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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how genes, particularly a nicotine receptor gene, influence responses to alcohol. Researchers are interested in how individuals with different versions of this gene react to alcohol and related cues. Participants will attend two sessions involving alcohol consumption and various tests, including an MRI scan to observe brain activity. This trial is suitable for healthy adults who drink alcohol and have smoked for at least a year or are non-smokers.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a unique opportunity to contribute to groundbreaking genetic research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

In a previous study, researchers discovered that nicotine and alcohol interact in the brain, potentially altering reactions to drinking. These findings enhance understanding of alcohol's safety in this study. The study involves controlled alcohol consumption, allowing researchers to explore genetic links to alcohol use.

Although the main focus isn't treatment safety, it's important to note that this is an early-phase study. Early-phase studies typically closely examine safety and treatment tolerance. Participants undergo careful monitoring, including heart rate checks and supervised alcohol use. This monitoring ensures any side effects are quickly identified and managed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they explore how genetic variations in nicotinic receptors can influence alcohol consumption and reward. Unlike current options that mainly focus on behavioral therapies or medications to reduce cravings, this study investigates the biological and genetic factors that might predispose individuals to alcohol use disorders. By understanding how specific genetic variations affect alcohol response, this approach could lead to personalized treatments that target the root cause of the disorder for more effective outcomes.

What evidence suggests that this trial's treatments could be effective for alcohol use disorder?

Research has shown that certain brain receptors, called nicotinic acetylcholine receptors, influence alcohol consumption. Studies have found that genetic differences in these receptors can affect how much alcohol a person drinks. For example, some genetic changes are linked to increased alcohol intake. Additionally, animal studies suggest that targeting these receptors can help reduce alcohol consumption. This trial will explore the role of these genetic variations in alcohol consumption through alcohol self-administration sessions. Understanding these genetic differences could be important for managing or treating alcohol use disorders. ^{2 6 7 8 9}

Who Is on the Research Team?

Vijay A Ramchandani, Ph.D.

Principal Investigator

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Are You a Good Fit for This Trial?

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

Left-handedness

I regularly use medication that affects my blood flow.

Fear of enclosed spaces

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4754113/

Recent Advances in Nicotinic Receptor Signaling in Alcohol ... Confirming this, the nAChR ligands were found to reduce ethanol-taking behavior in a genetic animal model for alcohol abuse and dependence or inbred mice, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03294460

Nicotinic Receptor Genetic Variation and Alcohol Reward This study examines how a nicotine receptor gene affects alcohol response in healthy adults, using two 9-hour visits with alcohol infusion and MRI scans.

3. sciencedirect.com sciencedirect.com/science/article/pii/S1043661823000610

The role of nicotinic receptors in alcohol consumption Nicotinic acetylcholine receptors are involved in alcohol consumption. Most nicotinic receptor ligands tested reduce alcohol consumption.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4647894/

Neuronal nicotinic acetylcholine receptors are important ... Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence. Alcoholism is a serious public health problem and has ...

5. nature.com nature.com/articles/srep45116

Nicotine enhances alcohol intake and dopaminergic ... Alcohol and nicotine are the most widely co-abused drugs. Both modify the activity of dopaminergic (DA) neurons of the Ventral Tegmental ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7487170/

The role of nicotinic acetylcholine receptors in alcohol-related ... Results from both human and animal models demonstrate a genetic correlation between alcohol and nicotine behaviors. These data support the idea of shared ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0166432804002402

Genetic correlation between the free-choice oral ... Studies have estimated that approximately 50–60% of individual variation in either alcohol or tobacco consumption can be attributed to genetic factors [7], [18] ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11450629/

Smoking-Related Increases in Alcohol Outcomes and ... Alcohol and nicotine interact with the nicotinic acetylcholine receptor system to alter reward-related responses, thereby contributing to the co-use and ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1877117315002069

Recent Advances in Nicotinic Receptor Signaling ... Here, we review recent insights into the rewarding effects of alcohol, as they pertain to different nAChR subtypes, associated signaling molecules, and pathways ...