Supplements

Ketone Esters

Updated · 22 sources · Editorial policy

Ketone esters are drinks that raise blood ketone levels within minutes, without fasting or a ketogenic diet. The best-studied one is the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, developed by researchers at the University of Oxford and the US National Institutes of Health. The body splits it into D-β-hydroxybutyrate (BHB), the main ketone body, and a precursor that the liver also turns into ketones. Ketone salts (BHB bound to sodium, potassium or other minerals) are an alternative that raises blood ketones much less.

Interest in sport took off after a 2016 study in elite cyclists reported a 2% longer distance covered in a 30-minute time trial. Later trials and three systematic reviews have not confirmed a reliable performance benefit, and some trials found performance got worse. In the US the monoester is a food ingredient covered by a GRAS (“generally recognized as safe”) notice, and it is not on the WADA Prohibited List.

This page summarizes what the clinical trials, meta-analyses and regulators report. It is for education only and is not medical advice.

Property Detail
Class Exogenous ketone; food ingredient / dietary supplement
Main form Ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (C₈H₁₆O₄, 176.21 g/mol)
Other forms Ketone diester (1,3-butanediol acetoacetate); ketone salts (sodium, potassium BHB)
Route Oral drink
Doses in trials Monoester ≈ 140–714 mg/kg per serving; 25 mL (26.8 g) three times daily for 28 days
Peak blood BHB ≈ 1–5 mM with monoesters; ≈ 1 mM with salts at a matched BHB dose
BHB half-life 0.8–3.1 h after a single monoester drink
US status Food ingredient; FDA “no questions” letter on GRAS notice GRN 515 (2015)
WADA status Not named on the 2026 Prohibited List

What it is

Ketone bodies are small fuel molecules that the liver makes from fat during fasting or a very low-carbohydrate diet. The two main ones in blood are BHB and acetoacetate. Resting BHB was about 0.1 mM in healthy volunteers (Soto-Mota et al., Regul Toxicol Pharmacol 2019). Nutritional ketosis is generally defined as blood ketones above 0.5 mM, the level a ketogenic diet aims for (ISSN position stand, JISSN 2024).

Ketone esters deliver ketones directly. The monoester joins one BHB molecule to (R)-1,3-butanediol through an ester bond (PubChem CID 44631890). Enzymes in the gut, blood and liver split the ester. The liver then converts the butanediol part into more BHB and acetoacetate using alcohol and aldehyde dehydrogenase (Clarke et al., Regul Toxicol Pharmacol 2012). According to the Oxford group, one mole of monoester yields two moles of BHB equivalents (Stubbs et al., Front Physiol 2017).

Form What it contains Notes from trials
Ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate Raises D-BHB the most; bitter taste; lowers blood pH slightly
Ketone diester 1,3-butanediol acetoacetate Used in some sport trials; linked to gut discomfort in elite cyclists
Ketone salts Sodium, potassium (or calcium) BHB Much lower D-BHB peak; often a 50:50 mix of D- and L-BHB; large mineral load

The proposed mechanism for sport is a fuel shift. With high blood ketones, muscle may burn more ketones and fat and rely less on glycogen (stored carbohydrate). That idea came from the Cox 2016 study described below.

How it works in the body

The key kinetic data come from the Oxford trials in healthy adults.

Study Dose Result
Clarke 2012, single dose 140, 357 or 714 mg/kg Peak BHB within 1–2 h; 3.30 mM BHB and 1.19 mM acetoacetate at the top dose; intact ester not detected in plasma
Clarke 2012, half-life Same BHB elimination half-life 0.8–3.1 h; acetoacetate 8–14 h
Stubbs 2017, ester vs salt ≈ 12 or 24 g BHB Peak D-BHB 2.8 mM (ester) vs 1.0 mM (salts); back to baseline within 3–4 h
Stubbs 2017, with food 395 mg/kg A meal cut peak D-BHB by 33% (2.2 vs 3.3 mM fasted)
Holdsworth 2017 Monoester drink after exercise Peak D-BHB 5.3 mM vs 0.7 mM with control
Soto-Mota 2019 25 mL three times daily, 28 days BHB rose from 0.1 to 4.1 mM after each drink

Sources: Clarke et al. 2012; Stubbs et al. 2017; Holdsworth et al., MSSE 2017; Soto-Mota et al., Regul Toxicol Pharmacol 2019.

