What are Exogenous Ketones?

Authored by Justin Liau • 
May 8, 2018

Exogenous ketones are ketones that come from a synthetic source (they are not made by the body). Normally, the liver produces endogenous ketones only during fasting, caloric restriction, or following a ketogenic diet. Scientists have developed ways to synthesize exogenous ketones which can be consumed to raise ketone levels significantly and safely

Ketones often get a bad rap due to their association with ketoacidosis and diabetes. Why would anyone want to consume more of these ketone bodies then? Emerging research shows that moderate levels of ketones can pay dividends in health and performance, in contrast to the extreme, harmful levels that occur in ketoacidosis. 

Exogenous ketones give us a 'new lever' to fuel our bodies. By consuming exogenous ketones, we can enter a metabolic state that would not normally occur naturally: the state of having full carbohydrate stores as well as elevated ketones in the blood. This could be advantageous to athletes looking to boost their physical performance

For all the keto dieters out there, note that consuming exogenous ketones is not the same as following a ketogenic diet. This is because the ketones in your blood have not come from breaking down your own fat stores. However, scientists believe that many of the health benefits of the keto diet and fasting (aside from weight loss) are actually triggered by ketones themselves! Therefore, raising ketone levels through either endogenous or exogenous ketosis could help to improve health and performance by:

  • Reducing inflammation: ketones reduce activation of inflammatory processes1
  • Reducing oxidative stress: ketones scavenge harmful reactive oxygen species2.
  • Affecting gene expression and cellular processes associated with brain health and longevity.

The Unique Effects of Exogenous Ketones

Our bodies are capable of creating three types of ketone bodies: beta-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone. These ketones can be used as a fuel for the body; research shows that both BHB and AcAc improved oxygen efficiency required for cells to do work3. Taking exogenous ketones means that the body can use ketones to produce energy to partially replace energy from carbs or fats. 

Ketone Salts

Ketone salts are powdered supplements that consist of a ketone molecule bound to one of several mineral salts: sodium, calcium, magnesium, or potassium.

Advantages of Ketone Salts

  • Mildly raise BHB up to ~0.8 mM.
  • Currently cheaper to produce than ketone esters.
  • It is possible to add amino acids as an organic salt to BHB, delivering other nutrients along with BHB.

Disadvantages of Ketone Salts

  • Regular use of ketone salts results in an intake of sodium (or another electrolyte) far higher than the FDA’s recommended daily intake of 2,300 mg per day. High salt intake is linked to conditions such as hypertension, cardiovascular disease, and stomach cancer4
  • Ketone salts can cause gastrointestinal issues, especially at high doses. 
  • Most ketone salts are a mixture of the two optical isoforms of BHB (D- and L-). Human metabolism of L-BHB has not been studied, although it does not appear to be metabolized as rapidly as D-BHB5
  • Many of the ketone salts currently available are not considered FDA GRAS (generally regarded as safe)

Ketone Salt Research

Despite the recent growth of the ketone salt market, there is very little published work looking at the effects of these drinks on any biomarkers or performance measures in humans. Several studies have been carried out in rats67 , with blood BHB levels after salt drinks being relatively low (<0.5 mM). Similarly, in humans ketone salts gave peak D-BHB levels of 1 mM, whereas the same amount of BHB in a ketone ester (BD-BHB) raised blood BHB to 2.8 mM5

It’s also important to note that there was a high amount of L-BHB in the blood after salt drinks (> 2 mM). L-BHB took far longer to be removed from the blood compared with D-BHB, indicating that L-BHB likely has a different metabolic fate to D-BHB. 

Recently, two published studies investigated the effects of ketone salts in athletes (total n = 22)89. Performance over a 4-minute cycling time-trial and a 150 kJ ( ~11 mins) cycling time trial were compared between ketone salts vs. carbohydrate. In the 4 minute trial there was no change in performance, and in the 150 kJ test, performance was decreased by 7%. Blood BHB levels peaked at 0.6 and 0.8 mM in these studies.

Some commercial ketone salt supplements contain other ingredients such as Medium Chain Triglycerides (MCT’s), caffeine, and even carbohydrate, but it is unknown if adding these ingredients will help or hinder the effects of the ketone salt consumed. 

