Ketone Ester for Alcoholism

Recruiting in Palo Alto (17 mi)

Overseen by Corinde E Wiers, Ph.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: University of Pennsylvania

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

Disqualifiers: Major psychiatric disorder, Epilepsy, Diabetes, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The purpose of this research is to study how a nutritional ketone ester may effect brain function and alcohol consumption in regular alcohol users. The study will see how the brain responds, once after drinking the ketone ester and once after drinking a "placebo", which will look and taste the same as the ketone ester drink. Metabolic ketosis induced by a ketogenic diet has been previously shown to elevate brain ketone bodies and reduce alcohol withdrawal symptoms in humans with AUD, and reduce alcohol consumption in alcohol-dependent rats. The study investigates whether metabolic ketosis induced by a one-dose nutritional ketone ester (KE) reduces brain reactivity to alcohol cues (fMRI), alcohol craving and alcohol consumption in humans with AUD, and if KE elevates ketone bodies using proton spectroscopy. This study uses a double blind, random ordered, 2-way crossover design in n=20 non-treatment seeking AUD who come in on two separate testing days: on one testing day the participants consume KE ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate), and on another testing day a drink with isocaloric dextrose (DEXT), after which participants are scanned for 1H-MRS and fMRI and complete an alcohol consumption paradigm each day after scanning.

Will I have to stop taking my current medications?

The trial requires participants to refrain from using psychoactive medications or any medication that may affect study results within 24 hours of MRI procedures. If you are taking such medications, you may need to stop or adjust them before participating.

What data supports the effectiveness of the drug (R)-3-hydroxybutyl (R)-3-hydroxybutyrate for alcoholism?

The research does not directly address the effectiveness of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate for alcoholism, but it shows that gamma-hydroxybutyric acid (GHB), a similar compound, has been effective in reducing alcohol craving and maintaining abstinence in alcohol-dependent patients. ^{1 2 3 4 5}

Is (R)-3-hydroxybutyl (R)-3-hydroxybutyrate safe for human use?

Research shows that (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, also known as ketone ester, is generally safe for humans. In studies with healthy adults, it was well-tolerated, though some people experienced mild stomach issues at high doses. Animal studies also support its safety, with no significant harmful effects observed even at high intake levels. ^{1 3 6 7 8}

How is the ketone ester treatment for alcoholism different from other treatments?

The ketone ester treatment for alcoholism is unique because it uses a compound that elevates blood ketone levels, which may help improve cognitive and physical performance, unlike traditional treatments that focus on reducing alcohol cravings or blocking alcohol's effects. This treatment is administered as a meal replacement drink, offering a novel approach compared to standard medications. ^{1 2 7 9 10}

Research Team

Corinde E Wiers, Ph.D.

Principal Investigator

University of Pennsylvania

Eligibility Criteria

This trial is for adults aged 21-65 with Alcohol Use Disorder (AUD) who consume at least 15 alcoholic drinks weekly and are not seeking treatment. Participants must be willing to use reliable birth control if applicable, have no major psychiatric disorders requiring hospitalization or daily medication, and cannot have conditions like epilepsy, diabetes, liver disease, or a history of severe head trauma.

Inclusion Criteria

Willingness to provide signed, informed consent and commit to completing the procedures in the study

Average weekly ethanol consumption of at least 15 standard drinks over the past month prior to consent (self-report)

I am between 21 and 65 years old.

Exclusion Criteria

Urine drug screen positive for recent use of opioids, cocaine, or amphetamines on study visits (may be repeated once and if the result is negative on repeat it is not exclusionary)

Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head, fear of enclosed spaces, or other standard contraindication to MRI (self-report checklist)

You have a fear of small spaces (claustrophobia) or any other medical condition that makes it difficult for you to lie comfortably on your back for up to 2 hours inside an MRI machine.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Testing Day 1

Participants consume a ketone ester drink, undergo MRI scanning, and participate in an alcohol consumption paradigm

1 day

1 visit (in-person)

Testing Day 2

Participants consume a placebo drink, undergo MRI scanning, and participate in an alcohol consumption paradigm

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the testing days

4 weeks

Treatment Details

Interventions

• (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (Other)

Trial Overview Researchers are testing whether a one-time dose of Ketone Ester can reduce brain reactivity to alcohol cues and craving in people with AUD using fMRI scans. The study compares the effects of Ketone Ester against an isocaloric dextrose placebo in a double-blind crossover design involving two separate test days.

