Ketone Supplementation for Enhancing Ketosis
(STAK: OK'd Trial)
Recruiting in Palo Alto (17 mi)
Overseen ByJeff S Volek, PhD
Age: 18 - 65
Sex: Male
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Ohio State University
Disqualifiers: Hypertension, Diabetes, Neurologic, Psychiatric, others
Trial Summary
What is the purpose of this trial?This trial tests different types of ketone supplements and a precursor to see how they affect metabolism. The study involves participants who meet specific health and dietary criteria. These supplements increase ketone levels in the blood, offering an alternative energy source to glucose.
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.
What data supports the effectiveness of the treatment Ketone Supplementation for Enhancing Ketosis?
Research shows that ketone esters, like the ones in this treatment, can increase blood ketone levels, which may help reduce seizures in epilepsy and decrease body weight and liver fat in mice. Additionally, ketone drinks have been shown to effectively induce ketosis in humans, which is linked to various health benefits.
12345Is ketone supplementation safe for humans?
Research shows that ketone supplementation, such as (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, is generally safe and well-tolerated in humans, although some people may experience mild stomach issues when consuming large amounts.
12367How does the ketone supplementation treatment differ from other treatments for enhancing ketosis?
This treatment is unique because it uses ketone esters and diesters to induce ketosis without requiring dietary changes, unlike traditional methods that rely on a high-fat, low-carbohydrate diet. It elevates blood ketone levels quickly and is generally well-tolerated, offering a practical alternative to achieve ketosis.
45689Eligibility Criteria
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.
+3 more
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.
+8 more
Trial Timeline
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
Participant Groups
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.
9Treatment groups
Experimental Treatment
Placebo Group
Group I: C8 Ketone Di-ester 360mg/kgExperimental Treatment7 Interventions
Group II: C8 Ketone Di-ester 180mg/kgExperimental Treatment7 Interventions
Group III: BHB mono-ester 360mg/kgExperimental Treatment7 Interventions
Group IV: BHB Mono-ester 180mg/kgExperimental Treatment7 Interventions
Group V: AcAc Di-ester 360mg/kgExperimental Treatment7 Interventions
Group VI: AcAc Di-ester 180mg/kgExperimental Treatment7 Interventions
Group VII: (R)-1,3 butanediol 360mg/kgExperimental Treatment7 Interventions
Group VIII: (R)-1,3 butanediol 180mg/kgExperimental Treatment7 Interventions
Group IX: ControlPlacebo Group8 Interventions
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The Ohio State UniversityColumbus, OH
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Who Is Running the Clinical Trial?
Ohio State UniversityLead Sponsor
Ohio State University Comprehensive Cancer CenterLead Sponsor
References
Anticonvulsant properties of an oral ketone ester in a pentylenetetrazole-model of seizure. [2015]The ketogenic diet is known to have an anti-epileptic effect; in fact it is currently used to treat drug resistant epilepsies. The efficacy of this diet is thought to be correlated to the elevation of blood ketone bodies. Because of problems with compliance to this diet, there is an interest in evaluating alternative pharmacological treatments that can have anti-seizure effects by elevating ketone bodies. In the present experiment, an orally administered synthetic ketone ester (R,S - 1,3-butanediol acetoacetate diester, or BD-AcAc2) was evaluated for its anti-seizure efficacy in a rat model. The threshold for seizure induction with progressive intravenous infusion of pentylenetrazole (PTZ) was evaluated in anesthetized Wistar rats two hours after a single 1 ml intragastric administration of BD-AcAc2 (i.e. 4 g/kg b.w., treated group) or water (control group). After correction for the dose of anesthetic, the results showed that the administration of BD-AcAc2 induced an elevation of the PTZ threshold (140 ± 11 mg/kg for the treated group, 122 ± 6 mg/kg for the control group), along with an increased level of blood β-hydroxybutyrate (2.7 ± 0.3mM for the treated group, 1.4 ± 0.1mM for the control group). This result suggests that ketone esters may pave the road towards the establishment of a "ketogenic diet in a pill".
