Investigating how a specific gene affects alcohol consumption and brain activity

Role of Metal Ion Transporter ZIP8 in Alcohol Related Behaviors

This study is testing how a specific gene might influence drinking habits and brain activity in healthy adults aged 21 to 60.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 21 Years to 60 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (nih)
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT06819189 on ClinicalTrials.gov

What this trial studies

This study aims to explore the relationship between the ZIP8 gene and alcohol-related behaviors in healthy volunteers. Participants aged 21 to 60, who are non-smokers and of European ancestry, will undergo a controlled alcohol infusion to assess their drinking behavior and brain activity through functional MRI scans. The study will classify participants based on their genetic variation in the SLC39A8 gene and evaluate how this affects their alcohol consumption and brain responses. The findings could provide insights into genetic factors influencing alcohol use disorder susceptibility.

Who should consider this trial

Good fit: Ideal candidates for this study are healthy individuals aged 21 to 60 years, non-smokers, with no history of alcohol use disorder, and of European ancestry.

Not a fit: Patients with a history of alcohol use disorder or those who smoke may not benefit from this study.

Why it matters

Potential benefit: If successful, this research could lead to a better understanding of genetic influences on alcohol consumption, potentially informing prevention and treatment strategies for alcohol use disorders.

How similar studies have performed: While studies have explored genetic influences on alcohol use, this specific investigation into the ZIP8 gene's role is novel and has not been extensively tested.

Eligibility criteria

* INCLUSION CRITERIA:

  1. Male and female participants between 21-60 years of age. \[Based on: identification provided to Clinical Center Admissions office\].
  2. Non-smokers with no history of smoking in the past year and not a daily smoker for more than 1 month in their lifetime. \[Based on: smoking history questionnaire, Additional History Form\]
  3. Participants of European ancestry: the minor T allele of rs13107325, has a frequency of 0.08 in European ancestry, but is almost absent in Asian and African populations (http://www.ensembl.org). Due to the rare occurrence of the T allele and to avoid populations stratification in this small sample-sized study, only participants with self-reported White racial category (European ancestry) will be enrolled in this study.
  4. Inclusion criteria for persons of childbearing potential: Use of adequate method of birth control during the study, if participant is sexually active and is not surgically sterilized. Adequate methods of contraception include use of oral contraceptives; use of barrier method of contraceptive; use of an approved IUD or other long-acting reversible contraceptive (LARC); have a male sexual partner who is surgically sterilized; or have exclusively same-sex sexual partner(s). Justification: To minimize the risk of administering alcohol to pregnant persons of childbearing potential, given the known effects of alcohol exposure on fetuses. \[Based on: medical history\].
  5. Ability to understand the written consent form and willing to sign it. \[Based on: consent quiz\].

EXCLUSION CRITERIA:

1. Current history (past 12 months) of major medical illness, including CNS, cardiovascular, respiratory, gastrointestinal, hepatic, renal, endocrine, or reproductive disorders, or positive hepatitis (A, B antigen, or C), or HIV test. Justification: Many illnesses may alter the neuropsychological effects of alcohol as well as MRI measures. Hepatitis can alter liver function and alcohol pharmacokinetics. HIV infection can alter brain function. \[Based on: clinically significant findings on medical history and physical exam, ECG, laboratory tests\].
2. Current history of psychiatric disorders, including depressive disorder, bipolar disorder, or anxiety disorders. Justification: Concurrent psychopathology can alter brain function and alcohol response. \[Based on: SCID interview\]
3. Lifetime history of psychotic disorders, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), or eating disorder. Justification: These disorders can have long-term effects on brain function and alcohol response. \[Based on: SCID interview\]
4. Current or lifetime diagnosis of alcohol or substance use disorder. Past mild AUD or past mild SUD with no current symptoms for at least 2 years will not be exclusionary. Justification: History of moderate to severe alcohol or substance use disorder will impact brain function and alcohol response We do not anticipate past mild AUD or SUD in remission for 2+ years would have such impact on brain function and alcohol response. We will examine this in an exploratory analysis. We will also do a follow-up telephone/telehealth visit with these participants to assess any changes in alcohol or substance use or problems related to their participation in the study. \[Based on: SCID interview\].
5. Currently seeking treatment for alcohol use disorders. Justification: It would be unethical to administer alcohol to individuals seeking treatment for alcohol problems. Also, this study does not provide treatment for individuals with alcohol use disorder. \[Based on: medical history\]
6. Non-drinkers (alcohol-naive individuals or current abstainers) or individuals with no experience drinking 5 or more drinks on one occasion in their lifetime. Justification: It would be unethical to administer alcohol to individuals that do not drink alcohol. \[Based on: medical history\].
7. Current or prior history of alcohol-induced flushing reactions, including rapid reddening of the face, rapid heart rate and breathing, and nausea after 1 or 2 drinks. Justification: It would not be safe to administer alcohol to individuals with the highly aversive flushing response to alcohol. \[Based on: alcohol flushing questionnaire\].
8. Positive result on urine drug screen or positive breathalyzer during screening visit. Positive urine drug screen or breathalyzer reading during more than 1 study visit will result in participant withdrawal from the study. Justification: Current or recent exposure to alcohol or drugs of abuse could impact brain function and alcohol response. \[Based on: laboratory tests and breathalyzer test\].
9. History of significant withdrawal symptoms or presence of clinically significant withdrawal symptoms (Clinical Institute Withdrawal Assessment (CIWA) score \> 8) at screening. Justification: Withdrawal symptoms would be indicative of alcohol use disorder, which is already an exclusion criterion. Additionally, withdrawal symptoms would be a major safety concern for participants, and a major confound in the assessment of alcohol response and brain function. \[Based on: CIWA assessment\].
10. Medication exclusion criteria: \[Based on Medical history and physical exam, Additional History Form\].

    * Use of prescription or OTC medication known to interact with alcohol 2 weeks prior to screening or screening update visit. These include but may not be limited to: isosorbide; nitroglycerine; benzodiazepines; warfarin; anti-depressants such as amitriptyline, clomipramine and nefazodone; anti diabetes medications such as glyburide, metformin and tolbutamide; H2-antagonists for heartburn such as famotidine, cimetidine and ranitidine; muscle relaxants; anti-epileptics including phenytoin and phenobarbital; codeine and opioid analgesics including Darvocet, Percocet and hydrocodone.
    * Regular (more than once a week) or prescribed use of antihistamines, pain medicines, and anti-inflammatories such as aspirin, ibuprofen, acetaminophen, celecoxib, and naproxen, and unable to refrain from these medications for 48 hours prior to study visits.NOTE: Seasonal use of antihistamines is not-exclusionary unless participants are unable to refrain from these medications for

      48 hours prior to study visits.
    * Use of medications known to inhibit or induce enzymes that metabolize alcohol for 4 weeks prior to screening or screening update visit. These include chlorzoxazone, isoniazid, metronidazole, and disulfiram.
    * Use of drugs known to affect hemodynamic response 2 weeks prior to screening or screening update visit. These include antihypertensives, insulin, and thyroid medications.
11. Exclusion criteria for MRI:

    * Left-handedness (Edinburgh Handedness Scale). Justification: To avoid lateralized effects on brain function measures and reduce potential variance in MRI signals.
    * Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head (including but not limited to pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips, metallic prostheses, permanent eyeliner, implanted delivery pump, or shrapnel fragments).
    * Fear of enclosed spaces. Justification: To minimize risk and discomfort.
    * Inability to lie comfortable on back for up to 2 hours in the MRI scanner. Justification: To minimize risk and discomfort.

    \[Based on: MRI Safety Screening Questionnaire, Additional History Form\]
12. Exclusion criteria for persons of childbearing potential:

Justification: To minimize the risk of administering alcohol to pregnant or nursing persons, given the known effects of alcohol exposure on fetuses and infants.

* Pregnant \[Based on: urine beta-hCG test at screening\]. Persons of childbearing potential must also test negative on urine beta-hCG test at the start of every study visit.
* Breast-feeding \[Based on: Medical history and physical exam\].

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (RECRUITING)

Study contacts

• Principal investigator: Vijay A Ramchandani, Ph.D. — National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Study coordinator: Vijay A Ramchandani, Ph.D.

Conditions: Healthy Volunteer, Alcohol