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?

This trial aims to determine if certain diets and ketone supplements can reduce issues caused by sleep deprivation, such as difficulty focusing and increased errors. Participants will follow one of three regimens: a ketogenic diet (low-carb, high-fat), a Mediterranean diet with ketone ester supplements, or a Mediterranean diet with a placebo. The trial seeks to discover if these methods can alleviate the effects of reducing sleep by half for five days. Individuals who typically sleep 7 hours a night, are healthy, and can adhere to a specific diet for about 9 weeks may be suitable candidates. As an unphased trial, this study provides a unique opportunity to contribute to innovative research on diet and 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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both ketogenic diets and ketone esters, which are supplements that increase ketone levels in the blood, are generally safe for people. Studies have found that ketogenic diets might improve sleep quality and reduce daytime sleepiness, indicating their safety. Another study found that people on ketogenic diets experienced positive health effects, with no major negative effects reported.

For ketone esters, research indicates they can enhance sleep quality after exercise. In one study, older adults safely consumed up to 25 grams per day of ketone esters without major side effects. Further findings suggest that ketone esters effectively raise blood ketone levels and are usually well-tolerated, with fewer side effects compared to other ketone supplements.

Overall, this evidence suggests that both ketogenic diets and ketone esters are safe for most people, with few negative effects reported in studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments being studied for sleep deprivation because they explore dietary approaches that could offer unique benefits over current strategies like medication or behavioral interventions. The Ketogenic Diet Arm focuses on achieving nutritional ketosis, which may improve energy levels and cognitive function during sleep deprivation by providing a steady supply of ketones as an alternative energy source for the brain. The Mediterranean Diet + Ketone Ester arm combines a heart-healthy Mediterranean diet with ketone esters, potentially enhancing brain energy metabolism and reducing the negative effects of sleep loss. These dietary interventions could offer a more natural and sustainable way to manage sleep deprivation compared to traditional treatments.

What evidence suggests that this trial's treatments could be effective for sleep deprivation?

Research has shown that both ketogenic diets and ketone ester supplements, studied in this trial, might help with sleep problems caused by insufficient rest. Participants in the ketogenic diet arm will follow a diet that has improved sleep quality and prevented cognitive issues linked to sleep deprivation. Meanwhile, those in the Mediterranean Diet + Ketone Ester arm will receive ketone ester supplements, which have improved sleep duration and quality, especially after intense exercise. These supplements might also reduce the negative effects of sleep deprivation. Both methods increase ketones in the blood, potentially enhancing brain function under stress. Overall, evidence suggests these treatments could effectively manage sleep deprivation challenges. ^{1 6 7 8 9}

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

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]

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]

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 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]

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 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]

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

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Exogenous Ketosis Improves Sleep Efficiency and ... These data indicate that KE ingestion improves sleep efficiency and quality after high-intensity exercise.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06075914

Ketone Conferred Resiliency Against Sleep Restriction ... 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 ...

3. frontiersin.org frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2022.998292/full

Ketogenic diet prevents chronic sleep deprivation-induced ... The results showed that KD can prevent the cognitive deficiency, amyloid deposition and hyperphosphorylated tau induced by chronic SD. Analysis ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10210275/

Effects of ketogenic diet on health outcomes: an umbrella ... With regards to KD effects on lipid profiles, our results demonstrate an effective reduction in serum triglyceride levels with 3 months of ...

5. translational-medicine.biomedcentral.com translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04280-7

Can the ketogenic diet improve our dreams? Effect of very low ... In conclusion, VLCKD determined an improvement of sleep quality in women with overweight and obesity, that was mostly mediated by the reduction ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10574428/

Ketogenic Diet and Multiple Health Outcomes: An Umbrella ... Numerous studies have examined the effects of ketogenic diets (KD) on health-related outcomes through meta-analyses.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9473641/

Ketogenic dietary lifestyle intervention effects on sleep ... The MCI Sleep Study assesses longitudinal changes in objective and subjective measures of sleep between two investigational diet groups.

8. sciencedirect.com sciencedirect.com/science/article/pii/S1389945723003945

Ketogenic diet may improve sleep quality and daytime ... After ketogenic diet, patients reported lower prevalence of poor sleep quality and daytime somnolence.

9. bmcmedicine.biomedcentral.com bmcmedicine.biomedcentral.com/articles/10.1186/s12916-023-02874-y

Effects of ketogenic diet on health outcomes: an umbrella ... This umbrella review found beneficial associations of KD supported by moderate to high-quality evidence on seizure and several cardiometabolic parameters.