Ketone Ester for Alcoholism

Overseen By Gabriel Kass, M.A.

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University of Pennsylvania

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

Disqualifiers: Major psychiatric disorder, Epilepsy, Diabetes, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how a special drink, called a ketone ester, might assist people who regularly use alcohol. Researchers aim to determine if this drink affects the brain's reaction to alcohol and reduces cravings and consumption. Participants will try both the ketone ester and a similar-tasting placebo to compare effects. This trial is ideal for those with Alcohol Use Disorder (AUD) who consume at least 15 standard drinks a week and are not currently seeking treatment. As a Phase 2 and Phase 3 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group and is in the final step before FDA approval, offering a unique opportunity to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that the ketone ester "(R)-3-hydroxybutyl (R)-3-hydroxybutyrate" is generally safe for humans. In studies with healthy adults, participants tolerated this compound well. Another study found that using a ketone ester to increase blood ketone levels is a safe and simple method. Participants did not report major side effects from this treatment.

The treatment raises ketone levels in the body within one hour and works non-invasively, requiring no surgery or injections. This can reassure those concerned about more intrusive treatments. Overall, evidence suggests that this ketone ester is a safe option to consider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for alcoholism?

Unlike the standard treatments for alcoholism, which typically involve medications like naltrexone or acamprosate that target neurotransmitters to reduce cravings, the ketone ester treatment uses (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. This compound is designed to alter brain metabolism by increasing ketone levels, which may modulate brain energy use and impact alcohol cravings differently than traditional methods. Researchers are excited about this novel mechanism of action because it could offer a new way to address alcohol dependence, potentially leading to more effective treatments for those who do not respond well to existing therapies.

What evidence suggests that this treatment might be an effective treatment for alcoholism?

Research has shown that ketone esters, such as "(R)-3-hydroxybutyl (R)-3-hydroxybutyrate," can reduce alcohol consumption and cravings. In this trial, one group of participants will receive the ketone ester, while another group will receive an isocaloric dextrose placebo drink. Studies have found that this ketone ester can increase ketone levels in the brain, potentially lessening withdrawal symptoms and cravings in people with alcohol use disorder (AUD). Specifically, the ketone ester lowered alcohol craving scores from the baseline in a group with AUD. It also reduced blood sugar levels and increased a certain type of ketone in the blood. These findings suggest that ketone esters might help people drink less alcohol and manage their cravings. ^{1 3 6 7 8}

Who Is on the Research Team?

Corinde E Wiers, Ph.D.

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

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

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.

How Is the Trial Designed?

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.

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Collaborator

Trials

865

Recruited

1,091,000+

Published Research Related to This Trial

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]

In a study involving 14 healthy young adults, both ketone monoester (KME) and ketone monoester/salt (KMES) formulations significantly increased circulating R-beta-hydroxybutyrate (R-βHB) levels in a dose-dependent manner, with KME10 reaching a peak concentration of 2.4 mM after 15 minutes.

Both formulations were well-tolerated, but KMES was slightly more acceptable due to a better taste, while KME was associated with a more frequent decrease in appetite, indicating that user experience may vary between different ketone products.

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]

TCN006, a formulation of (R)-3-Hydroxybutyrate glycerides, was found to be safe in extensive toxicity studies on rats, with a no observed adverse effect level (NOAEL) established at 200,000 ppm, the highest dose tested.

The studies showed no signs of genotoxicity or ketoacidosis, even at high doses, indicating that TCN006 could be a safe option for enhancing ketone intake in humans.

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]

In a study of 55 alcohol-dependent patients treated for 3 months, the combination of gamma-hydroxybutyric acid (GHB) and naltrexone (NTX) was the most effective in maintaining abstinence, with 72.2% of patients remaining abstinent compared to 40% for GHB alone and only 5.9% for NTX alone.

The combination therapy not only showed higher abstinence rates but also suggested a synergistic effect, meaning that GHB and NTX work well together without interfering with each other's benefits.

