging [e.g., magnetic resonance imaging (MRI)], relates to alcohol craving, neurocognitive impairment (e.g., memory, attention, etc.), and alcohol use in non-treatment seeking individuals with AUD. The study will also determine whether minocycline (MINO), an FDA-approved antibiotic medication, affects any of the above listed measures. In the proposed study, healthy controls (n = 36) and non-treatment seeking individuals with a current Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 AUD diagnosis (n = 36) will be randomized to receive either 200 mg of minocycline per day or placebo for approximately 28 days and complete two laboratory sessions. The first laboratory session will be performed immediately before commencing the medication regimen (day 0) and the second will be completed after taking the medication daily for approximately 28 days. Within each laboratory session, participants will complete a cue reactivity paradigm, neurocognitive performance tasks, and a magnetic resonance imaging (MRI) session. Additionally, blood samples will be drawn on days 0, 7, 14, 21, and 28 of treatment to measure circulating levels of proinflammatory molecules in order to identify the specific immune signaling pathways underlying neuroinflammation in AUD. Clinical labs (e.g., blood chemistry, liver function tests) and adverse events (AEs) will also be assessed at these five visits.

Conditions

Alcohol Drinking; Alcohol-Related Disorders; Disease; Inflammation; Alcoholism; Cognitive Dysfunction; Pathologic Processes; Drinking Behavior; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorder; Cognition Disorder; Neurocognitive Disorders; Minocycline; Anti-Bacterial Agents; Anti-Infective Agents

Keywords

Minocycline

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

AUD-Minocycline

Participants diagnosed with alcohol use disorder will be randomly assigned to take minocycline for 4 weeks. The randomization is double-blinded and will alternate between minocycline and placebo.

Group Type: ACTIVE_COMPARATOR

Minocycline

Intervention Type: DRUG

200 mg/day

AUD-Placebo

Participants diagnosed with alcohol use disorder will be randomly assigned to take placebo for 4 weeks. The randomization is double-blinded and will alternate between minocycline and placebo.

Group Type: PLACEBO_COMPARATOR

Sugar pill

Intervention Type: DRUG

Matched placebo

Healthy Control-Minocycline

Healthy control participants will be randomly assigned to take minocycline for 4 weeks. The randomization is double-blinded and will alternate between minocycline and placebo.

Group Type: ACTIVE_COMPARATOR

Minocycline

Intervention Type: DRUG

200 mg/day

Healthy Control-Placebo

Healthy control participants will be randomly assigned to take placebo for 4 weeks. The randomization is double-blinded and will alternate between minocycline and placebo.

Group Type: PLACEBO_COMPARATOR

Sugar pill

Intervention Type: DRUG

Matched placebo

Interventions

Minocycline

200 mg/day

Intervention Type: DRUG

Sugar pill

Matched placebo

Intervention Type: DRUG

Other Intervention Names

Placebo

Eligibility Criteria

Inclusion Criteria

• Meet DSM-5 diagnostic criteria for an AUD
• In the 30-day period before enrollment, consume ≥ 14 and ≥ 7 standard drinks per week for men and women, respectively, AND
• In the 30-day period before enrollment, engage in heavy drinking (5 or more drinks for men, 4 or more drinks for women) and ≥ 5 times per month

• Does not meet DSM-5 diagnostic criteria for an AUD (current or lifetime)
• In the 30-day period before enrollment, consume ≤ 14 and ≤ 7 standard drinks per week for men and women, respectively
• Engage in infrequent heavy drinking during the past 6 months (≤ 2 heavy drinking events in past 6 months)

