Ketone Ester (D-Beta-Hydroxybutyrate Monoester)

Evidence Level
Limited
8 Clinical Trials
6 Documented Benefits
2/5 Evidence Score

The ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a bitter drink ingredient that joins the ketone body D-beta-hydroxybutyrate (BHB) to (R)-1,3-butanediol. The body splits the two apart and the liver turns the butanediol into more BHB, so blood ketones rise within 1 to 2 hours without fasting or a ketogenic diet. It was developed by University of Oxford and US NIH scientists, with early safety testing funded by the US military agency DARPA, and is sold as deltaG; FDA had no questions about its GRAS notice for bars, gels and drinks. Exercise trials disagree: one small early study found a better cycling time trial, most later trials found no gain, and one found lower power. Single drinks lowered blood glucose and hunger in small studies of healthy adults. Large doses cause stomach upset. It is different from BHB salts and from (R)-1,3-butanediol taken alone.

Studied Dose Single drinks of 0.33 to 0.75 g/kg body weight (about 23 to 53 g at 70 kg) in exercise and metabolic studies; 25 g after training and before sleep in training studies; 26.8 g three times daily for 28 days in a safety study. FDA GRAS notice: 0.36 g/kg per serving.
Active Compound (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester of D-beta-hydroxybutyrate and (R)-1,3-butanediol; each molecule supplies two molecules of D-BHB equivalents after it is split and the butanediol is converted in the liver.

Benefits

Raises blood ketone (BHB) levels within one to two hours

In healthy adults, single drinks of 140 to 714 mg/kg raised blood BHB to a peak within 1 to 2 hours, reaching 3.3 mmol/L at the top dose, with levels back to baseline within 3 to 4 hours. At a similar BHB dose, the ester gave a peak almost three times that of ketone salts (2.8 vs 1.0 mmol/L), and a meal beforehand lowered the peak by a third. A higher reading is a change in blood chemistry, not a benefit in itself.

Endurance time-trial performance in trained athletes

In 8 endurance athletes tested after an overnight fast, the ester plus carbohydrate added about 2% (411 m) to the distance covered in a 30-minute cycling time trial versus carbohydrate alone. Later trials did not repeat this: no change in a 10 km run (8 runners), a team-sport shuttle run (11 athletes) or a simulated cycling race (12 cyclists), and 2.4% lower power in a 20-minute time trial (23 cyclists).

Endurance training adaptations with intake after exercise

Two trials from one Belgian research group gave 25 g after training and before sleep. In 3 weeks of overload training (18 fit men), sustainable training load and late-session power were 15% higher than with a control drink. Over 8 weeks of cycling training (28 trained men), 30-minute time-trial power ended 4% higher and peak oxygen uptake rose 12% versus 6%. Both trials enrolled men only.

Lower blood glucose response after a glucose drink

In 20 healthy young adults, a ketone ester drink 30 minutes before a 75 g glucose drink cut the glucose area under the curve by 17% versus water, without raising insulin secretion. Taken before each meal for 14 days, it lowered glucose after meals by about 8% in 14 adults with obesity but did not improve glucose control in 15 adults with type 2 diabetes, and 28 days of use left fasting glucose unchanged in healthy adults.

Hunger and the appetite hormone ghrelin after a single drink

In 15 normal-weight adults, a ketone ester drink raised BHB to 3.3 mmol/L and, compared with a dextrose drink of equal calories, lowered ghrelin 2 to 4 hours later and lowered hunger and desire to eat at 1.5 hours. The fullness hormones GLP-1 and PYY were also lower. The study tracked ratings and hormones for a few hours, not food intake or body weight.

Thinking speed and accuracy during fatigue or low oxygen

In 11 team-sport athletes, errors on a multitasking test rose after exhausting shuttle running with carbohydrate alone but not with the ester added. In 16 military personnel breathing low-oxygen air at rest, the ester gave 6.8 more correct responses per minute on a coding task and a smaller fall in blood oxygen. In 8 runners, reaction time and multitasking did not change after a 10 km run.

