Alcohol Response and Genetics for Alcohol Consumption

Overseen By Vijay A Ramchandani, Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Must not be taking: Antidepressants, Antihypertensives, Insulin, others

Disqualifiers: Major medical illness, Hepatitis, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

128 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: People with the brain disease AUD (alcohol use disorder) have a serious problem with drinking. Researchers want to study how different people react to alcohol, and how genes affect this. They will focus on a nicotine receptor gene that may increase a person s AUD risk. Objectives: To see if people with variations of a nicotine receptor gene take alcohol differently and have different brain responses to alcohol cues. Eligibility: Healthy adults ages 21 - 60. This study includes smokers and non-smokers. Design: Participation will be based on evaluation under the NIAAA natural history protocol (14-AA-0181) or a screening visit under this protocol. Participants will have two 9-hour visits. They must have no alcohol or non-prescription drugs before all visits and no food or drink before the first visit. At every visit, participants will: * Get a light meal * Have breath and urine tests * Get taxi rides there and back At visits 1, participants will: * Have a thin plastic tube inserted in an arm and connected to a pump for alcohol infusion. * Have sensors on their chest to monitor heart rate. * Sit in a chair for 2.5 hours and get alcohol by pushing a button. Their breath alcohol level will be monitored. * Answer questions about mood and effects of alcohol * Give blood samples * Relax at the clinic while their breath alcohol level drops At visit 2, participants will: * Answer questions and do computer tests * Have an alcoholic drink and a snack * Have a magnetic resonance imaging (MRI) scan. They will lie in a machine that takes pictures of the brain. They will do computer tasks. * Have another drink and snack * Relax until their alcohol level drops Participants will have a follow-up call after each visit.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before participating in the trial. Specifically, you should not use prescription or over-the-counter medications that interact with alcohol for two weeks before screening. Additionally, you should refrain from using certain medications like anti-histamines, pain medicines, and anti-inflammatories for 48 hours before study visits. Always consult with a physician before discontinuing any medications.

What evidence supports the effectiveness of the treatment involving Alcohol Reward and Nicotinic Receptor Genetic Variation for alcohol consumption?

Research suggests that certain genetic variations in nicotinic acetylcholine receptors (nAChRs) are linked to heavy alcohol use, indicating that these receptors play a role in alcohol reward. This connection suggests that targeting nAChRs could be a promising strategy for developing treatments for alcohol use disorders. ^{1 2 3 4 5}

Is the treatment involving nicotinic acetylcholine receptors generally safe for humans?

The research does not provide specific safety data for humans, but studies in mice suggest that genetic variations in nicotinic acetylcholine receptors may influence alcohol consumption without indicating harmful effects. ^{1 2 5 6 7}

How does the drug Alcohol Reward, Nicotinic Receptor Genetic Variation differ from other treatments for alcohol consumption?

This drug is unique because it targets specific genetic variations in nicotinic acetylcholine receptors, which are involved in the brain's reward system. By focusing on these genetic components, it aims to address the underlying genetic factors that contribute to alcohol and nicotine co-addiction, potentially offering a more personalized treatment approach. ^{1 3 5 8 9}

Research Team

Vijay A Ramchandani, Ph.D.

Principal Investigator

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Eligibility Criteria

Adults aged 21-60, both smokers (with at least a year of daily smoking and certain cotinine levels) and non-smokers (with no recent smoking history), can join this study. Women must use effective birth control if they're sexually active. People with alcohol or substance disorders, seeking treatment for such issues, or with significant withdrawal symptoms are excluded.

Inclusion Criteria

Smokers will have a history of at least 1 year of daily smoking, defined as individuals who smoke more than 20 uses of nicotinic products/week on average, and a cotinine level, measured by the NarcoCheck PreDosage Nicotine Test (PNT) test, of >= 2. [assessment: Smoking history questionnaire, Additional medical history, PreDosage Nicotine test]

I am between 21 and 60 years old.

I have not smoked or used nicotine products more than 20 times in my life.

Exclusion Criteria

I regularly use medication that affects my blood flow.

Left-handedness

Fear of enclosed spaces

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Visit 1 - Alcohol Self-Administration

Participants undergo an IV alcohol self-administration session using the Computer-Assisted Infusion System (CAIS) to measure BrAC and subjective responses.

1 day

1 visit (9 hours)

Visit 2 - MRI and Alcohol Consumption

Participants undergo an MRI session while performing tasks to assess neural processing of alcohol rewards, followed by alcohol consumption.

1 day

1 visit (9 hours)

Follow-up

Participants are monitored for safety and effectiveness after treatment through follow-up calls.

1 week

Treatment Details

Interventions

• Alcohol Reward
• Nicotinic Receptor Genetic Variation

Trial Overview The trial is testing how genetic variations in a nicotine receptor gene affect the way people consume alcohol and their brain's response to it. Participants will undergo two sessions involving alcohol consumption via different methods and monitoring through breath tests, blood samples, questionnaires, and MRI scans.

Participant Groups

Group I: 1 Experimental Treatment 3 Interventions

Alcohol self-administration (IV ethanol for sessions 1 and oral for session 2)

Who Is Running the Clinical Trial?

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Lead Sponsor

Trials

865

Recruited

1,091,000+

Findings from Research

This study identified specific haplotypes in the CHRNA6 gene that are associated with heavy alcohol consumption in a Spanish population of 417 individuals, suggesting a genetic link to alcohol use disorder.

