Ketone Supplementation for Enhancing Ketosis

(STAK: OK'd Trial)

Overseen By Jeff S Volek, PhD

Age: 18 - 65

Sex: Male

Trial Phase: Academic

Sponsor: Ohio State University

Disqualifiers: Hypertension, Diabetes, Neurologic, Psychiatric, others

Compensation: Varies

Number of Visits: 3

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how different ketone supplements affect metabolism and signaling processes in the body. It compares several types of ketone supplements, such as BHB Monoester and AcAc Diester, to assess their impact on blood sugar and acid balance. Men aged 20-30 with a BMI between 18 and 29 who can adhere to specific fasting and lifestyle guidelines may qualify. The goal is to identify effects common to all supplements and those unique to each one. As an unphased trial, this study allows participants to contribute to foundational research that could influence future dietary supplement recommendations.

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 you maintain your medication habits throughout the study. If you have unstable use of a medication that might affect the trial outcomes, you may be excluded.

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

Research shows that many ketone supplements, like those in this trial, have undergone safety testing in humans.

For the AcAc Diester, studies have shown that the FDA has granted it Generally Recognized as Safe (GRAS) status, meaning it is considered safe to consume.

The BHB Monoester, another ketone supplement in this trial, is safe and generally well-tolerated, though some people may experience mild side effects like stomach upset or diarrhea.

C6 Diester is a newer ketone ester, but early studies suggest it is safe for boosting blood ketone levels for energy.

Lastly, BDO, or R-1,3-butanediol, also holds GRAS status, indicating it is generally safe for human use based on current evidence.

Overall, these supplements have undergone safety testing, and while they are generally well-tolerated, some people might experience mild side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they promise a novel way to enhance ketosis by using different ketone esters and diesters. Unlike typical treatments that focus on dietary changes like the ketogenic diet, these treatments use compounds such as AcAc Diester, BHB Monoester, and C6 Diester. These compounds can potentially increase ketone levels in the blood more rapidly and efficiently. This means they could offer a quicker and more controlled way to achieve and maintain ketosis, which is particularly appealing for both therapeutic and performance-enhancing purposes. Additionally, the variety in the compounds being tested allows researchers to determine which formulation might be most effective or have the best safety profile.

What evidence suggests that this trial's treatments could be effective for enhancing ketosis?

Research has shown that different ketone supplements can effectively increase blood ketone levels, potentially offering various health benefits. In this trial, participants will receive one of several ketone supplements. The AcAc Diester, one of the supplements being tested, helps maintain ketosis—a state where the body uses fat for energy instead of carbohydrates—and may improve heart and muscle function. Another supplement, the BHB Monoester, quickly raises blood ketone levels and is known to be safe and easy to tolerate. The C8 Ketone Diester, also under study, quickly induces nutritional ketosis, which might benefit brain and heart health. R-1,3-Butanediol, another supplement in this trial, converts into ketones in the body, helping to maintain ketosis with potential benefits for metabolism and heart health. These supplements increase ketone levels, which could lead to better energy use in the body. ^{1 2 3 5 6}

Who Is on the Research Team?

Jeff S Volek, PhD

Principal Investigator

Ohio State University

Are You a Good Fit for This Trial?

This trial is for healthy males aged 20-30, with a BMI of 18-29 kg/m^2 who don't smoke or use cannabis, haven't used ketone supplements or followed a low-carb diet recently, and aren't taking part in other studies. They must be able to fast and avoid alcohol before test days.

Inclusion Criteria

I understand the study and have signed the consent forms.

I am male.

Your body mass index (BMI) is between 18 and 29.

Exclusion Criteria

Participant has a known allergy, intolerance, or sensitivity to any of the ingredients in the study beverages

Participant has had a blood draw or donation in the last 8 weeks

I have a serious stomach or intestine condition that could affect the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants consume different ketone esters and precursors, with repeated blood sampling and metabolic measurements

6 weeks

Multiple visits (in-person) every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• AcAc Diester
• BDO
• BHB Monoester
• C6 Diester

Trial Overview The study compares the effects of different Ketone Ester (KE) compounds and Butanediol (BDO), which are believed to affect metabolism differently. It's a full crossover study where participants will try all KE types at two serving sizes to see how they impact ketones, glucose, and acid-base balance.

How Is the Trial Designed?

Group I: C8 Ketone Di-ester 360mg/kg Experimental Treatment 7 Interventions

Group II: C8 Ketone Di-ester 180mg/kg Experimental Treatment 7 Interventions

Group III: BHB mono-ester 360mg/kg Experimental Treatment 7 Interventions

Group IV: BHB Mono-ester 180mg/kg Experimental Treatment 7 Interventions

Group V: AcAc Di-ester 360mg/kg Experimental Treatment 7 Interventions

Group VI: AcAc Di-ester 180mg/kg Experimental Treatment 7 Interventions

Group VII: (R)-1,3 butanediol 360mg/kg Experimental Treatment 7 Interventions

Group VIII: (R)-1,3 butanediol 180mg/kg Experimental Treatment 7 Interventions

Group IX: Control Placebo Group 8 Interventions

Who Is Running the Clinical Trial?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

Ohio State University Comprehensive Cancer Center

Lead Sponsor

Trials

350

Recruited

295,000+

Published Research Related to This Trial

Oral administration of the ketone ester BD-AcAc(2) significantly delayed the onset of CNS oxygen toxicity seizures in rats by increasing levels of acetoacetate and acetone, demonstrating a potential new strategy for seizure mitigation.