Other findings from the Stubbs study:

  • Ketone salts contained 50% L-BHB, the mirror-image form. L-BHB stayed in blood for over 8 hours and appears to be used less readily as fuel.
  • Less than 1.5% of ingested BHB was lost in urine.
  • Acid-base shifts. The monoester lowered blood pH by 0.10 and bicarbonate from 23.6 to 17.0 mM, within the normal range. The salt drink instead raised urine pH from 5.7 to 8.5.
  • Glucose and fats. All ketone drinks lowered blood glucose, free fatty acids and triglycerides.

The glucose drop has been confirmed by meta-analysis. Across 43 trials with 586 participants, exogenous ketones raised blood BHB by 1.98 mM and lowered blood glucose by 0.47 mM (≈ 8.5 mg/dL) compared with placebo. Monoesters had larger effects than salts (Falkenhain et al., Adv Nutr 2022).

Regulatory status

  • US food ingredient. TdeltaS Ltd (the Oxford spin-out) filed GRAS notice GRN 515 for “D-beta-hydroxybutyrate ester” on May 8, 2014, for use in bars, gels and beverages at up to 0.36 g/kg body weight per serving. FDA closed the notice on March 5, 2015 with a “no questions” letter (FDA GRN 515). A “no questions” letter means FDA did not object to the company’s GRAS conclusion; it is not a drug approval and says nothing about performance.
  • Related ingredients. Free D-BHB (not an ester) received a separate “no questions” letter as GRN 1032 in 2022, for up to 6 g per serving in sports drinks, bars and gels (FDA GRN 1032).
  • Not a drug. No ketone ester is FDA-approved to treat any disease.
  • Anti-doping. The WADA 2026 Prohibited List does not name ketone esters, ketone salts or BHB. The metabolic modulators it bans (class S4.4) are AMPK activators, PPARδ agonists, Rev-erbα agonists, insulins, meldonium and trimetazidine.

What the research shows

Endurance performance: the original positive study

Cox and colleagues at Oxford ran five studies in 39 high-performance athletes (Cox et al., Cell Metab 2016). The performance test used 8 elite cyclists (6 men, 2 women). They drank about 576 mg/kg of the monoester plus carbohydrate, or an equal-calorie carbohydrate drink, before a 30-minute time trial. With the ketone drink they covered about 2% more distance (Margolis & O’Fallon, Adv Nutr 2020).

The study also reported less muscle glycolysis, lower blood lactate and more burning of fat stored inside muscle. These findings drove much of the later interest in ketone drinks.

Later trials: mostly null, some negative

Trial Population Ketone dose Performance result
Leckey et al., Front Physiol 2017 10 elite male cyclists, crossover Diester, 2 × 250 mg/kg ≈ 31 km time trial 2% slower; more gut discomfort and perceived effort
Evans et al., MSSE 2019 8 trained runners, crossover Monoester 573 mg/kg plus carbohydrate 10 km time: 2402 vs 2422 s, no difference (p = 0.483)
Whitfield et al., MSSE 2021 18 elite race walkers Monoester 573 mg/kg BHB peaked at 3.2 mM but oxygen cost was unchanged; adding the ester to a 5-day low-carb diet did not prevent a ≈ 6% slower 10 km race
Poffé et al., MSSE 2021 9 trained male cyclists, crossover 65 g monoester, alone or with sodium bicarbonate Ester alone: no gain in 15-minute time trial; ester plus bicarbonate: 5% higher power vs control
Engelbrecht et al., MSSE 2026 18 trained cyclists, 8-day simulated race 25 g monoester after each stage and before sleep No benefit for performance, recovery, sleep or cognition

The Poffé study suggests one reason for the mixed results. In that trial the ester alone dropped blood pH from 7.43 to 7.36 and bicarbonate from 25.5 to 20.5 mM. Only when sodium bicarbonate (300 mg/kg) was added to offset this acid load did performance improve. That combination has been tested in very few athletes.

Systematic reviews and meta-analyses

Review Studies Pooled effect on performance
Valenzuela et al., IJSPP 2020 13 RCTs Hedges g −0.05 (95% CI −0.30 to 0.20); esters g −0.07; salts g −0.02; all not significant
Margolis & O’Fallon, Adv Nutr 2020 10 RCTs, 112 participants (109 men) Of 16 outcomes: 3 positive, 10 null, 3 negative; very high heterogeneity
Brooks et al., IJSNEM 2022 8 RCTs, 80 participants Hedges g 0.136 (95% CI −0.195 to 0.467), not significant

Hedges g is a standardized effect size; values near 0 mean no effect. All three reviews agree that ketone drinks reliably raise blood ketones but do not reliably improve performance in events from sprints up to about 50 minutes. Almost all participants were men.

