Ketone Supplements

• Ketone bodies (acetone, acetoacetate and beta-hydroxy-butyrate [ßHB]) are chemicals produced by the liver during periods of low energy or low carbohydrate availability, with high circulating levels seen during starvation, prolonged fasting and extreme carbohydrate restriction (e.g. ketogenic low carbohydrate high fat [LCHF] diets).
• ßHB is the most important ketone body (“ketone”) from a metabolic perspective and blood concentrations of 1-3 mmol/L are considered to be the optimal range for it to exert metabolic effects.¹
• Ketone supplements are taken to acutely increase blood concentrations of ßHB/ ketones without the need to undertake energy or carbohydrate restrictions. A range of benefits has been proposed or investigated including:
  • Direct benefit to physiological and cognitive aspects of endurance performance via fuelling mechanisms^2-4
  • Superior post-exercise recovery with potential use as a chronically used supplement⁵
  • Strategic chronic or periodised use to enhance health and training adaptations⁶
• The first major interest in the use of oral ketone supplements in sports is attributed to work of Oxford University’s Professor Kieran Clarke, who developed a ketone ester (“DeltaG”) that was part of a campaign to prepare British athletes for the 2012 London Olympic Games. This product has also been highly used within professional road cycling teams for the benefits previously identified, as well as other claims such as appetite suppression to support body composition goals.

• Ketone supplements are available in three different forms.
  • Ketone salts (sodium, magnesium or calcium salts of the ßHB).
  • 1-3- Butanediol (precursor to ßHB).
  • Ketone esters.
    • The ketone mono-ester [®-3-hydroxybutyl (R)-3-hydroxy-butyrate) developed as DeltaG at Oxford University is now commercialised as HVMN Ketone Ester.
    • Patents for di-esters have been established but are only involved in clinical research.
• Some manufactured ketone supplements contain a racemic mixture (i.e. equal parts D- and L- stereoisomers) of ßHB. Only the D-isomer (R-ßHB) is considered to have high metabolic activity.

Acute use for exercise

• A variety of protocols have been investigated in scientific trials with the most common involving the intake of the ketone ester before, and sometimes during, endurance exercise.
• Total dose = ~570-750 mg/kg (40-60 g). Note that one 40 g bottle of the Ketone Ester contains 25 g of the active compound.
• The protocols of use associated with testimonials in some sports (e.g. road cycling) are unknown.

Chronic or periodic use

• Protocols recommended for chronic or periodic use have not yet been established.

Current evidence to support the use of ketone supplements is summarised in the table below. >

Equivocal scientific support

• The evidence for benefits of acute or chronic supplementation on health and performance is unclear. There is a wide range in the protocols of use, and in the scenarios of exercise, in which it has been investigated. It is difficult to integrate the various findings of these studies.
• The effects of high blood ketone levels on metabolism and other physiological outcomes is extremely complex. Different protocols of use may achieve variable effects on the timing and increase in blood ßHB concentrations with differential effects on substrate metabolism and physiological effects. It may be difficult to pinpoint beneficial uses and the window of benefit may be small. In addition, some of the effects may impair sports performance.
  • Ketone supplementation creates major effects on substrate use (reduces glycolysis, lipolysis, glycogen use and increases use of intramuscular triglycerides. Some of these effects may be counter-productive to some sports scenarios.
  • Causes increase in blood acidity which may be counter-productive to some sports scenarios.
• Some recent studies suggest that the ßHB provides a minor substrate for the muscle (~5% of fuel use) and the claimed benefits to exercise economy (reduced oxygen use) are equivocal.
• The current investigations on ketone ester supplementation fail to cover most of the anecdotal uses/testimonials and the claims around longterm/chronic use.

Nuances of specific supplements

• Ketone ester supplements
  • These are expensive and often hard to obtain due to limited capacity for commercial manufacture (~$50 per 25 g bottle for HVMN supplement).
• Ketone salts
  • These produce a high salt load and gastrointestinal side effects.
  • These appear extremely unlikely to sufficiently increase blood ßHB (> 1 mmol/L).

Perceptions around their use

• Ketone ester supplements are not included on the WADA Prohibited List and it would seem impractical as well as illogical for them to meet the criteria for such a ban.
• Nevertheless, the initial use of “DeltaG” supplement by UK sporting teams and professional cycling teams has received much media/public criticism as being “frankenscience”.

Supplement safety information www.sportintegrity.gov.au/what-we-do/anti-doping/supplements-sport, opens in a new tab

1. Evans, M., Cogan, K.E., & Egan, B. (2017). Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol, 595(9), 2857-71.
2. Shaw, D.M., Merien, F., Braakhuis, A., Maunder, E., & Dulson, D.K. (2020). Exogenous Ketone Supplementation and Keto-Adaptation for Endurance Performance: Disentangling the Effects of Two Distinct Metabolic States. Sports Med, 50, 641-656.
3. Valenzuela, P.L., Castillo-García, A., Morales, J.S., & Lucia, A (2020). Update on the Acute Effects of Ketone Supplements in Athletes. Adv Nutr, 11(4),1050-1.
4. Margolis, L.M. & O’Fallon, K.S. (2019). Utility of Ketone Supplementation to Enhance Physical Performance: A Systematic Review. Adv Nutr. 11, 412-419.
5. Poffe, C., Ramaekers, M., Van Thienen, R., & Hespel, P. (2019) Ketone ester supplementation blunts overreaching symptoms during endurance training overload. J Physiol, 597(12), 3009-27.
6. Poffé C, Hespel P. Ketone bodies: beyond their role as a potential energy substrate in exercise. J Physiol. 2020 Nov;598(21):4749-50.
7. Valenzuela, P.L., Castillo-Garcia, A., Morales, J.S., & Lucia, A. (2020) Perspective: Ketone Supplementation in Sports-Does It Work? Adv Nutr. In press.
8. Valenzuela, P.L., Morales, J.S., Castillo-García, A., & Lucia, A. (2020) Acute Ketone Supplementation and Exercise Performance: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Int J Sports Physiol Perform,15(3), 298-308.
9. Cox, P.J., Kirk,T,. Ashmore, T., Willerton, K., Evans, R., Smith A, et al. (2016). Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab, 24(2), 256-68.
10. Poffe, C., Ramaekers, M., Bogaerts, S., & Hespel, P. (2021). Bicarbonate Unlocks the Ergogenic Action of Ketone Monoester Intake in Endurance Exercise. Med Sci Sports Exerc.53, 431-441.
11. Poffe, C., Wyns, F., Ramaekers,. M, & Hespel, P. Exogenous Ketosis Impairs 30-min Time-Trial Performance Independent of Bicarbonate Supplementation. Med Sci Sports Exerc, in press.