Mechanism of action

1

Split into BHB and (R)-1,3-butanediol, which the liver turns into BHB

Esterases in the gut, blood and liver are expected to split the ester into D-BHB and (R)-1,3-butanediol, and the liver converts the butanediol to BHB and acetoacetate using alcohol and aldehyde dehydrogenase. The intact ester was not detected in blood after drinking it. The BHB supplied is the D form the body makes itself, whereas ketone salts can be about half the L form.

2

Adds a short-lived acid load the body offsets by breathing harder

Blood pH and bicarbonate fall for a few hours after a drink. In healthy adults, pH fell from 7.41 to 7.31 and bicarbonate from 23.6 to 17.0 mmol/L an hour after a drink, staying within the normal range; in a cycling race study pH dropped from about 7.42 to 7.36 and bicarbonate from 26.0 to 21.6 mmol/L. Those researchers suggested lower buffering capacity could matter in the hardest final part of a race.

3

Shifts muscle fuel use during exercise

In the first athlete studies, ketosis lowered blood lactate and muscle glycolysis and raised use of fat stored in muscle, even with carbohydrate on board. A later trial that provided a carbohydrate-rich meal and matched carbohydrate intake found no sparing of muscle glycogen during a 3-hour simulated race, so this fuel shift does not reliably appear.

Clinical trials

1
Ketone Ester Plus Carbohydrate and a 30-Minute Cycling Time Trial (gain of about 2%)
PubMed

Five studies of fuel use in high-performance athletes; in the performance study, a randomized crossover after an overnight fast compared 573 mg/kg of the ester plus carbohydrate with an isocaloric carbohydrate drink before 1 hour of cycling at 75% of maximal power and a 30-minute distance time trial. Funded by DARPA and UK Sport; authors included inventors of the ester and TdeltaS employees. (Cox et al. 2016, Cell Metab)

39 high-performance athletes across five studies; 8 endurance athletes (6 men, 2 women) in the time-trial study.

Ketosis lowered muscle glycolysis and blood lactate and increased oxidation of fat stored in muscle. In the time trial, athletes cycled about 411 m (about 2%) further with the ester than with carbohydrate alone. The performance group was small and tested fasted, and later trials in fed athletes with matched carbohydrate have not reproduced the gain.

2
Ketone Monoester and a 10 km Running Time Trial (no benefit)
PubMed

Double-blind randomized crossover: 573 mg/kg of ketone monoester with an 8% carbohydrate drink versus the carbohydrate drink alone, before 1 hour of running at about 65% of VO2max and a self-paced 10 km treadmill time trial. (Evans et al. 2019, Med Sci Sports Exerc)

8 endurance-trained runners.

Plasma BHB was about 1.0 to 1.3 mmol/L during exercise, but 10 km time did not differ (2,402 vs 2,422 seconds, P = 0.483). Running economy, heart rate, effort ratings, blood glucose and lactate, reaction time and multitasking were also unchanged.

3
Ketone Ester During a Simulated Cycling Race: Glycogen and Performance (no benefit)
PubMed

Randomized crossover: three ketone ester doses (25, 20 and 20 g) or a control drink, with 60 g carbohydrate per hour, during 3 hours of intermittent cycling followed by a 15-minute time trial and a maximal sprint; funded by Research Fund Flanders. (Poffé et al. 2020, J Appl Physiol)

12 highly trained male cyclists.

Blood BHB rose to about 3 mmol/L in the first half of the race, while blood pH fell from about 7.42 to 7.36 and bicarbonate from 26.0 to 21.6 mmol/L. Muscle glycogen use did not differ, and 15-minute time-trial power (273 vs 272 W) and sprint time to exhaustion (59 vs 58 seconds) matched the control condition.

4
Ketone Monoester Before a 20-Minute Cycling Time Trial (lower power)
PubMed

Randomized, triple-blind crossover sized for adequate statistical power: 0.35 g/kg of the ketone monoester or a flavor-matched placebo 30 minutes before a 15-minute warm-up and a 20-minute time trial. (McCarthy et al. 2023, Int J Sport Nutr Exerc Metab)

23 trained cyclists who rode more than 5 hours a week.