Exclusion Criteria

• Currently in treatment for AUD, a history of treatment within the 30 days before enrollment, or currently seeking immediate treatment
• Current (last 12 months) DSM-5 diagnosis of substance use disorder for any psychoactive substances other than alcohol and nicotine
• Currently prescribed a psychotropic medication for the treatment of schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, depressive disorders, anxiety disorders, and mood disorders.
• Lifetime DSM-5 diagnosis of schizophrenia spectrum and other psychotic disorders and bipolar and related disorders
• Positive urine toxicology screen for the following substances: cocaine, opiates, amphetamines, methamphetamine, phencyclidine, barbiturates, benzodiazepine, methadone, and tricyclic antidepressants.
• Self-reported daily use of cannabidiol (CBD) or opioids (including prescribed)
• Serious alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised
• If female: pregnancy, nursing, or refusal to use reliable method of birth control; if using hormonal contraceptives, refusal to use secondary birth control method
• Any autoimmune or inflammatory medical disorder or medical condition that may interfere with safe study participation and/or study aims (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or γ-glutamyl transferase (GGT) ≥ 4 times upper normal limit
• Attempted suicide in the past 3 years and/or serious suicidal intention or plan within the past year
• Currently on prescription medication that contraindicates use of minocycline, including but not necessarily limited to: isoretinoin, ergot alkaloids, and anti-coagulants.
• Previously known hypersensitivity to tetracyclines
• Current or recent (within one month) treatment with any antibiotic
• Regular use of a prebiotic or probiotic supplement
• Claustrophobia or physical issues preventing MRI scan
• Presence of a metal device in the body (e.g., pacemaker, infusion pump, aneurysm clip, metal prosthesis or plate)
• Current or recent (within 3 months) participation in a clinical trial involving medication administration
• Suffered a mild or moderate traumatic brain injury (TBI) within the last 12 months, a severe TBI at any point in their life, or a moderate TBI before the age of 12.
• Having below a 6th grade reading level
• Within the last 3 months, tested positive for COVID-19 (i.e. the SARS-CoV-2 virus) and experienced common related symptoms.
• Any other circumstances that, in the opinion of the investigators, compromises participant safety, ability of the investigators to conduct the study as designed, and/or study integrity.

• Lifetime DSM-5 diagnosis of substance use disorder for any psychoactive substances other than nicotine
• Self-reported daily use of cannabidiol (CBD) or opioids (including prescribed)
• Lifetime DSM-5 diagnosis of schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, depressive disorders, anxiety disorders (panic disorder, agoraphobia, social anxiety, and generalized anxiety), obsessive-compulsive and related disorders, trauma- and stressor-related disorders, feeding and eating disorders (binge eating, anorexia, and bulimia), conduct disorders, and gambling disorder
• Positive urine toxicology screen for the following substances: cocaine, opiates, amphetamines, methamphetamine, phencyclidine, barbiturates, benzodiazepine, methadone, and tricyclic antidepressants.
• Serious alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised
• If female: pregnancy, nursing, or refusal to use reliable method of birth control; if using hormonal contraceptives, refusal to use secondary birth control method
• Any autoimmune or inflammatory medical disorder or medical condition that may interfere with safe study participation and/or study aims (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or γ-glutamyl transferase (GGT) ≥ 4 times upper normal limit
• Attempted suicide in the past 3 years and/or serious suicidal intention or plan within the past year
• Currently on prescription medication that contraindicates use of minocycline, including but not necessarily limited to: isoretinoin, ergot alkaloids, and anti-coagulants.
• Previously known hypersensitivity to tetracyclines
• Current or recent (within one month) treatment with any antibiotic
• Regular use of a prebiotic or probiotic supplement
• Claustrophobia or physical issues preventing MRI scan
• Presence of a metal device in the body (e.g., pacemaker, infusion pump, aneurysm clip, metal prosthesis or plate)
• Current or recent (within 3 months) participation in a clinical trial involving medication administration
• Suffered a mild or moderate traumatic brain injury (TBI) within the last 12 months, a severe TBI at any point in their life, or a moderate TBI before the age of 12.
• Having below a 6th grade reading level
• Within the last 3 months, tested positive for COVID-19 (i.e. the SARS-CoV-2 virus) and experienced common related symptoms.
• Any other circumstances that, in the opinion of the investigators, compromises participant safety, ability of the investigators to conduct the study as designed, and/or study integrity.

• Minimum Eligible Age: 25 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

NIH

Sponsor Role: collaborator

University of Maryland, Baltimore

OTHER

Sponsor Role: lead

Responsible Party

Daniel Roche

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Daniel Roche, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Maryland, Baltimore

Locations

Maryland Psychiatric Research Center (MPRC) Treatment Research Program (TRP)

Catonsville, Maryland, United States

Countries

United States

References

Wheeler PB, Mackey CD, Moskal D, Brady DJ, Foster KT, Marks RM, Dickerson DL, Kelly DL, Bennett ME, Roche DJO. Religiosity and the relationship between sexual trauma, alcohol use, and sleep quality: a moderated mediation model. Alcohol Alcohol. 2025 May 14;60(4):agaf030. doi: 10.1093/alcalc/agaf030.

Reference Type: DERIVED

PMID: 40483726 (View on PubMed)

Other Identifiers

5K01AA026005-03

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HP-00080891

Identifier Type: -

Identifier Source: org_study_id