Ketone Ester + Nutritional Intervention for Sleep Deprivation

Overseen By Madison L Kackley, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Ohio State University

Must not be taking: Diabetic medications

Disqualifiers: Sleeping disorders, Diabetes, Liver, others

Compensation: Varies

Number of Visits: 11

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Sleep deprivation is a major problem in military populations. Some major consequences of sleep loss are inability to concentrate, poor work efficiency, and increase in errors during daily tasks. Ketogenic supplementation is speculated to alleviate some sleep deprivation issues via action of ketones. Ketones are small molecules that appear in the blood when following a ketogenic diet or consuming ketone supplements. The goal of this project is to find out if diet and/or ketones can improve sleep deprivation detriments over 5 days of sleep restriction (-50% from habitual sleep).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are using diabetic medications other than metformin, you may not be eligible to participate.

Is the Ketone Ester + Nutritional Intervention safe for humans?

Research shows that ketone esters, like bis-hexanoyl-(R)-1,3-butanediol and (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, are generally safe and well-tolerated in healthy adults, with no significant changes in vital signs or lab measurements. Some mild gastrointestinal effects were reported at high doses, but overall, these supplements are considered safe for increasing blood ketone levels. ^{1 2 3 4 5}

How does the Ketone Ester + Nutritional Intervention treatment for sleep deprivation differ from other treatments?

This treatment is unique because it uses ketone esters to quickly induce a state of ketosis, which may improve sleep quality by counteracting disruptions caused by factors like strenuous exercise. Unlike traditional methods that require dietary changes, this approach allows for rapid ketosis through oral supplementation, potentially offering a novel way to enhance sleep without significant lifestyle alterations. ^{1 2 5 6 7}

What data supports the effectiveness of the treatment Ketone Ester + Nutritional Intervention for Sleep Deprivation?

Research suggests that ketone bodies, which can be increased through ketone ester intake, may improve sleep quality and counteract sleep disruptions, especially after strenuous exercise. This indicates potential benefits for sleep deprivation. ^{1 2 4 5 7}

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 adults aged 18-40 with a BMI of 20-35, who sleep at least 7 hours nightly and are willing to undergo about 9 weeks of testing with provided food. Excluded are those with sleeping or major psychiatric disorders, certain dietary habits or conditions, recent significant weight loss, pregnancy, excessive alcohol consumption, or metabolic/endocrine dysfunctions.

Inclusion Criteria

You need to sleep for at least 7 hours each night.

Willing to adhere to all study procedures

I am healthy and between 18 to 40 years old.

Exclusion Criteria

Have any conditions or contraindications to blood draws

You have a BMI over 35.

Gastrointestinal disorders or food allergies that would interfere with consuming the study supplements

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo baseline assessments including familiarization with physical performance tests and baseline cognitive and physical testing

1 day

1 visit (in-person)

Sleep Restriction and Testing

Participants undergo a 5-day sleep restriction protocol with cognitive and physical performance testing

5 days

5 visits (in-person)

Feeding Intervention

Participants follow a 6-week diet intervention with either ketogenic diet, Mediterranean diet with ketone ester, or Mediterranean diet with placebo

6 weeks

Weekly food pickup

Second Sleep Restriction and Testing

Participants replicate the 5-day sleep restriction protocol with cognitive and physical performance testing after the feeding intervention

5 days

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the intervention

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ketogenic Intervention
• Ketone Ester
• Mediterranean Intervention
• Placebo

Trial Overview The study investigates if diets (Mediterranean or Ketogenic) or ketone supplements can mitigate the negative effects of sleep deprivation over five days where participants get half their usual amount of sleep. Participants will receive either a ketone ester supplement, Mediterranean diet intervention, ketogenic diet intervention, or placebo.

How Is the Trial Designed?

Group I: Ketogenic Diet Arm Experimental Treatment 1 Intervention

The goal of the KD is to have participants achieve consistent blood BHB ≥0.5 mM; preferably in the range of \>1 to 3 mM. We will measure ketones daily via finger stick to provide individual feedback and provide a quantitative measure of compliance. The KD will consist of approximately 50 g carbohydrate and 1.5 g/kg reference weight protein. These may be adjusted based on daily BHB readings. Fat will comprise the remaining calories with an emphasis on monounsaturated and saturated sources from whole foods. A wide range of foods will be incorporated including non-starchy vegetables, fruits (berries, olives, tomatoes, lemons/limes), meats (beef, chicken, pork, fish, lamb), nuts and seeds, oils (olive, canola, coconut), cheese, butter, cream, eggs, and fatty fish (salmon, sardines). Nutritional ketosis is associated with natriuresis that will lead to sodium and fluid loss if the extra sodium excreted is not compensated, thus slightly higher sodium and potassium intakes will be required.