Ketone Esters

Ketone esters are salt-free liquids that exist in monoester (one), diester (two), or triester (three) form. Instead of being bound to a mineral, like ketone salts are, the ketone molecule (BHB or AcAc) is bound to a ketone precursor (e.g. butanediol or glycerol) via an ester bond. There are several types of ketone ester in exsistance and they affect the body differently. Therefore it is important to distinguish which ketone ester is being used.

HVMN Ketone (D-BHB Ketone Monoester)

  • Acutely raises D-Betahydroxybutyrate to high levels (up to 3-6 mmol/L) within 30 minutes 5,10,11,12.
  • HVMN Ketone delivers D-BHB without salt or acid load.
  • HVMN Ketone is considered FDA Generally Recognized as Safe (GRAS) for use as a food.
  • HVMN Ketone is not prohibited for use in sport by the World Anti-Doping Agency (WADA).
  • With single doses of the D-BHB ester as a sports water, gastrointestinal (GI) side effects are VERY rare. Some studies have reported mild GI side-effects of HVMN Ketone drinks at extremely high doses (4x serving size) or when given in a thick, meal replacement formulation 10,13. However, other studies of athletes report that there were no side-effects of ketone ester drinks that affected sport performance 11,14.
  • Published clinical evidence demonstrates efficacy for performance and/or recovery.
  • Distinct bitter taste.

Acetoacetate Diester

  • Mildly raises D-BHB to moderate levels (~1 mmol/L) 1.
  • In current formulation, some report GI symptoms 1.
  • No improvement in performance (may be related to GI symptoms)1.

Ketone Ester Research

Let’s take a look at the research that’s been done on ketone esters. The first ketone ester was developed in the late 1970’s15 and more were developed in the mid-1990’s16. Currently, two different ketone esters are under active investigation in rodents and humans. Both can rapidly elevate blood ketone levels up to 7 mM. 

A research group at the University of Oxford and National Institute of Health received funding from the US Military to develop one of these ketone ester compounds: R-1,3-butanediol-R-3-hydroxybutyrate (BD-BHB). This is the ketone ester in HVMN Ketone. When taken as a drink, the ester bonds are broken down, thereby releasing butanediol (BDO) and D-BHB into the blood. BDO is easily metabolized by the liver to form D-BHB. Then, both molecules of D-BHB reach the blood, as the liver is unable to use ketones. Consumption of this ketone ester elevates blood ketone levels in humans safely, with few side effects (Clarke2012). HVMN Ketone is WADA compliant and safe to use in all levels of sports. It is designated as a foodstuff and is FDA GRAS. Each lot is 3rd party certified and batch tested for banned substances. 

The second ketone ester compound was developed at the University of South Florida. This is a di-ester of AcAc and BDO. In rodents, this ketone ester raises blood D-BHB to 1-4 mM and blood AcAc to up to 5 mM17. There is one published study of this ketone ester in humans; results showed a 2% decrease in 31km cycling time trial performance18. This is likely due to the high rate of side effects of this ester studied. Other factors may have been low levels of BHB (<2 mM), the short, high-intensity time trial used, or the use of AcAc vs. BHB. Read Geoff Woo's take on that study and a published response to the science journal by Dr Brianna Stubbs and Dr Dom D'Agostino to find out more. 

Choosing an Exogenous Ketone

When considering ketone supplements, you should consider factors such as: 

  • The impact on blood ketone levels and the resulting level of ketosis.
  • Is the supplement of a good quality and free of impurities? What other ingredients are added (e.g., sugar, MCT powder or caffeine)?
  • What is your overall experience (price, taste, tolerability or side effects, etc.)?

Exogenous ketones are a new and exciting dietary tool. They may give some of the benefits of 'ketosis' without having to follow a ketogenic diet to trigger ketone production. Further research is required to understand where exogenous ketones are equivalent, better, or worse than the ketogenic diet. Stay on the lookout for human studies of exogenous ketones and ketone supplement reviews as they become more widely available!

Scientific Citations

1.Volek, J.S., Phinney, S.D., Forsythe, C.E., Quann, E.E., Wood, R.J., Puglisi, M.J., Kraemer, W.J., Bibus, D.M., Fernandez, M.L., and Feinman, R.D. (2008). Carbohydrate Restriction has a More Favorable Impact on the Metabolic Syndrome than a Low Fat Diet. Lipids 44, 297-309.
2.Shimazu, T., Hirschey, M.D., Newman, J., He, W., Shirakawa, K., Le Moan, N., Grueter, C.A., Lim, H., Saunders, L.R., Stevens, R.D., Newgard, C.B., Farese Jr, R.V., De Cabo, R., Ulrich, S., Akassoglou, K., and Verdin, E. (2013). Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211-214.
3.Lardy HA, Hansen RG, Phillips PH. The metabolism of bovine epididymal spermatazoa. Arch Biochem. 1945;6:41–51.
4.Strazzullo, P., D'Elia, L., Kandala, N.B., and Cappuccio, F.P. (2009). Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies. BMJ 339, b4567.
5.Stubbs, B.Cox, P.; Evans, R.; Santer, P.; Miller, J.; Faull, O.; Magor-Elliott, S.; Hiyama, S.; Stirling, M.; Clarke, K. (2017). On the metabolism of exogenous ketones in humans. Front. Physiol.
6.Ari, C., Kovács, Z., Juhasz, G., Murdun, C., Goldhagen, C.R., Koutnik, A.P., Poff, A.M., Kesl, S.L., and D’Agostino, D.P. (2016). Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats. Front. Mol. Neurosci. 9, 137.
7.Caminhotto, R.d.O., Komino, A.C.M., de Fatima Silva, F., Andreotti, S., Sertié, R.A.L., Boltes Reis, G., and Lima, F.B. (2017). Oral β-hydroxybutyrate increases ketonemia, decreases visceral adipocyte volume and improves serum lipid profile in Wistar rats. Nutr. Metab. 14, 31.
8.Rodger, S., Plews, D., Laursen, P., and Driller, M. (2017). The effects of an oral β-hydroxybutyrate supplement on exercise metabolism and cycling performance.
9.O’Malley, T., Myette-Cote, E., Durrer, C., and Little, J.P. (2017). Nutritional ketone salts increase fat oxidation but impair high-intensity exercise performance in healthy adult males. Applied Physiology, Nutrition, and Metabolism, 1-5.
10.Clarke, K., Tchabanenko, K., Pawlosky, R., Carter, E., Todd King, M., Musa-Veloso, K., Ho, M., Roberts, A., Robertson, J., Vanitallie, T.B., et al. (2012). Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul. Toxicol. Pharmacol. 63, 401-408.
11.Cox, P.J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., Murray, Andrew J., Stubbs, B., West, J., McLure, Stewart W., et al. (2016). Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metabolism 24, 1-13.
12.Shivva, V., Cox, P.J., Clarke, K., Veech, R.L., Tucker, I.G., and Duffull, S.B. (2016). The Population Pharmacokinetics of d-β-hydroxybutyrate Following Administration of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate. The AAPS journal, 1-11.
13.Vandoorne, T., De Smet, S., Ramaekers, M., Van Thienen, R., De Bock, K., Clarke, K., and Hespel, P. (2017). Intake of a Ketone Ester Drink during Recovery from Exercise Promotes mTORC1 Signaling but Not Glycogen Resynthesis in Human Muscle. Front. Physiol. 8, 310.
14.Holdsworth, D.A., Cox, P.J., Kirk, T., Stradling, H., Impey, S.G., and Clarke, K. (2017). A Ketone Ester Drink Increases Postexercise Muscle Glycogen Synthesis in Humans. Med Sci Sports Exerc.
15.Leckey, J.J., Ross, M.L., Quod, M., Hawley, J.A., and Burke, L.M. (2017). Ketone Diester Ingestion Impairs Time-Trial Performance in Professional Cyclists. Front. Physiol. 8, 806.
16.Birkhahn RH, Border JR.Intravenous feeding of the rat with short chain fatty acid esters. II. Monoacetoacetin. Am J Clin Nutr. 1978 Mar;31(3):436-41.
17.Desrochers, S., David, F., Garneau, M., Jette, M., and Brunengraber, H. (1992). Metabolism of R-1,3-Butanediol and S-1,3-Butanediol in Perfused Livers from Meal-Fed and Starved Rats. Biochem. J. 285, 647-653.
18.D'Agostino, D.P., Pilla, R., Held, H.E., Landon, C.S., Puchowicz, M., Brunengraber, H., Ari, C., Arnold, P., and Dean, J.B. (2013). Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304, R829-836.
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