Recovery and training

The recovery evidence is small and mixed:

  • Glycogen refilling. In 12 trained men, a monoester drink followed by a 2-hour glucose clamp (glucose infused to hold blood sugar at 10 mM) raised insulin twofold and muscle glycogen by 50% compared with control (Holdsworth et al., MSSE 2017). A clamp is a lab condition, not a normal meal. In a second study of 8 men who drank a standard protein-carbohydrate recovery drink, adding the ester did not change glycogen resynthesis. It did increase mTORC1 signaling, a pathway linked to muscle protein synthesis (Vandoorne et al., Front Physiol 2017).
  • Overreaching. In a 3-week training overload, 18 fit men took a monoester or control drink after each session. The ketone group sustained a 15% higher training load in week 3. They also had smaller rises in nighttime stress hormones and did not drift into negative energy balance (Poffé et al., J Physiol 2019).
  • Multi-day racing. The same research group later found no recovery or performance benefit over an 8-day simulated stage race (Engelbrecht et al. 2026).

Cognition

Ketones can fuel the brain, so they have been marketed for focus. The trial data are inconsistent:

  • Pooled data. A 2026 meta-analysis of 29 trial protocols (1,117 participants) found a small benefit on cognitive tests compared with placebo (SMD 0.29, 95% CI 0.16–0.41). SMD is a standardized mean difference; about 0.2–0.3 is usually considered small. Several authors held equity or jobs with companies that sell ketone products (Bonnechère et al., Front Nutr 2026).
  • Athletes. Reaction time and multitasking did not change in the 10 km running trial (Evans et al. 2019), and cognition did not improve over the 8-day cycling race (Engelbrecht et al. 2026).

Athletes looking at alertness aids will also find caffeine, which has its own page and a much larger evidence base.

Side effects and risks

Gut symptoms

Gut upset is the most common problem, and it rises with dose:

  • Clarke 2012 (5-day study, 12 per dose group). At the highest dose, 2,142 mg/kg/day, two participants withdrew: one for severe vomiting and one for nausea, diarrhea, chest pain and abdominal pain. Others in that group reported flatulence, nausea, diarrhea, constipation, vomiting and bloating, mild to moderate. Headache, dizziness and drowsiness were also reported (Clarke et al. 2012).
  • Soto-Mota 2019 (28 days). At 26.8 g three times daily, mild nausea followed 6 of 2,016 drinks (Soto-Mota et al. 2019).
  • Sport. The diester’s 2% slower time trial in elite cyclists came with gut discomfort (Leckey et al. 2017).

The monoester tastes strongly bitter. In the Stubbs study, ester and salt drinks could not be blinded because one was bitter and the other salty.

Longer-term safety

The longest safety study ran 28 days in 24 healthy adults aged 18–70. It found no change in body weight or composition, fasting glucose, cholesterol, triglycerides, electrolytes, blood gases or kidney function (Soto-Mota et al. 2019). There are no long-term (months to years) safety trials. The key safety studies were run by the group that developed and patented the monoester.

Acid load and blood sugar

  • Acid load. Monoester drinks cause a small, short-lived drop in blood pH and bicarbonate. In healthy volunteers this stayed within normal limits (Stubbs et al. 2017).
  • Lower blood sugar. Ketone drinks reliably lower blood glucose by about 0.5 mM (Falkenhain et al. 2022). The trials above were in healthy volunteers, so the data do not show how ketone drinks interact with diabetes medicines.

Ketone salts: mineral load

To reach ketosis, salt products deliver large amounts of minerals. In the Stubbs study, a salt drink contained 1.6–3.2 g each of sodium and potassium, and still produced only about 1 mM D-BHB (Stubbs et al. 2017). About half of the BHB in that product was the less-used L-form.

Key takeaways

  • They reliably raise blood ketones. Monoester drinks reach about 1–5 mM BHB within 1–2 hours, far more than ketone salts (about 1 mM), and levels fall back within 3–4 hours.
  • Performance benefit is not established. After a 2% gain in one 2016 study, three systematic reviews found no overall effect, and a few trials showed slower times.
  • Acid load may cancel any benefit. The ester lowers blood pH and bicarbonate. One small trial found a gain only when sodium bicarbonate was added.
  • Recovery and cognition data are mixed. Some lab studies show benefits, but recent field-style trials found none, and the cognition meta-analysis shows a small effect with industry ties.
  • Gut symptoms rise with dose. Nausea, bloating and diarrhea were common at very high doses; only a 28-day safety study exists.
  • Legal and not banned in sport. The monoester is a US food ingredient under GRAS notice GRN 515, and the WADA 2026 list does not name ketones.