In contrast, another compound, 1,3-butanediol, induced ketosis but did not delay seizures, highlighting the specific efficacy of BD-AcAc(2) in enhancing seizure latency through its unique metabolic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. D'Agostino, DP., Pilla, R., Held, HE., et al.[2020]

In a study involving 16 male mice on a high-fat, high-sugar diet, the addition of the ketone diester BD-AcAc2 significantly reduced weight gain (only 13% increase compared to 56% in the control group) and markers of liver disease, indicating its potential efficacy in managing obesity-related liver issues.

The KE group showed significantly lower levels of hepatic inflammation and fibrosis compared to the control group, suggesting that BD-AcAc2 can effectively mitigate liver damage even when carbohydrate intake is not restricted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary ketone ester attenuates the accretion of adiposity and liver steatosis in mice fed a high-fat, high-sugar diet. Rushing, KA., Bolyard, ML., Kelty, T., et al.[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]

A synthetic ketone ester (BD-AcAc2) was found to effectively raise the seizure threshold in a rat model, indicating its potential as an anti-seizure treatment by elevating blood ketone levels.

The study showed that BD-AcAc2 increased blood β-hydroxybutyrate levels significantly compared to the control, suggesting that this compound could serve as a pharmacological alternative to the ketogenic diet for managing epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticonvulsant properties of an oral ketone ester in a pentylenetetrazole-model of seizure. Viggiano, A., Pilla, R., Arnold, P., et al.[2015]

A diet with 30% energy from the ketone ester BD-AcAc2 led to a significant 12% reduction in energy intake compared to the control group, resulting in lower body weight and fat mass in mice.

Diets with 20% and 25% energy from BD-AcAc2 also reduced body weight and fat mass without affecting energy intake or expenditure, suggesting that these concentrations can effectively promote weight loss independently of calorie consumption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concentration-Dependent Effects of a Dietary Ketone Ester on Components of Energy Balance in Mice. Deemer, SE., Davis, RAH., Gower, BA., et al.[2022]

Exogenous ketone drinks, such as ketone esters and ketone salts, effectively raise blood D-β-hydroxybutyrate (D-βHB) levels, with significant increases observed in a study of 15 participants, indicating a practical alternative to traditional ketogenic diets.

Both types of ketone drinks lowered blood glucose and triglyceride levels without causing adverse effects on blood electrolytes, suggesting they are safe and beneficial for metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

On the Metabolism of Exogenous Ketones in Humans. Stubbs, BJ., Cox, PJ., Evans, RD., et al.[2022]

In a 28-day study involving 59 healthy adults, the novel exogenous ketone diester bis-hexanoyl-(R)-1,3-butanediol (BH-BD) was found to be well-tolerated and safe, with no significant differences in tolerability scores compared to a placebo.

BH-BD effectively increased blood ketone levels one hour after consumption, indicating its potential for promoting nutritional ketosis without adverse effects on vital signs or laboratory measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. Chen, O., Blonquist, TM., Mah, E., et al.[2021]

In a study with conscious dogs, the ingestion of R,S-1,3-butanediol diacetoacetate induced ketosis, but the achieved level (0.8 mM) was lower than the levels (1-3 mM) seen in children on a ketogenic diet for epilepsy.

The study suggests that while the ketosis level in dogs was lower, humans might experience higher ketone body concentrations from the same doses of the ester, potentially making it a viable option for managing seizures in children with intractable epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dog model of therapeutic ketosis induced by oral administration of R,S-1,3-butanediol diacetoacetate. Puchowicz, MA., Smith, CL., Bomont, C., et al.[2022]

A novel ketone di-ester, bis hexanoyl (R)-1,3-butanediol (BH-BD), effectively raises blood levels of beta-hydroxybutyrate (BHB) to 0.8-1.7 mM in healthy adults, indicating successful induction of ketosis without dietary changes.

The study showed that higher doses of BH-BD (25g) resulted in greater increases in BHB levels compared to lower doses (12.5g), while also decreasing plasma glucose and free fatty acids, suggesting potential metabolic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bis Hexanoyl (R)-1,3-Butanediol, a Novel Ketogenic Ester, Acutely Increases Circulating r- and s-ß-Hydroxybutyrate Concentrations in Healthy Adults. Crabtree, CD., Blade, T., Hyde, PN., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9734240/

Exogenous Ketone Supplements in Athletic Contexts The ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (βHB) have pleiotropic effects in multiple organs including brain, heart, and skeletal muscle by ...

2. mdpi.com mdpi.com/2072-6643/17/10/1665

Effectiveness of Exogenous Ketone Salts in Enhancing ... Consuming ketone salts (KS) significantly increased plasma acetoacetate (AcAc) levels in healthy adults, an effect markedly greater than with a placebo, ...

3. ahajournals.org ahajournals.org/doi/10.1161/CIRCRESAHA.123.321872

Ketones and the Heart: Metabolic Principles ... The ketone bodies acetoacetate (AcAc) and D-ß-hydroxybutyrate (D ... The diester had more sustained ketosis than the monoester ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0022227520356571

Ketone body therapy: from the ketogenic diet to the oral ... Because the ketogenic diet (KD) is difficult to prepare and follow, and effectiveness of KB treatment in certain patients may be enhanced by raising plasma KB ...

5. frontiersin.org frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1485280/full

Exogenous ketone bodies and the ketogenic diet as a ... Ketosis was confirmed with serum BHBs. Of the 18 patients, 2 patients saw a significant reduction in their CARS score (>12 units), 8 patients ...

6. journals.lww.com journals.lww.com/acsm-csmr/fulltext/2020/07000/nutritional_ketosis_with_ketogenic_diets_or.4.aspx

Nutritional Ketosis with Ketogenic Diets or Exogenous... Encouragingly, some of the most well-characterized KEs have received Generally Recognized as Safe (GRAS) status by the FDA, such as the R,S-BD AcAc diester and ...