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]

The novel ketone ester bis hexanoyl (R)-1,3-butanediol (BH-BD) effectively increases blood levels of beta-hydroxybutyrate (BHB) in a dose-dependent manner, as demonstrated in studies with Sprague Dawley rats and C57/BL6 mice.

BH-BD is well tolerated at all tested doses, and its metabolism involves hydrolysis into hexanoate and (R)-1,3-butanediol, which are then converted into BHB, indicating its potential as a safe energy substrate and signaling metabolite.

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]

Two validated LC-MS methods were developed to accurately measure ketone ester and its metabolites in human plasma, ensuring reliable pharmacokinetic profiling for potential therapeutic use.

The study found that ketone ester undergoes non-saturable metabolism in human plasma, indicating its metabolic stability at high concentrations, and that human serum albumin plays a role in its metabolism.

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]

The ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate effectively elevates blood ketone levels in healthy volunteers, reaching maximum plasma concentrations of 3.30 mM for β-hydroxybutyrate within 1-2 hours after ingestion.

This ketone monoester was generally well-tolerated over a 5-day period, although some gastrointestinal side effects were noted at higher doses, indicating it is a safe alternative to traditional ketogenic diets for enhancing physical and cognitive performance.

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 randomized double-blind study of 82 alcoholics over three months, those treated with gamma-hydroxybutyric acid showed significantly higher rates of abstinence (11 patients) and controlled drinking (15 patients) compared to the placebo group (2 and 6 patients, respectively).

Gamma-hydroxybutyric acid also effectively reduced alcohol cravings during the treatment period, suggesting its potential as a beneficial intervention for alcohol dependence, despite some transient side effects reported by a few patients.

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]

In a study of 179 patients with alcohol dependence, the sodium salt of 4-hydroxybutyric acid (GHB) was found to be effective in achieving complete abstinence during treatment, with 78% of patients remaining abstinent while on the medication.

The treatment was generally well-tolerated over a 6-month period, with no serious side effects reported, although 10.1% of patients experienced cravings for GHB and increased their doses significantly.

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]

A 28-day toxicity study in rats showed that (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester, is safe, as it did not cause any significant toxic effects or abnormalities in blood parameters, despite some differences observed.

In a developmental toxicity study, pregnant rats given the ketone monoester showed no adverse effects on pregnancy outcomes or fetal development, further supporting its safety for potential use.

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04616781

Ketone Ester Intervention in Alcohol Use Disorder The KE "(R)-3-hydroxybutyl (R)-3-hydroxybutyrate" is a safe, effective, and non-invasive way to increases ketone levels within 1 hr to concentrations similar to ...

2. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04616781/ketone-ester-intervention-in-alcohol-use-disorder

Ketone Ester Intervention in Alcohol Use Disorder The purpose of this research is to study how a nutritional ketone ester may effect brain function and alcohol consumption in regular alcohol ...

3. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/387124

Ketone Ester Intervention in Alcohol Use Disorder Primary outcome measures. Determine the effects of ketone ester "R)-3-hydroxybutyl (R)-3-hydroxybutyrate" (KE) on alcohol consumption (4 hours).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8670944/

Nutritional Ketosis as a Potential Treatment for Alcohol Use ... The nutritional supplement (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (Ketone Ester; KE) is a safe (13, 33), effective, and commercially available method ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37808798/

Pharmacokinetic effects of a single-dose nutritional ketone ... In the AUD group, KE reduced alcohol craving scores compared to baseline. KE decreased blood glucose levels and elevated blood β-hydroxybutyrate ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31655093/

Safety and tolerability of sustained exogenous ketosis ... We conclude that sustained exogenous ketosis using a ketone monoester is safe and well-tolerated by healthy adults.

7. withpower.com withpower.com/trial/phase-2-and-3-alcoholism-3-2021-ae274

Ketone Ester for Alcoholism 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 ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3810007/

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R) These results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels.