Ketone Supplement for Sleep Deprivation

(STAK-Sleep Trial)

Overseen By Madison L Kackley, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Ohio State University Comprehensive Cancer Center

Must not be taking: Diabetic medications

Disqualifiers: Sleeping disorders, Diabetes, Liver dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

60 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications, but it does require you to maintain your medication habits throughout the study.

What evidence supports the effectiveness of the ketone supplement treatment for sleep deprivation?

Research suggests that ketone bodies, like those in ketone supplements, may improve sleep quality by enhancing sleep efficiency and counteracting sleep disruptions, especially after strenuous activities. Additionally, ketone bodies have been linked to better sleep regulation and have shown potential benefits in treating sleep disorders. ^{1 2 3 4 5}

Is the ketone supplement safe for humans?

Research shows that ketone supplements, like ketone esters and diesters, are generally safe and well-tolerated in healthy adults. Some mild side effects, such as gastrointestinal discomfort, have been reported, but no serious safety concerns were found in studies lasting up to 28 days. ^{1 3 6 7 8}

How does the ketone supplement treatment for sleep deprivation differ from other treatments?

The ketone supplement treatment for sleep deprivation is unique because it uses ketone bodies, like β-hydroxybutyrate and acetoacetate, to provide an alternative energy source for the brain, potentially improving sleep regulation. Unlike traditional methods that may focus on sleep aids or lifestyle changes, this treatment elevates blood ketone levels through a meal replacement drink, offering a novel approach to managing sleep deprivation. ^{1 4 6 9 10}

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. There is some evidence that ketone ester supplements may lessen the adverse effects of sleep restriction. The main purpose of these supplements is to raise your blood concentration of ketones, which are safe, small molecules that appear in the blood during fasting, when following a ketogenic diet, or consuming ketone supplements. The main purpose of this study is to examine if ingesting a ketone ester supplement, twice daily, can improve cognitive and physical performance during short-term sleep restriction.

Research Team

Jeff S Volek, PhD

Principal Investigator

Ohio State University

Eligibility Criteria

This trial is for healthy adults aged 18-40, with a BMI of ≤35, who can follow study procedures like fasting and controlled feeding. It's not for those with psychiatric disorders, recent significant weight loss, sleep or gastrointestinal disorders, heavy alcohol use, metabolic diseases (except metformin users), current/recent ketogenic dieters, or pregnant/lactating women.

Inclusion Criteria

Participant understands the study procedures and signs forms providing informed consent to participate in the study and authorizes the release of relevant protected health information to the Investigator

Participant has no health conditions that would prevent completion of the study requirements as judged by the Investigator based on health history

Participant is willing and able to comply with all study procedures including fasting (>10 h; water only), no alcohol (>24 h), no exercise (>24 h), no acute illness and controlled feeding before each Test Day, maintain diet, exercise, medication, and supplement habits throughout the study

Exclusion Criteria

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

You drink more than 3 drinks a day or 14 drinks a week.

Have any major psychiatric disorders (e.g., schizophrenia, bipolar disorder)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a ketone ester or placebo supplement twice daily during short-term sleep restriction

4 weeks

Multiple visits for assessments and interventions

Washout

A 2-week washout period between crossover interventions

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ketone Supplement

Trial Overview The study tests if a ketone ester supplement taken twice daily can boost cognitive and physical performance when sleep is restricted. Participants will undergo various assessments including sleep monitoring, heart rate tracking, diet control and performance tests while experiencing short-term sleep deprivation.

Participant Groups

Group I: Ketone Ester First Experimental Treatment 13 Interventions

Patients will be randomize to take the ketone ester for the first trial of the intervention, then after a 2 week washout, participants will perform the same intervention but with a placebo

Group II: Placebo First Active Control 13 Interventions

Patients will be randomize to take the placebo for the first trial of the intervention, then after a 2 week washout, participants will perform the same intervention but with a ketone ester.

Who Is Running the Clinical Trial?

Ohio State University Comprehensive Cancer Center

Lead Sponsor

Trials

350

Recruited

295,000+

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

Findings from Research

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]

Sleep disorders are often overlooked and can include a variety of conditions such as insomnia and sleep apnea, highlighting the need for better recognition and treatment.

The ketogenic diet (KD), which is high in fats and low in carbohydrates, has shown promise in treating sleep disorders, particularly obstructive sleep apnea, by potentially influencing sleep homeostasis through the effects of ketone bodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is there a relationship between the ketogenic diet and sleep disorders? Barrea, L., Pugliese, G., Frias-Toral, E., et al.[2022]

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]

Sleep deprivation in mice led to increased levels of ketone bodies, particularly acetoacetate, which suggests a link between energy metabolism and sleep regulation.

