Mavoglurant for Alcoholism

Overseen By Godfrey Pearlson, M.D

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Yale University

Must not be taking: Antidepressants, Antipsychotics

Disqualifiers: Psychotic disorder, Severe AUD, others

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

Compensation: Varies

Number of Visits: 2

Duration: 2 weeks

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The purpose of this study is to evaluate the role of Mavoglurant in clarifying the neurobiology of alcoholism risk. This is a one-site, randomized, within subjects, counterbalanced double-blind study of a single dose (200mg) of Mavoglurant and placebo.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it requires that your medication treatment is stable for 6 weeks before joining the study. This suggests you should not change your medications during this time.

How does the drug Mavoglurant work for alcoholism?

Mavoglurant is unique because it targets the mGluR1 receptor, which is involved in the brain's response to alcohol. This drug works by modulating glutamate neurotransmission, potentially reducing the motivation to consume alcohol, which is different from traditional treatments that often focus on managing withdrawal symptoms or blocking the effects of alcohol. ^{1 2 3 4 5}

Who Is on the Research Team?

Godfrey D Pearlson, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for individuals aged 18-45 with an IQ over 70, who can follow study procedures and have no major neurological disorders, medical conditions like cancer, significant head trauma, or metal implants. Participants must test negative for drugs/alcohol and women must not be pregnant nor planning to become so during the trial.

Inclusion Criteria

Stable medication treatment 6 weeks prior to study enrollment

Negative urine drug and breathe alcohol test at time of MRI scan

I have no known allergies or reactions to the study medication.

Exclusion Criteria

I have not been diagnosed with a psychotic, mood, or anxiety disorder.

Other specific fMRI exclusions include metal devices, clips or fragments in body (orbital xray performed if needed)

I had a head injury with unconsciousness over 30 minutes or a recent concussion.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of Mavoglurant or placebo in a double-blind, randomized, counterbalanced manner, with two separate visits separated by 1 week.

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, focusing on changes in BOLD activation and brain function related to alcoholism vulnerability.

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Mavoglurant (AFQ056)
• Placebo

Trial Overview The study tests Mavoglurant's effects on alcoholism risk by comparing it against a placebo in a controlled environment. Each participant will receive both treatments at different times (200mg dose) without knowing which one they're getting first.

How Is the Trial Designed?

Group I: FHP; Placebo-Mavoglurant Experimental Treatment 2 Interventions

Family History Positive (FHP) or alcoholism will be given a single dose of placebo then AFQ056 (200 mg) in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.

Group II: FHP; Mavoglurant-Placebo Experimental Treatment 2 Interventions

Family History Positive (FHP) for alcoholism will be given a single dose of AFQ056 (200 mg) then placebo in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.

Group III: FHN; Placebo-Mavoglurant Experimental Treatment 2 Interventions

Family History Negative (FHN) for alcoholism will be given a single dose of placebo then AFQ056 (200 mg) in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.

Group IV: FHN; Mavoglurant-Placebo Experimental Treatment 2 Interventions

Family History Negative (FHN) for alcoholism will be given a single dose of AFQ056 (200 mg) then placebo in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.

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

The study found that the mGluR1 negative allosteric modulator JNJ-16259685 effectively reduced alcohol consumption in mice, indicating its potential as a treatment for alcohol use disorders.

The reduction in alcohol intake was linked to mGluR1-PLC signaling in the nucleus accumbens, and this effect depended on the presence of the Homer2 protein, highlighting a specific neuroanatomical and molecular mechanism involved in alcohol reinforcement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mGluR1 within the nucleus accumbens regulates alcohol intake in mice under limited-access conditions. Lum, EN., Campbell, RR., Rostock, C., et al.[2021]

Low concentrations of ethanol (EtOH) significantly reduce NMDA receptor-mediated excitatory postsynaptic potentials (EPSPs) in the nucleus accumbens (NAcc) neurons, suggesting a mechanism by which EtOH may influence reward pathways associated with addiction.

The effects of EtOH on NMDA currents are dose-dependent and occur independently of opioid receptors, indicating that EtOH may modulate glutamate signaling both pre- and postsynaptically, which could contribute to its reinforcing properties in alcohol use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ethanol inhibits glutamatergic neurotransmission in nucleus accumbens neurons by multiple mechanisms. Nie, Z., Madamba, SG., Siggins, GR.[2018]

In a preclinical study with male Long Evans rats, the mixed mGlu4/mGlu7 agonist LSP2-9166 significantly reduced ethanol self-administration and motivation for ethanol, suggesting its potential as a treatment for alcohol addiction.

The study demonstrated that LSP2-9166 effectively decreased the reacquisition of ethanol self-administration after a period of abstinence, supporting the idea that targeting mGlu receptors could help prevent relapse in addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological activation of mGlu4 and mGlu7 receptors, by LSP2-9166, reduces ethanol consumption and relapse in rat. Lebourgeois, S., Vilpoux, C., Jeanblanc, J., et al.[2018]

The cyclized dipeptide glycyl-L-glutamine (c-GQ) significantly reduced ethanol consumption in both high-drinking (P) and low-drinking (Sprague-Dawley) rats, with an average decrease of 34.4% and 39.4% respectively after peripheral injections.

These results suggest that c-GQ has therapeutic potential for reducing alcohol intake, indicating its effectiveness across different drinking behaviors in rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclo-glycyl-glutamine inhibits ethanol intake in P and Sprague-Dawley rats. Resch, GE., Simpson, CW.[2018]

The mu-opioid receptor antagonist CTOP significantly reduced alcohol consumption in both male and female AA rats over three days, indicating its potential as a treatment for alcohol use.

In contrast, the delta-opioid receptor antagonist ICI 174,864 had no effect on alcohol drinking in males and caused adverse effects, such as hind limb dysfunction, in many females, highlighting the safety concerns associated with targeting delta-opioid receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Involvement of mu-opioid receptors in alcohol drinking by alcohol-preferring AA rats. Hyytiä, P.[2019]

Citations

1. England pubmed.ncbi.nlm.nih.gov

mGluR1 within the nucleus accumbens regulates alcohol intake in mice under limited-access conditions. [2021]

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

Ethanol inhibits glutamatergic neurotransmission in nucleus accumbens neurons by multiple mechanisms. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Pharmacological activation of mGlu4 and mGlu7 receptors, by LSP2-9166, reduces ethanol consumption and relapse in rat. [2018]

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

Cyclo-glycyl-glutamine inhibits ethanol intake in P and Sprague-Dawley rats. [2018]

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

Involvement of mu-opioid receptors in alcohol drinking by alcohol-preferring AA rats. [2019]