Dietary ketone ester attenuates the accretion of adiposity and liver steatosis in mice fed a high-fat, high-sugar diet. [2023]Objective: The ketone diester, R,S-1,3-butanediol diacetoacetate (BD-AcAc2), attenuates the accretion of adiposity and reduces hepatic steatosis in high-fat diet-induced obese mice when carbohydrate energy is removed from the diet to accommodate energy from the ester. Reducing carbohydrate energy is a potential confounder due to the well-known effects of carbohydrate restriction on components of energy balance and metabolism. Therefore, the current investigation was designed to determine whether the addition of BD-AcAc2 to a high-fat, high-sugar diet (with no reduction in carbohydrate energy) would attenuate the accretion of adiposity and markers of hepatic steatosis and inflammation. Methods: Sixteen 11-week-old male C57BL/6J mice were randomized to one of two groups for 9 weeks (n = 8 per group): 1) Control (CON, HFHS diet) or 2) Ketone ester (KE, HFHS diet + BD-AcAc2, 25% by kcals). Results: Body weight increased by 56% in CON (27.8 ± 2.5 to 43.4 ± 3.7 g, p < 0.001) and by 13% in KE (28.0 ± 0.8 to 31.7 ± 3.1 g, p = 0.001). Non-alcoholic fatty liver disease activity scores (NAS) for hepatic steatosis, inflammation, and ballooning were lower in the KE group compared to CON (p < 0.001 for all). Markers of hepatic inflammation [Tnfα (p = 0.036); Mcp1 (p < 0.001)], macrophage content [(Cd68 (p = 0.012)], and collagen deposition and hepatic stellate cell activation [(αSma (p = 0.004); Col1A1 (p < 0.001)] were significantly lower in the KE group compared to CON. Conclusion: These findings extend those of our previous work and show that BD-AcAc2 attenuates the accretion of adiposity and reduces markers of liver steatosis, inflammation, ballooning, and fibrosis in lean mice placed on a HFHS diet where carbohydrate energy was not removed to accommodate energy from addition of the diester.
Concentration-Dependent Effects of a Dietary Ketone Ester on Components of Energy Balance in Mice. [2022]Objectives: Exogenous ketones may provide therapeutic benefit in treatment of obesity. Administration of the ketone ester (KE) R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) decreases body weight in mice, but effects on energy balance have not been extensively characterized. The purpose of this investigation was to explore concentration-dependent effects of BD-AcAc2 on energy intake and expenditure in mice. Methods: Forty-two male C57BL/6J mice were randomly assigned to one of seven isocaloric diets (n = 6 per group): (1) Control (CON, 0% KE by kcals); (2) KE5 (5% KE); (3) KE10 (10% KE); (4) KE15 (15% KE); (5) KE20 (20% KE); (6) KE25 (25% KE); and (7) KE30 (30% KE) for 3 weeks. Energy intake and body weight were measured daily. Fat mass (FM), lean body mass (LBM), and energy expenditure (EE) were measured at completion of the study. Differences among groups were compared to CON using ANOVA and ANCOVA. Results: Mean energy intake was similar between CON and each concentration of KE, except KE30 which was 12% lower than CON (P < 0.01). KE25 and KE30 had lower body weight and FM compared to CON, while only KE30 had lower LBM (P < 0.03). Adjusted resting and total EE were lower in KE30 compared to CON (P < 0.03), but similar for all other groups. Conclusions: A diet comprised of 30% energy from BD-AcAc2 results in lower energy intake, coincident with lower body weight and whole animal adiposity; while KE20 and KE25 have significantly lower body weight and adiposity effects independent of changes in energy intake or expenditure.
On the Metabolism of Exogenous Ketones in Humans. [2022]Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate "ketogenic" diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium βHB. Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3-4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3-1.4 moles.min. Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.
Bis Hexanoyl (R)-1,3-Butanediol, a Novel Ketogenic Ester, Acutely Increases Circulating r- and s-ß-Hydroxybutyrate Concentrations in Healthy Adults. [2023]Ketosis has been reported to benefit healthspan and resilience, which has driven considerable interest in development of exogenous ketones to induce ketosis without dietary changes. Bis hexanoyl (R)-1,3-butanediol (BH-BD) is a novel ketone di-ester that can be used as a food ingredient that increases hepatic ketogenesis and blood beta-hydroxybutyrate (BHB) concentrations.
Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. [2022]Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1-2h, reaching 3.30 mM and 1.19 mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8-3.1h for β-hydroxybutyrate and 8-14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.
Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. [2020]Central nervous system oxygen toxicity (CNS-OT) seizures occur with little or no warning, and no effective mitigation strategy has been identified. Ketogenic diets (KD) elevate blood ketones and have successfully treated drug-resistant epilepsy. We hypothesized that a ketone ester given orally as R,S-1,3-butanediol acetoacetate diester (BD-AcAc(2)) would delay CNS-OT seizures in rats breathing hyperbaric oxygen (HBO(2)). Adult male rats (n = 60) were implanted with radiotelemetry units to measure electroencephalogram (EEG). One week postsurgery, rats were administered a single oral dose of BD-AcAc(2), 1,3-butanediol (BD), or water 30 min before being placed into a hyperbaric chamber and pressurized to 5 atmospheres absolute (ATA) O2. Latency to seizure (LS) was measured from the time maximum pressure was reached until the onset of increased EEG activity and tonic-clonic contractions. Blood was drawn at room pressure from an arterial catheter in an additional 18 animals that were administered the same compounds, and levels of glucose, pH, Po(2), Pco(2), β-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone were analyzed. BD-AcAc(2) caused a rapid (30 min) and sustained (>4 h) elevation of BHB (>3 mM) and AcAc (>3 mM), which exceeded values reported with a KD or starvation. BD-AcAc(2) increased LS by 574 ± 116% compared with control (water) and was due to the effect of AcAc and acetone but not BHB. BD produced ketosis in rats by elevating BHB (>5 mM), but AcAc and acetone remained low or undetectable. BD did not increase LS. In conclusion, acute oral administration of BD-AcAc(2) produced sustained ketosis and significantly delayed CNS-OT seizures by elevating AcAc and acetone.
Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. [2021]Nutritional ketosis is a state of mildly elevated blood ketone concentrations resulting from dietary changes (e.g., fasting or reduced carbohydrate intake) or exogenous ketone consumption. In this study, we determined the tolerability and safety of a novel exogenous ketone diester, bis-hexanoyl-(R)-1,3-butanediol (BH-BD), in a 28-day, randomized, double-blind, placebo-controlled, parallel trial (NCT04707989). Healthy adults (n = 59, mean (SD), age: 42.8 (13.4) y, body mass index: 27.8 (3.9) kg/m2) were randomized to consume a beverage containing 12.5 g (Days 0-7) and 25 g (Days 7-28) of BH-BD or a taste-matched placebo daily with breakfast. Tolerability, stimulation, and sedation were assessed daily by standardized questionnaires, and blood and urine samples were collected at Days 0, 7, 14, and 28 for safety assessment. There were no differences in at-home composite systemic and gastrointestinal tolerability scores between BH-BD and placebo at any time in the study, or in acute tolerability measured 1-h post-consumption in-clinic. Weekly at-home composite tolerability scores did not change when BH-BD servings were doubled. At-home scores for stimulation and sedation did not differ between groups. BH-BD significantly increased blood ketone concentrations 1-h post-consumption. No clinically meaningful changes in safety measures including vital signs and clinical laboratory measurements were detected within or between groups. These results support the overall tolerability and safety of consumption of up to 25 g/day BH-BD.
Dog model of therapeutic ketosis induced by oral administration of R,S-1,3-butanediol diacetoacetate. [2022]A high-fat, almost carbohydrate-free diet is used in children with intractable epilepsy to help control seizures by inducing a permanent state of ketosis. Esters of ketone bodies have been previously studied for their potential as parenteral and enteral nutrients. We tested in conscious dogs whether ketosis could be induced by repeated ingestion of R,S-1,3-butanediol diacetoacetate with or without carbohydrates. This ester is a water-soluble precursor of ketone bodies. Two constraints were imposed on this preclinical study: The rate of ester administration was limited to one half of the daily caloric requirement and to one half of the capacity of the liver to oxidize butanediol derived from ester hydrolysis. Under these conditions, the level of ketosis achieved in this dog model (0.8 mM) was lower than the level measured in children whose seizures were controlled by the ketogenic diet (1-3 mM). However, because humans may have a lower capacity for ketone body utilization than dogs, the doses of R,S-butanediol diacetoacetate used in the present study might induce higher average ketone body concentrations in humans than in dogs.