Pre-exercise BHB was 2.0 vs 0.2 mmol/L. Mean time-trial power was 2.4% lower after the ester than after placebo (255 vs 261 W, p < .01). The authors could not explain why performance was impaired.

5
Ketone Ester After Training During 3 Weeks of Overload Training
PubMed

Randomized controlled trial: 25 g of ketone ester after each of two daily training sessions and 30 minutes before sleep, versus an isocaloric control drink, for 3 weeks (6 days a week) of intensified endurance training; funded by Research Fund Flanders, with the ester bought from TdeltaS. (Poffé et al. 2019, J Physiol)

18 fit men (9 ketone ester, 9 control).

Sustainable training load in week 3 and power in the final 30 minutes of a 2-hour session were 15% higher with the ester. It blunted the rise in night-time adrenaline and noradrenaline and the fall in heart rate, and energy balance stayed near neutral (+198 kJ/day) instead of turning negative (-2,135 kJ/day). A small single-lab trial that drew several published comments in the journal.

6
Ketone Ester After Exercise During 8 Weeks of Endurance Training
PubMed

Randomized trial: 25 g of the ketone monoester or an isocaloric placebo after exercise and before sleep during 8 weeks of supervised, periodized cycling training. (Robberechts et al. 2026, J Physiol)

28 trained men (14 per group).

After training, 30-minute time-trial power was 4% higher with the ester (302 vs 291 W). Relative peak oxygen uptake rose 12% versus 6%, and the muscle mitochondrial enzyme citrate synthase was 14% higher, while cardiac adaptations did not differ. Same research group as the 3-week overload trial; men only.

7
Ketone Monoester Before a Glucose Tolerance Test in Healthy Adults
PubMed

Randomized crossover with blinded participants and laboratory analysts: ketone monoester (deltaG, 0.45 mL/kg body weight) or water 30 minutes before a 75 g oral glucose tolerance test. (Myette-Côté et al. 2018, J Physiol)

20 healthy adults aged 18 to 35 (10 men, 10 women).

BHB rose to 3.2 mmol/L within 30 minutes. Versus water, the glucose area under the curve fell 17%, fatty acids fell 44%, and an oral insulin sensitivity index improved by about 11%, without higher insulin secretion. A single-dose study in healthy young adults.

8
Ketone Monoester and Thinking During Simulated High Altitude (military-funded)
PubMed

Single-blind randomized crossover: 650 mg/kg of ketone monoester (split dose) or a taste-matched placebo before 20 minutes of breathing 9.7% oxygen (equal to 6,096 m altitude) at rest; funded by US Special Operations Command through a contract awarded to HVMN Inc. (McClure et al. 2024, Exp Physiol)

16 male military personnel.

BHB exceeded 4 mmol/L and blood glucose was about 20 mg/dL lower than with placebo. During low oxygen, the ester condition gave 6.8 more correct responses per minute on a code-substitution task, and oxygen saturation fell less (76.8% vs 70.4%). One author held stock in HVMN and other ketone companies.

Side effects and drug interactions

Common Potential side effects

Stomach upset at high doses: at 714 mg/kg three times a day for 5 days (about 1.1 liters of milk-based drink within 30 minutes each time), all 12 people had treatment-related side effects such as nausea, vomiting, diarrhea, bloating and abdominal pain, and 2 withdrew. Lower doses were generally well tolerated.
In a 28-day study of 26.8 g three times a day in 24 healthy adults, mild nausea followed 6 of 2,016 drinks, and blood tests, including kidney function, stayed normal.
Headache, dizziness, tiredness and sleepiness were reported at the highest dose in the 5-day safety study.
Lowers blood pH and bicarbonate for a few hours (a mild acid load); the body compensates by breathing more.
Lowers blood glucose; in one study glucose was about 20 mg/dL lower than with placebo.
The drink tastes strongly bitter.
Trials enrolled healthy, non-pregnant adults; safety in pregnancy, breastfeeding and children has not been studied.

