Brain Imaging for Alcoholism

(Mu Kappa Trial)

Overseen By Marc Grasso

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Yale University

Must not be taking: Antidepressants, Antipsychotics, Anxiolytics, others

Disqualifiers: Neurological, Cardiovascular, Psychiatric, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand the role of certain brain receptors (MOR and KOR) in alcohol cravings and withdrawal symptoms during a quit attempt. Participants will undergo a detoxification program, which includes Nalmefene to help reduce alcohol dependence, and their brains will be scanned using PET imaging. The study involves individuals with alcohol use disorder (defined as consistently drinking more than 14 drinks weekly for men and more than 7 for women) and healthy individuals who drink less than 5 drinks a week. As an early-phase study, participants must be willing to attempt quitting alcohol. This Phase 1 trial focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking insights.

Will I have to stop taking my current medications?

The trial does not require participants to stop taking their current medications. However, if you regularly use prescription, psychoactive, or herbal medications that could affect the study data, you may not be eligible to participate.

What prior data suggests that this brain imaging technique is safe for participants?

Research has shown that detox programs are generally safe for people with alcohol use disorder. These programs help individuals stop drinking alcohol safely with medical support. Studies have found that detox under medical supervision is well-tolerated, especially when followed by additional treatments like counseling.

However, this trial is in "Early Phase 1," indicating limited information about the treatment's safety. Early Phase 1 studies focus on assessing safety, so participants might encounter some unknown risks. Discuss any concerns with the research team before joining. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it aims to uncover how brain imaging can enhance our understanding of alcoholism, potentially leading to better treatment strategies. This approach uses advanced PET imaging techniques, specifically [11C]CFN and [11C]PKAB, to observe brain activity in individuals with Alcohol Use Disorder before and after detoxification. Unlike standard treatments that focus on behavioral or pharmaceutical interventions, this trial seeks to pinpoint specific brain changes associated with detoxification. By identifying these changes, the hope is to develop more targeted and effective treatments for alcoholism in the future.

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

Research has shown that detox programs can help treat alcohol use disorder (AUD). In this trial, participants in the Alcohol Use Disorder population arm will complete a detoxification program. Studies have found that detox programs, when combined with medications like naltrexone, reduce the urge to drink and help prevent relapse. Naltrexone blocks certain brain signals, making alcohol less enjoyable. In Europe, nalmefene is used to help people drink less. Choosing detox, followed by expert care, has been linked to positive outcomes for those trying to stop drinking. These findings suggest that detox programs, especially when combined with the right medication and follow-up care, offer a promising option for those struggling with AUD. ^{5 6 7 8 9}

Who Is on the Research Team?

Kelly Cosgrove, PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for adults with Alcohol Use Disorder (AUD) who drink heavily and are diagnosed according to DSM-5 criteria. Men must consume more than 14 drinks weekly, exceeding 4 per day twice a week; women over 7 weekly, exceeding 3 per day twice. Participants must be willing to try quitting alcohol and can read/write English.

Inclusion Criteria

You have a current diagnosis of alcohol use disorder (AUD) according to specific criteria outlined in the DSM-5.

I am willing to try quitting alcohol.

I don't have a history of alcohol or significant substance abuse and drink less than 5 alcoholic drinks per week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Up to 3 months

Detoxification

Participants with AUD undergo a detoxification program for 1-3 days before PET imaging

1-3 days

Daily meetings (in-person)

Early Abstinence

Participants with AUD are monitored for changes in MOR and KOR availability during early abstinence

6 days

Daily meetings (in-person)

Outpatient Quit Attempt

Participants continue abstinence with outpatient support and contingency management

3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3-6 weeks

1 visit (in-person) for PET and MRI scans

What Are the Treatments Tested in This Trial?

Interventions

• CFN
• Detoxification Program
• PKAB

Trial Overview The study uses PET brain imaging to measure Mu-Opioid and Kappa-Opioid receptors in people with AUD during a quit attempt. It aims to understand how these receptors relate to cravings, mood, withdrawal symptoms, and the time until they lapse back into drinking.

How Is the Trial Designed?

Group I: Healthy Control population Experimental Treatment 2 Interventions

Subjects will be asked to complete both a 90 minute \[11C\]CFN and a 90 minute \[11C\]PKAB PET Imaging.

Group II: Alcohol Use Disorder population completing Detoxification Experimental Treatment 3 Interventions

Subjects will be asked to complete both 90 minute \[11C\]CFN and 90 minute \[11C\]PKAB PET Imaging after 1-3 days of a detoxification program.

Detoxification Program is already approved in European Union, United States for the following indications:

Approved in European Union as Selincro for:

• Reduction of alcohol consumption in adults with alcohol dependence

Approved in United States as Revex for:

• Complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Collaborator

Trials

865

Recruited

1,091,000+

Published Research Related to This Trial

A study using multi-modal MRI on Marchigian-Sardinian rats showed that just one month of alcohol consumption led to distinct brain changes that could be identified even after a week of abstinence, indicating potential biomarkers for early diagnosis of alcohol use disorders.

Treatment with naltrexone during early abstinence resulted in specific brain changes, suggesting that this medication may aid in the recovery process from alcohol-induced brain alterations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-modal MRI classifiers identify excessive alcohol consumption and treatment effects in the brain. Cosa, A., Moreno, A., Pacheco-Torres, J., et al.[2018]

Nalmefene, an opioid system modulator, has been shown to significantly reduce heavy drinking days and total alcohol consumption in alcohol-dependent adults when used as needed, based on results from two multinational trials (ESENSE 1 and ESENSE 2) and a longer-term study (SENSE).

The treatment was generally well tolerated, with common side effects including nausea, insomnia, and dizziness, making nalmefene a promising option for managing alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nalmefene: a review of its use in the treatment of alcohol dependence. Keating, GM.[2022]

Nalmefene, an opioid receptor modulator, has been shown to significantly reduce heavy drinking days and total alcohol consumption in alcohol-dependent patients when used as needed, based on a phase 3 study involving Japanese patients.

While nalmefene is generally safe, with most side effects being mild to moderate, common adverse events included nausea and dizziness, occurring more frequently than in the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological profile and clinical findings of nalmefene (Selincro&#174;) for reducing alcohol consumption in patients with alcohol dependence]. Tadori, Y.[2020]

Nalmefene, an opioid receptor antagonist approved for reducing alcohol consumption, has been associated with 200 documented adverse drug reactions globally, highlighting the need for careful monitoring.

In 10.5% of cases, nalmefene was used alongside opioids, leading to withdrawal symptoms, indicating that this combination should be avoided to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Nalmefene and Opioid Withdrawal Syndrome: Analysis of the Global Pharmacovigilance Database for Adverse Drug Reactions]. Dahmke, H., Kupferschmidt, H., Kullak-Ublick, GA., et al.[2015]

Nalmefene is the first drug approved in the E.U. specifically to reduce alcohol consumption in alcohol-dependent patients, showing significant efficacy over 6 months by reducing total alcohol intake by an average of 7.6 g/day and heavy drinking days by 2 days per month.

The drug is generally well tolerated with good compliance rates (over 80% adherence) among patients using it as needed, making it a promising new approach in treating alcohol dependence alongside brief psychosocial interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nalmefene and its use in alcohol dependence. Gual, A., Bruguera, P., López-Pelayo, H.[2017]

Chronic ethanol intake leads to significant functional and structural changes in neurons, which are linked to impaired mental function, highlighting the need for effective treatments for alcohol dependence.

Nalmefene, a partial agonist for κ opioid receptors and antagonist for δ and µ receptors, has been shown to effectively reduce ethanol intake in dependent patients by modulating dopamine levels in the brain, alleviating negative emotional states associated with alcohol withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Neurobiology of alcohol and pharmacological aspects of nalmefene]. Biggio, G.[2016]

Nalmefene, an opioid receptor antagonist, significantly reduced mortality from ethanol-induced neurotoxicity in male adolescent rats, decreasing mortality from 71% to 14% when pretreatment was administered before ethanol exposure.

PET imaging with the radioligand [18 F]DPA-714 revealed that nalmefene pretreatment alleviated the neuroinflammatory response in the brain caused by ethanol, indicating its potential as a protective strategy against binge drinking effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nalmefene alleviates the neuroimmune response to repeated binge-like ethanol exposure: A TSPO PET imaging study in adolescent rats. Tournier, N., Pottier, G., Caillé, F., et al.[2021]

Nalmefene, an opioid system regulator approved for treating alcohol dependence, was associated with fatigue and deep sleepiness in two patients after just two days of treatment.

Symptoms resolved quickly after discontinuing the drug, highlighting the need for careful monitoring of adverse effects when prescribing nalmefene for alcohol use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience about an unexpected adverse event during nalmefene treatment in two patients with alcohol use disorder. Milano, G., Zavan, V., Natta, WM., et al.[2016]

Citations

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2. bmcmedicine.biomedcentral.com bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0664-9

Evaluation in alcohol use disorders - BMC Medicine Nalmefene was the first treatment approved by the European Medicines Agency for reducing alcohol consumption in adult patients with alcohol dependence.

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A Double-blind, Placebo-Controlled Study of Oral ... Naltrexone (ReVia), an opioid antagonist, was approved in 1994 as a nonaversive prescription drug for alcohol dependence on the basis of 2 small placebo- ...

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Safety and Persistence of Nalmefene Treatment for Alcohol ... Short Summary: Two studies were used to evaluate the safety and persistence of nalmefene in the routine management of alcohol dependence in ...

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Home | SAMHSA - Substance Abuse and Mental Health ... SAMHSA leads efforts to advance behavioral health across the U.S., offering resources for mental health, substance use, and community well-being.

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Home‐based detoxification for individuals with alcohol or drug ... For example, patients with severe alcohol use disorder who undergo medically supervised detox before starting psychosocial treatment are significantly more ...

8. uptodate.com uptodate.com/contents/alcohol-use-disorder-pharmacologic-management

Alcohol use disorder: Pharmacologic management - UpToDate Medication development has focused on several neurotransmitter systems that mediate reinforcement, including opioid, glutamate, gamma-aminobutyric acid, and ...

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Pharmacotherapy for Alcohol Use Disorder: A Systematic ... These findings support the use of oral naltrexone at 50 mg/d and acamprosate as first-line pharmacotherapies for alcohol use disorder.