Group II: Mediterranean Diet + Ketone Ester Active Control 2 Interventions

The MD+KE arm will consume the exact same diet as the MD+PL group with the exception they will consume two daily doses of KE instead of the placebo.

Group III: Mediterranean Diet + Placebo Placebo Group 2 Interventions

The MD+PL arm will be modeled after a Mediterranean style eating pattern. It will contain the same amount of protein as the KD, but with slight variations in protein sources, including limiting red meat to 1x/wk. The diet will provide unprocessed, higher-fiber foods with emphasis on vegetables, fruits, nuts and seeds, legumes, tubers, whole grains, and fish and seafood. Poultry, eggs, cheese, and yogurt will be included in moderate amounts. Use of olive oil and other monounsaturated fat sources (e.g., avocados and olives) will be encouraged while keeping added sugars to a minimum and avoiding highly processed foods (refined grains, fruit juice, processed meats). Saturated fat will be \<10% of energy. We will include adequate omega-3 fats (e.g., salmon). No alcohol will be included in both diets, but we will track consumption. This group will also consume two daily doses of placebo.

Who Is Running the Clinical Trial?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

Published Research Related to This Trial

A one-day ketogenic diet significantly increased total energy expenditure by about 110 calories compared to an isocaloric control diet, suggesting it may help with energy balance.

Supplementation with exogenous ketone salts did not enhance energy expenditure or appetite regulation compared to the isocaloric control diet, indicating that they may not provide additional benefits in energy balance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of one-day fasting, ketogenic diet or exogenous ketones on control of energy balance in healthy participants. Hägele, FA., Dörner, R., Koop, J., et al.[2023]

In a study involving 10 well-trained cyclists, ketone ester (KE) intake significantly improved sleep efficiency and quality after strenuous exercise, counteracting disruptions like reduced REM sleep and increased wakefulness.

The positive effects of KE on sleep were linked to increased dopamine excretion, suggesting that KE may enhance sleep regulation mechanisms following high-intensity workouts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exogenous Ketosis Improves Sleep Efficiency and Counteracts the Decline in REM Sleep after Strenuous Exercise. Robberechts, R., Albouy, G., Hespel, P., et al.[2023]

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]

Oral administration of exogenous ketone supplements over 28 days effectively induced sustained nutritional ketosis in male rats, achieving ketone levels greater than 0.5 mM without the need for carbohydrate restriction.

The study showed that these supplements led to a rapid increase in β-hydroxybutyrate (βHB) levels and a decrease in blood glucose, while having minimal impact on lipid levels, indicating their potential safety and efficacy for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. Kesl, SL., Poff, AM., Ward, NP., et al.[2020]

The ketogenic diet and exogenous ketone supplements can effectively increase serum ketone levels, providing an alternative energy source for high-demand tissues like the brain and heart, which may enhance overall health.

Nutritional ketosis has shown potential therapeutic benefits for various conditions, including heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders, suggesting a growing interest in its application for precision nutrition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention. Saris, CGJ., Timmers, S.[2022]

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]

Oral administration of the ketone ester (KE) significantly increases ketosis levels in non-fasted mice, reaching a peak of 6.83 mmol/L within 30 minutes, indicating its rapid effectiveness in generating ketone bodies.

The study reveals that KE enhances brain metabolism by increasing acetyl-CoA and citric cycle intermediates, which may inhibit glycolysis and suggest a potential therapeutic role for KE in acute neurological diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ingested Ketone Ester Leads to a Rapid Rise of Acetyl-CoA and Competes with Glucose Metabolism in the Brain of Non-Fasted Mice. Suissa, L., Kotchetkov, P., Guigonis, JM., et al.[2021]

Citations

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

Impact of one-day fasting, ketogenic diet or exogenous ketones on control of energy balance in healthy participants. [2023]

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

Exogenous Ketosis Improves Sleep Efficiency and Counteracts the Decline in REM Sleep after Strenuous Exercise. [2023]

3. Switzerland 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. [2021]

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

Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. [2020]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

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

7. Switzerland pubmed.ncbi.nlm.nih.gov

Ingested Ketone Ester Leads to a Rapid Rise of Acetyl-CoA and Competes with Glucose Metabolism in the Brain of Non-Fasted Mice. [2021]