Important Drug interactions

Formal drug-interaction studies of the ketone ester are lacking.
Insulin, sulfonylureas and other glucose-lowering medicines: ketone ester drinks lower blood glucose, so the effects could add up; monitor blood sugar and ask your prescriber first.
Alcohol: the (R)-1,3-butanediol half is processed by the same liver enzymes (alcohol and aldehyde dehydrogenase) as drinking alcohol; the combination has not been studied for the ester, so avoid mixing them.
Anyone with kidney disease or another condition that affects acid-base balance should ask a doctor first, because the ester briefly lowers blood pH and bicarbonate.

Frequently asked questions about Ketone Ester (D-Beta-Hydroxybutyrate Monoester)

How is the ketone ester different from BHB salts and (R)-1,3-butanediol?

All three raise blood ketones by different routes. Salts bind BHB to minerals and, at a similar BHB dose, reached about a third of the ester's peak in a direct comparison, with half of that salt as the poorly used L form. (R)-1,3-butanediol contains no BHB and relies on the liver. The ester is BHB joined to butanediol, so it delivers D-BHB directly plus butanediol that the liver converts.

Does a ketone ester drink improve endurance performance?

Usually not when taken before a single event. One early study of 8 cyclists found about 2% more distance in a time trial, but later trials in runners and cyclists found no gain, and a 23-cyclist trial found 2.4% lower power. Two trials from one research group found better training results when the ester was taken after sessions for 3 to 8 weeks; independent confirmation is still needed.

How high do blood ketones go, and for how long?

Typical study doses raise blood BHB to about 1 to 4 mmol/L within 30 minutes to 2 hours, depending on dose, food and exercise; the higher end is similar to levels after several days of fasting. BHB falls back to baseline within about 3 to 4 hours. Taking it after a meal lowered the peak by about a third in one study.

Has daily use been studied for more than a few days?

The longest safety study gave 24 healthy adults 26.8 g three times a day for 28 days: mild nausea followed 6 of 2,016 drinks, and body weight, fasting glucose, blood fats, electrolytes, blood gases and kidney function stayed normal. It had no control group. Training studies gave 25 g after sessions and before sleep for 3 to 8 weeks. Use has not been studied in pregnancy, breastfeeding or children.

What is Ketone Ester?

The ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a bitter drink ingredient that joins the ketone body D-beta-hydroxybutyrate (BHB) to (R)-1,3-butanediol.

What is Ketone Ester used for?

Ketone Ester is researched primarily for Athletic Performance and Metabolic Health. In healthy adults, single drinks of 140 to 714 mg/kg raised blood BHB to a peak within 1 to 2 hours, reaching 3.3 mmol/L at the top dose, with levels back to baseline within 3 to 4 hours.

What is the recommended dosage of Ketone Ester?

The clinically studied dose is Single drinks of 0.33 to 0.75 g/kg body weight (about 23 to 53 g at 70 kg) in exercise and metabolic studies; 25 g after training and before sleep in training studies; 26.8 g three times daily for 28 days in a safety study. FDA GRAS notice: 0. Always follow the product label and check with a healthcare provider for personal advice.

Is Ketone Ester safe, and does it have side effects?

Side effects and cautions reported for Ketone Ester include: Stomach upset at high doses: at 714 mg/kg three times a day for 5 days (about 1.1 liters of milk-based drink within 30 minutes each time), all 12 people had treatment-related side effects such as nausea, vomiting, diarrhea, bloating and abdominal pain, and 2 withdrew. It may also interact with some medications. Ketone Ester is not right for everyone, so check with a healthcare provider first if you are pregnant or breastfeeding, have a medical condition, or take prescription medication.

Does Ketone Ester interact with any medications?

Possible interactions include: Formal drug-interaction studies of the ketone ester are lacking. Insulin, sulfonylureas and other glucose-lowering medicines: ketone ester drinks lower blood glucose, so the effects could add up; monitor blood sugar and ask your prescriber first. If you take prescription medication, check with a pharmacist or doctor before using it.

How strong is the scientific evidence for Ketone Ester?