Sources

  1. Clarke K, Tchabanenko K, Pawlosky R, et al. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012;63(3):401–408. PubMed.
  2. Stubbs BJ, Cox PJ, Evans RD, et al. On the metabolism of exogenous ketones in humans. Front Physiol. 2017;8:848. PubMed.
  3. Soto-Mota A, Vansant H, Evans RD, et al. Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Regul Toxicol Pharmacol. 2019;109:104506. PubMed.
  4. Holdsworth DA, Cox PJ, Kirk T, et al. A ketone ester drink increases postexercise muscle glycogen synthesis in humans. Med Sci Sports Exerc. 2017;49(9):1789–1795. PubMed.
  5. Falkenhain K, Daraei A, Forbes SC, et al. Effects of exogenous ketone supplementation on blood glucose: a systematic review and meta-analysis. Adv Nutr. 2022;13(5):1697–1714. PubMed.
  6. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24(2):256–268. PubMed.
  7. Margolis LM, O’Fallon KS. Utility of ketone supplementation to enhance physical performance: a systematic review. Adv Nutr. 2020;11(2):412–419. PubMed.
  8. Leckey JJ, Ross ML, Quod M, et al. Ketone diester ingestion impairs time-trial performance in professional cyclists. Front Physiol. 2017;8:806. PubMed.
  9. Evans M, McSwiney FT, Brady AJ, et al. No benefit of ingestion of a ketone monoester supplement on 10-km running performance. Med Sci Sports Exerc. 2019;51(12):2506–2515. PubMed.
  10. Whitfield J, Burke LM, McKay AKA, et al. Acute ketogenic diet and ketone ester supplementation impairs race walk performance. Med Sci Sports Exerc. 2021;53(4):776–784. PubMed.
  11. Poffé C, Ramaekers M, Bogaerts S, Hespel P. Bicarbonate unlocks the ergogenic action of ketone monoester intake in endurance exercise. Med Sci Sports Exerc. 2021;53(2):431–441. PubMed.
  12. Engelbrecht L, Lauriks W, Robberechts R, et al. Ketone ester intake did not improve performance, neither cognitive function or sleep, during an 8-day simulated cycling race. Med Sci Sports Exerc. 2026 (online ahead of print). PubMed.
  13. Valenzuela PL, Morales JS, Castillo-García A, Lucia A. Acute ketone supplementation and exercise performance: a systematic review and meta-analysis of randomized controlled trials. Int J Sports Physiol Perform. 2020;15(3):298–308. PubMed.
  14. Brooks E, Lamothe G, Nagpal TS, et al. Acute ingestion of ketone monoesters and precursors do not enhance endurance exercise performance: a systematic review and meta-analysis. Int J Sport Nutr Exerc Metab. 2022;32(3):214–225. PubMed.
  15. Vandoorne T, De Smet S, Ramaekers M, et al. Intake of a ketone ester drink during recovery from exercise promotes mTORC1 signaling but not glycogen resynthesis in human muscle. Front Physiol. 2017;8:310. PubMed.
  16. 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. PubMed.
  17. Bonnechère B, Stephens EB, Boileau AC, et al. The effect of exogenous ketone bodies on cognition across health and disease: a systematic review and meta-analysis. Front Nutr. 2026;13:1802531. PubMed.
  18. Leaf A, Rothschild JA, Sharpe TM, et al. International Society of Sports Nutrition position stand: ketogenic diets. J Int Soc Sports Nutr. 2024;21(1):2368167. PubMed.
  19. US Food and Drug Administration. GRAS Notice Inventory: GRN No. 515, D-beta-hydroxybutyrate ester (TdeltaS Limited); closed March 5, 2015, “FDA has no questions.” FDA.
  20. US Food and Drug Administration. GRAS Notice Inventory: GRN No. 1032, D-β-hydroxybutyrate (Osaka Gas Chemicals); closed June 2, 2022, “FDA has no questions.” FDA.
  21. World Anti-Doping Agency. The 2026 Prohibited List. In effect January 1, 2026. WADA.
  22. National Center for Biotechnology Information. PubChem Compound Summary for CID 44631890, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. PubChem.