Additionally, a haplotype in the CHRNA4 gene was found to be associated with increased body weight, particularly among heavy alcohol consumers, highlighting a potential genetic factor in co-occurring alcohol use and overeating.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of nAChR gene haplotypes with heavy alcohol use and body mass. Landgren, S., Engel, JA., Andersson, ME., et al.[2011]

Genetic factors play a significant role in individual responses to alcohol and vulnerability to alcohol dependence, with specific polymorphisms affecting alcohol metabolism and sensitivity.

Research on genetic variants related to GABA(A) receptors and other neurotransmitter systems is crucial for understanding alcohol's effects and developing targeted treatments for alcoholism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenetics of alcohol response and alcoholism: the interplay of genes and environmental factors in thresholds for alcoholism. Radel, M., Goldman, D.[2018]

In a study involving 263,954 individuals, it was found that smoking consumption and dependence are strongly associated with various diseases, indicating that these phenotypes can serve as reliable genetic proxies for nicotine dependence.

Conversely, the research revealed that alcohol consumption does not directly correlate with alcohol misuse, suggesting that it is not a suitable genetic proxy for understanding alcohol-related problems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alcohol and cigarette smoking consumption as genetic proxies for alcohol misuse and nicotine dependence. Sanchez-Roige, S., Cox, NJ., Johnson, EO., et al.[2023]

Alcoholism has a high heritability rate of 50-60% and is often complicated by co-occurring disorders, making treatment challenging; current therapies show only modest effects.

Genetic factors play a significant role in alcoholism, with specific neurotransmitter pathway genes being potential therapeutic targets, and understanding these genetic influences can help tailor more effective treatments for different types of alcoholics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenomics of alcohol response and addiction. Enoch, MA.[2019]

Genetic factors, particularly those related to neuronal nicotinic acetylcholine receptors (nAChRs), may play a significant role in the co-occurrence of alcohol and nicotine addiction, influencing early behaviors that increase the risk of dependence.

The dopaminergic system, which is activated by nAChRs, is crucial for the rewarding effects of both nicotine and alcohol, suggesting that understanding the genetic variations in nAChRs could lead to better insights into these addictions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The genetic components of alcohol and nicotine co-addiction: from genes to behavior. Schlaepfer, IR., Hoft, NR., Ehringer, MA.[2021]

The study identified a genetic link between specific nAChR subunit genes (Chrna3, Chrna4, Chrnb4, Chrnb2, Chrna5, and Chrna7) and alcohol preference in mice, suggesting these genes may influence susceptibility to alcohol addiction.

High-drinking mice carried alleles associated with alcohol preference from the alcohol-preferring C57BL/6J strain, while low-drinking mice had alleles from the alcohol-avoiding DBA/2J strain, indicating a potential genetic basis for alcohol consumption behaviors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delineation of the role of nicotinic acetylcholine receptor genes in alcohol preference in mice. Symons, MN., Weng, J., Diehl, E., et al.[2013]

Transgenic mice with overexpression of specific nicotinic acetylcholine receptor subunits (alpha 5, alpha 3, beta 4) showed reduced ethanol consumption compared to wild-type mice, indicating a potential role of these receptors in modulating alcohol intake.

Despite the differences in drinking behavior, both transgenic and wild-type mice exhibited similar sensitivity to various acute effects of ethanol, suggesting that the receptor subunit gene cluster may influence alcohol preference rather than its immediate effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transgenic over expression of nicotinic receptor alpha 5, alpha 3, and beta 4 subunit genes reduces ethanol intake in mice. Gallego, X., Ruiz-Medina, J., Valverde, O., et al.[2021]

Mice lacking the α6 subunit of the nicotinic acetylcholine receptor (Chrna6) showed a significantly delayed recovery from sedation caused by ethanol, indicating that this subunit plays a role in modulating the sedative effects of alcohol.

No significant effects on ethanol consumption or ataxia were observed in mice lacking the β3 subunit (Chrnb3), suggesting that the α6 subunit is more critical for the sedative response to ethanol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The α6 nicotinic acetylcholine receptor subunit influences ethanol-induced sedation. Kamens, HM., Hoft, NR., Cox, RJ., et al.[2021]

The study found that mice lacking the α5 nicotinic acetylcholine receptor (nAChR) subunit exhibited increased sensitivity to ethanol's effects, such as enhanced hypothermia and anxiolytic-like responses, compared to normal mice.

Deletion of the α5 nAChR subunit reduced the rewarding effects of ethanol, as shown by decreased conditioned place preference, suggesting that targeting these receptors could be a potential strategy for treating alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Knockout of alpha 5 nicotinic acetylcholine receptors subunit alters ethanol-mediated behavioral effects and reward in mice. Dawson, A., Wolstenholme, JT., Roni, MA., et al.[2020]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Association of nAChR gene haplotypes with heavy alcohol use and body mass. [2011]

2. United States pubmed.ncbi.nlm.nih.gov

Pharmacogenetics of alcohol response and alcoholism: the interplay of genes and environmental factors in thresholds for alcoholism. [2018]

3. Ireland pubmed.ncbi.nlm.nih.gov

Alcohol and cigarette smoking consumption as genetic proxies for alcohol misuse and nicotine dependence. [2023]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacogenomics of alcohol response and addiction. [2019]

5. United Arab Emirates pubmed.ncbi.nlm.nih.gov

The genetic components of alcohol and nicotine co-addiction: from genes to behavior. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Delineation of the role of nicotinic acetylcholine receptor genes in alcohol preference in mice. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Transgenic over expression of nicotinic receptor alpha 5, alpha 3, and beta 4 subunit genes reduces ethanol intake in mice. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

The α6 nicotinic acetylcholine receptor subunit influences ethanol-induced sedation. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Knockout of alpha 5 nicotinic acetylcholine receptors subunit alters ethanol-mediated behavioral effects and reward in mice. [2020]