NutraSmarts rates the evidence for Ketone Ester as Limited (2 out of 5). It is backed by 8 study summaries and 16 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(16 citations)

Evidence ratings on NutraSmarts are based on the totality of human clinical research, with emphasis on randomized controlled trials, meta-analyses, and systematic reviews. The references below directly support claims made throughout this page.

  1. Clarke K, Tchabanenko K, Pawlosky R, Carter E, Todd King M, Musa-Veloso K, Ho M, Roberts A, Robertson J, Vanitallie TB, Veech RL. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012;63(3):401-8. doi: 10.1016/j.yrtph.2012.04.008.PubMedUsed to support: Kinetics and safety study in healthy adults (18 single-dose, 36 repeated-dose): single drinks of 140, 357 or 714 mg/kg raised blood BHB to a peak within 1 to 2 hours (3.30 mmol/L at the top dose) with a BHB half-life of 0.8 to 3.1 hours; the intact ester was not detected in blood. Over 5 days, low and middle doses were well tolerated, but all 12 people at the top dose (about 1.1 liters of milk drink per serving) had treatment-related side effects, mostly digestive, and 2 withdrew. Funded by DARPA; inventors and a TdeltaS director among the authors. The paper describes splitting of the ester into D-BHB and (R)-1,3-butanediol and liver conversion of the butanediol by alcohol and aldehyde dehydrogenase.
  2. Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, Stirling M, Clarke K. On the Metabolism of Exogenous Ketones in Humans. Front Physiol. 2017;8:848. doi: 10.3389/fphys.2017.00848.PubMedUsed to support: Randomized metabolic studies in healthy adults: at about 12 or 24 g of BHB, the ketone ester raised blood D-BHB to a higher peak than ketone salts (2.8 vs 1.0 mmol/L), returning to baseline within 3 to 4 hours. In a further study the ester lowered blood pH from 7.41 to 7.31 and bicarbonate from 23.6 to 17.0 mmol/L after an hour, within the normal range. A meal before the drink lowered the peak by 33% (2.2 vs 3.3 mmol/L). All ketone drinks lowered blood glucose, free fatty acids and triglycerides, with normal electrolytes. One mole of ester supplied two moles of D-BHB equivalents, and the salt drink was 50% L-BHB. TdeltaS provided the ester (deltaG), and the first author was a TdeltaS employee at the time.
  3. Soto-Mota A, Vansant H, Evans RD, Clarke K. Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Regul Toxicol Pharmacol. 2019;109:104506. doi: 10.1016/j.yrtph.2019.104506.PubMedUsed to support: Safety study in 24 healthy adults aged 18 to 70 who drank 25 mL (26.8 g) of the ketone monoester three times a day for 28 days, raising blood BHB from 0.1 to about 4.1 mmol/L each time, similar to levels after several days of fasting. Body weight and composition, fasting glucose, cholesterol, triglycerides, electrolytes, blood gases and kidney function were unchanged and normal. Mild nausea followed 6 of 2,016 drinks. No control group.
  4. Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016;24(2):256-68. doi: 10.1016/j.cmet.2016.07.010.PubMedUsed to support: Five studies in 39 high-performance athletes: ketone ester drinks lowered muscle glycolysis and plasma lactate and increased oxidation of fat stored in muscle during exercise, even with carbohydrate and raised insulin. In the performance study, 8 highly trained athletes (6 men, 2 women) tested after an overnight fast took 573 mg/kg of the ester with dextrose or carbohydrate alone, then cycled 411 m (about 2%) further in a 30-minute time trial (p < 0.05). Funded by DARPA and UK Sport; authors included inventors of the ester and TdeltaS employees.