Injecting acetoacetate into the brain significantly enhanced slow-wave sleep activity and reduced glutamate release, indicating that acetoacetate may play a crucial role in maintaining sleep homeostasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone body metabolism and sleep homeostasis in mice. Chikahisa, S., Shimizu, N., Shiuchi, T., et al.[2015]

The medium-chain triglyceride ketogenic diet (MCT-KD) increased blood ketone levels without causing carbohydrate starvation, indicating that ketosis can occur independently of a fasting state.

While the MCT-KD did not significantly alter circadian rhythms or core clock gene expression, it was associated with a reduction in REM sleep duration and slightly decreased wheel-running activity in mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A ketogenic diet containing medium-chain triglycerides reduces REM sleep duration without significant influence on mouse circadian phenotypes. Zhuang, H., Fujikura, Y., Ohkura, N., 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]

A study involving 24 healthy adults showed that consuming a ketone monoester three times a day for 28 days safely elevated blood ketone levels without affecting body weight, blood glucose, cholesterol, or kidney function.

The only reported side effect was mild nausea in a small number of instances, indicating that the ketone monoester is well-tolerated for sustained use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Soto-Mota, A., Vansant, H., Evans, RD., et al.[2020]

In a 24-month study involving two patients with Alzheimer's disease, the administration of (R)-3-oxobutyl 3-hydroxybutanoate (OBHB) was well tolerated with no adverse effects, suggesting its safety as a treatment option.

Both patients showed significant improvements in mood, behavior, and cognitive performance, alongside a reduction in cholesterol levels, indicating that OBHB may effectively manage hyperketonemia and enhance quality of life in Alzheimer's patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

(R)-3-oxobutyl 3-hydroxybutanoate (OBHB) induces hyperketonemiain Alzheimer's disease. Chu, CB., Jiao, LD.[2020]

In a study involving seven male military personnel, a ketogenic diet (KD) significantly increased levels of D-β-hydroxybutyrate and decreased blood glucose compared to a carbohydrate-based diet, indicating a metabolic advantage during sleep deprivation.

The KD improved cognitive performance, mood, and reduced sleepiness during 36 hours of extended wakefulness, showing better results in tasks measuring attention and memory compared to the carbohydrate diet.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of a 2 week ketogenic diet, versus a carbohydrate-based diet, on cognitive performance, mood and subjective sleepiness during 36 h of extended wakefulness in military personnel: An exploratory study. Henderson, LR., van den Berg, M., Shaw, DM.[2023]

Both powdered and ready-to-drink (RTD) formulations of the novel ketone ester BH-BD effectively induce ketosis in healthy adults, increasing blood beta-hydroxybutyrate (BHB) levels within approximately 15 minutes after consumption.

The study found that a higher dose of the powdered formulation (25g) resulted in significantly greater BHB concentrations compared to lower doses and the RTD version, but both formulations were equally effective in raising BHB levels without affecting blood glucose concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Powder Formulation of the Ketone Ester, Bis Hexanoyl (R)-1,3-Butanediol, Rapidly Increases Circulating ß-Hydroxybutyrate Concentrations in Healthy Adults. Nieman, KM., Anthony, JC., Stubbs, BJ.[2023]

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. England pubmed.ncbi.nlm.nih.gov

Is there a relationship between the ketogenic diet and sleep disorders? [2022]

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

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

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

Ketone body metabolism and sleep homeostasis in mice. [2015]

5. Canada pubmed.ncbi.nlm.nih.gov

A ketogenic diet containing medium-chain triglycerides reduces REM sleep duration without significant influence on mouse circadian phenotypes. [2023]

6. 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]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. [2020]

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

(R)-3-oxobutyl 3-hydroxybutanoate (OBHB) induces hyperketonemiain Alzheimer's disease. [2020]

9. England pubmed.ncbi.nlm.nih.gov

The effect of a 2 week ketogenic diet, versus a carbohydrate-based diet, on cognitive performance, mood and subjective sleepiness during 36 h of extended wakefulness in military personnel: An exploratory study. [2023]

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

A Novel Powder Formulation of the Ketone Ester, Bis Hexanoyl (R)-1,3-Butanediol, Rapidly Increases Circulating ß-Hydroxybutyrate Concentrations in Healthy Adults. [2023]