Participant Groups

Group I: Ketone ester with alcohol consumption Active Control 2 Interventions

Drink a single dose of ketone ester 1.9 kcal/kg, complete 1 hour MRI scan, drink an alcohol priming dose to produce a 0.03 g/dl breath alcohol concentration (BrAC) followed by a choice paradigm in which subjects receive 2 trays of 4 min-drinks each beverages Each min-drink would achieve 0.015 g/ld BrAC over a 1 hour period to achieve a max 0.1 g/dl BrAC.

Group II: Isocaloric dextrose placebo drink with alcohol consumption Placebo Group 2 Interventions

Drink a single dose of Isocaloric dextrose placebo drink, complete 1 hour MRI scan, drink an alcohol priming dose to produce a 0.03 g/dl breath alcohol concentration (BrAC) followed by a choice paradigm in which subjects receive 2 trays of 4 min-drinks each beverages Each min-drink would achieve 0.015 g/ld BrAC over a 1 hour period to achieve a max 0.1 g/dl BrAC.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Pennsylvania Center for Studies of Addiction Philadelphia, PA

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2118

Patients Recruited

45,270,000+

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Collaborator

Trials

865

Patients Recruited

1,091,000+

Findings from Research

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Clarke, K., Tchabanenko, K., Pawlosky, R., et al.[2022]

In a study of 86 alcoholics, treatments with g-hydroxybutyrate (GHB), naltrexone (NTX), and disulfiram (DSF) were all effective in reducing alcohol intake and maintaining abstinence over 12 months.

GHB showed the most significant effects in reducing craving and improving biological markers of alcohol abuse, suggesting it may serve as both an anticraving agent and a cellular protector.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing treatments of alcoholism on craving and biochemical measures of alcohol consumptionst. Nava, F., Premi, S., Manzato, E., et al.[2015]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing and combining gamma-hydroxybutyric acid (GHB) and naltrexone in maintaining abstinence from alcohol: an open randomised comparative study. Caputo, F., Addolorato, G., Stoppo, M., et al.[2015]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

gamma-Hydroxybutyric acid in the treatment of alcohol dependence: a double-blind study. Gallimberti, L., Ferri, M., Ferrara, SD., et al.[2019]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open multicentric study evaluating 4-hydroxybutyric acid sodium salt in the medium-term treatment of 179 alcohol dependent subjects. GHB Study Group. Addolorato, G., Castelli, E., Stefanini, GF., et al.[2019]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity Investigations of (R)-3-Hydroxybutyrate Glycerides In Vitro and in Male and Female Rats. Dolan, LC., Karikachery, AR., Thipe, VC., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative Determination of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate (Ketone Ester) and Its Metabolites Beta-hydroxybutyrate, 1-3-Butanediol, and Acetoacetate in Human Plasma Using LC-MS. Panse, N., Halquist, M., Gerk, PM.[2023]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Clarke, K., Tchabanenko, K., Pawlosky, R., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. Bolyard, ML., Graziano, CM., Fontaine, KR., et al.[2023]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol. Stubbs, BJ., Blade, T., Mills, S., et al.[2021]

References

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

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. [2022]

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

Comparing treatments of alcoholism on craving and biochemical measures of alcohol consumptionst. [2015]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Comparing and combining gamma-hydroxybutyric acid (GHB) and naltrexone in maintaining abstinence from alcohol: an open randomised comparative study. [2015]

4. England pubmed.ncbi.nlm.nih.gov

gamma-Hydroxybutyric acid in the treatment of alcohol dependence: a double-blind study. [2019]

5. England pubmed.ncbi.nlm.nih.gov

An open multicentric study evaluating 4-hydroxybutyric acid sodium salt in the medium-term treatment of 179 alcohol dependent subjects. GHB Study Group. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Toxicity Investigations of (R)-3-Hydroxybutyrate Glycerides In Vitro and in Male and Female Rats. [2022]

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

Quantitative Determination of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate (Ketone Ester) and Its Metabolites Beta-hydroxybutyrate, 1-3-Butanediol, and Acetoacetate in Human Plasma Using LC-MS. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. [2023]

10. England pubmed.ncbi.nlm.nih.gov

In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol. [2021]