  5. Evans M, McSwiney FT, Brady AJ, Egan B. No Benefit of Ingestion of a Ketone Monoester Supplement on 10-km Running Performance. Med Sci Sports Exerc. 2019;51(12):2506-2515. doi: 10.1249/MSS.0000000000002065.PubMedUsed to support: Double-blind randomized crossover in 8 endurance-trained runners: 573 mg/kg of ketone monoester with carbohydrate raised plasma BHB to about 1.0 to 1.3 mmol/L, but 10 km time-trial time (2,402 vs 2,422 seconds, P = 0.483), running economy, heart rate, effort ratings, reaction time and multitasking did not differ from carbohydrate alone.
  6. Poffé C, Ramaekers M, Bogaerts S, Hespel P. Exogenous ketosis impacts neither performance nor muscle glycogen breakdown in prolonged endurance exercise. J Appl Physiol (1985). 2020;128(6):1643-1653. doi: 10.1152/japplphysiol.00092.2020.PubMedUsed to support: Randomized crossover in 12 highly trained male cyclists: 65 g of ketone ester in three doses with 60 g/h carbohydrate during a 3-hour simulated race raised BHB to about 3 mmol/L and lowered blood pH (about 7.42 to 7.36) and bicarbonate (26.0 to 21.6 mmol/L). Muscle glycogen use, 15-minute time-trial power and sprint time did not differ from control. The authors suggested the ketosis may reduce buffering capacity before the final effort. Funded by Research Fund Flanders; ester bought from TdeltaS; no conflicts declared.
  7. McCarthy DG, Bone J, Fong M, Pinckaers PJM, Bostad W, Richards DL, van Loon LJC, Gibala MJ. Acute Ketone Monoester Supplementation Impairs 20-min Time-Trial Performance in Trained Cyclists: A Randomized, Crossover Trial. Int J Sport Nutr Exerc Metab. 2023;33(4):181-188. doi: 10.1123/ijsnem.2022-0255.PubMedUsed to support: Randomized, triple-blind crossover in 23 trained cyclists: 0.35 g/kg of the ketone monoester 30 minutes before exercise raised BHB to 2.0 mmol/L and lowered mean 20-minute time-trial power by 2.4% versus a flavor-matched placebo (255 vs 261 W, p < .01). The study was sized to detect a 2% difference.
  8. Poffé C, Ramaekers M, Van Thienen R, Hespel P. Ketone ester supplementation blunts overreaching symptoms during endurance training overload. J Physiol. 2019;597(12):3009-3027. doi: 10.1113/JP277831.PubMedUsed to support: Randomized trial in 18 fit men during 3 weeks of twice-daily endurance overload training: 25 g of ketone ester after sessions and before sleep (n = 9) versus an isocaloric control drink (n = 9) gave 15% higher sustainable training load in week 3 and 15% higher power late in a 2-hour session, blunted rises in night-time adrenaline and noradrenaline and the drop in heart rate, and kept energy balance near neutral. Funded by Research Fund Flanders; ester bought from TdeltaS.
  9. Robberechts R, Bekhuis Y, Stalmans M, Lauriks W, Kusters M, Taha K, Rosseel T, Claessen G, Poffé C. Post-exercise ketone supplementation improves endurance performance and mitochondrial adaptations during an 8-week endurance training intervention. J Physiol. 2026;Online ahead of print. doi: 10.1113/JP290315.PubMedUsed to support: Randomized trial in 28 trained men during 8 weeks of periodized cycling training: 25 g of the ketone monoester after exercise and before sleep (n = 14) versus isocaloric placebo (n = 14) gave 4% higher 30-minute time-trial power at the end (302 vs 291 W), a larger rise in relative peak oxygen uptake (12% vs 6%) and 14% higher muscle citrate synthase activity, with no difference in cardiac adaptations. Published online ahead of print.
  10. Stubbs BJ, Cox PJ, Evans RD, Cyranka M, Clarke K, de Wet H. A Ketone Ester Drink Lowers Human Ghrelin and Appetite. Obesity (Silver Spring). 2018;26(2):269-273. doi: 10.1002/oby.22051.PubMedUsed to support: Acute crossover in 15 normal-weight adults: a ketone ester drink (1.9 kcal/kg) raised BHB from 0.2 to 3.3 mmol/L and, versus an isocaloric dextrose drink, lowered insulin, ghrelin, GLP-1 and PYY 2 to 4 hours later and lowered hunger and desire to eat at 1.5 hours. TdeltaS provided the ester; the first author held an industrial fellowship. Appetite ratings and hormones only.
  11. Myette-Côté É, Neudorf H, Rafiei H, Clarke K, Little JP. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. J Physiol. 2018;596(8):1385-1395. doi: 10.1113/JP275709.PubMedUsed to support: Randomized crossover in 20 healthy adults aged 18 to 35: a ketone monoester drink (deltaG, 0.45 mL/kg) 30 minutes before a 75 g oral glucose tolerance test raised BHB to 3.2 mmol/L and, versus water, lowered glucose area under the curve by 17% and fatty acids by 44% and improved an oral insulin sensitivity index by about 11% without raising insulin secretion.
  12. Evans M, Egan B. Intermittent Running and Cognitive Performance after Ketone Ester Ingestion. Med Sci Sports Exerc. 2018;50(11):2330-2338. doi: 10.1249/MSS.0000000000001700.PubMedUsed to support: Double-blind randomized crossover in 11 male team-sport athletes: 750 mg/kg of ketone ester with carbohydrate raised BHB to about 1.5 to 2.6 mmol/L and lowered glucose and lactate, but did not change sprint times or shuttle-run time to exhaustion (229 seconds with the ester vs 268 with carbohydrate alone, P = 0.126). Errors on a multitasking test rose after exercise with carbohydrate alone but not with the ester.
  13. McClure TS, Phillips J, Koutnik AP, Coleman K, Chappe E, Cutter GR, Egan B, Norell T, Stubbs BJ, Bamman MM, Kernagis D. Ketone monoester attenuates declines in cognitive performance and oxygen saturation during acute severe hypoxic exposure under resting conditions. Exp Physiol. 2024;109(10):1672-1682. doi: 10.1113/EP091794.PubMedUsed to support: Single-blind randomized crossover in 16 male military personnel: 650 mg/kg of ketone monoester before 20 minutes of breathing 9.7% oxygen at rest raised BHB above 4 mmol/L, lowered blood glucose by about 20 mg/dL, and gave 6.8 more correct responses per minute on a code-substitution task and a smaller drop in oxygen saturation versus placebo. Funded by US Special Operations Command through a contract awarded to HVMN Inc.; one author held stock in ketone companies including HVMN.
  14. Walsh JJ, Neudorf H, Little JP. 14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial. J Clin Endocrinol Metab. 2021;106(4):e1738-e1754. doi: 10.1210/clinem/dgaa925.PubMedUsed to support: Randomized crossover in 14 adults with obesity (mean age 56) with all meals provided: a ketone monoester drink (12 g BHB) or placebo 15 minutes before each meal for 14 days. On continuous glucose monitoring, glucose after meals was 8.0% lower and 24-hour average glucose 7.8% lower with the ester. Brachial artery flow-mediated dilation rose from 6.2% to 8.9% with the ester, and plasma cytokines did not change.
  15. Falkenhain K, Oliveira BF, Islam H, Neudorf H, Cen HH, Johnson JD, Madden K, Singer J, Walsh JJ, Little JP. The effect of acute and 14-day exogenous ketone supplementation on glycemic control in adults with type 2 diabetes: two randomized controlled trials. Am J Physiol Endocrinol Metab. 2024;326(1):E61-E72. doi: 10.1152/ajpendo.00332.2023.PubMedUsed to support: Two randomized, double-blind, placebo-controlled crossover trials in adults with type 2 diabetes. A single drink of 0.3 g/kg of the ketone monoester (n = 18) raised BHB to about 2 mmol/L but did not lower fasting plasma glucose, and 15 g three times a day before meals for 14 days (n = 15) did not change serum fructosamine, a marker of glucose control over that period. The single drink raised insulin and lowered fatty acids.
  16. US Food and Drug Administration. GRAS Notice No. GRN 000515: D-beta-hydroxybutyrate ester (notifier TdeltaS Limited). FDA GRAS Notice Inventory. 2015;GRN 515, closed March 5, 2015. Accessed 2026..SourceUsed to support: Not PubMed-indexed; official FDA inventory entry. TdeltaS notified FDA that the D-beta-hydroxybutyrate ester is GRAS for use in bars, gels and beverages at a level intended to provide 0.36 g/kg body weight per serving, and FDA responded that it had no questions (closed March 5, 2015).