What are Exogenous Ketones?

Authored by Nate Martins and Justin Liau • 
October 10, 2018
exogenous-ketones

Exogenous ketones come from a synthetic source–they are not produced in the body. Those are endogenous ketones, produced by the body during fasting, or while following a ketogenic diet–but this can take weeks or months.

With the advent of exogenous ketones, scientists have developed a way to raise ketone levels significantly and safely without the need to fast or diet.

For years, ketones got a bad rap; they were associated with ketoacidosis and diabetes. But emerging research shows moderate levels of ketones can increase health and performance, contrasting the extreme levels occurring during ketoacidosis.

Exogenous ketones provide the body with another fuel to employ. Think about it like an electric car that runs on both gas and electricity: by consuming ketones along with carbohydrates, the body will preferentially burn the ketones first, saving the carbohydrates for later. Exogenous ketones allow us to enter a metabolic state that wouldn't 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

Consuming exogenous ketones isn't the same as following a ketogenic diet–the ketones in the blood haven't been naturally produced by the breakdown of fat stores. However, scientists believe many of the health benefits of the keto diet and fasting (aside from weight loss) are triggered by ketones. 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
  • Metabolic flexibility: Affecting gene expression and cellular processes associated with brain health and longevity

Our bodies are produce three types of ketone bodies for fuel: beta-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone. Each is used by the body differently. Acetone is the least abundant, produced in much smaller amounts, and is usually exhaled through the lungs rather than being used as fuel.3 Acetoacetate is part of the metabolic pathway whereby humans make and use ketones, but it tends to be found in the blood at lower levels than BHB.

BHB is the predominant ketone body in the blood, which is why it's most often used in exogenous ketones.

Ketone Salts

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

Advantages

  • 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

  • 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)

Research

Despite the recent growth of the ketone salt market, there is very little published work analyzing the effects of these products on any biomarkers or performance measurements in humans. Several studies have been carried out in rats,6,7 with blood BHB levels being relatively low (<0.5 mM) post-consumption of salt drinks. In humans, ketone salts provided 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 mM.5

It’s also important to note 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 than D-BHB. 

Recently, two published studies investigated the effects of ketone salts in athletes (total n = 22).8,9 Performance over a four-minute cycling time-trial and a 150 kJ ( ~11 mins) cycling time trial were compared between ketone salts vs. carbohydrate. In the four-minute trial there was no change in performance, and in the 150 kJ test, performance 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 (MCTs), 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 in monoester (one), diester (two), or triester (three) form.

Instead of being bound to a mineral (like ketone salts), the ketone molecule (BHB or AcAc) is bound to a ketone precursor (e.g. butanediol or glycerol) via an ester bond. While there aren't as many esters on the market as salts, there is still some variance–especially when looking at the ketone molecule in these products. Before selecting the best one for you, it's important to gather all the necessary information to make your decision.

HVMN Ketone (D-BHB Ketone Monoester)

  • Acutely raises D-Betahydroxybutyrate to high levels (up to 3-6 mmol/L) within 30 minutes5,10,11,12
  • Delivers D-BHB without salt or acid load
  • Considered FDA Generally Recognized as Safe (GRAS) for use as a food
  • Approved for use in sport by the World Anti-Doping Agency (WADA)
  • With single doses of the D-BHB ester as a sports drink, gastrointestinal (GI) side effects are 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 reported there were no side-effects of ketone ester drinks hindering sport performance.11,14
  • Published clinical evidence demonstrates efficacy for performance and/or recovery
  • Improved cognitive ability15
  • Distinct bitter taste

Acetoacetate Diester

  • Mildly raises D-BHB to moderate levels (~1 mmol/L)16
  • In current formulation, some report GI symptoms16
  • No improvement in performance (may be related to GI symptoms)16

Research

The first ketone ester was developed in the late 1970s17 and more were developed in the mid-1990s.18 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 to release 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.10 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 diester of AcAc and BDO. In rodents, this ketone ester raises blood D-BHB to 1-4 mM and blood AcAc to up to 5 mM.19 There is one published study of this ketone ester in humans; results showed a 2% decrease in 31 km cycling time trial performance.16 This may be 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 Geoffrey 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, it's imperative to consider:

  • The impact on blood ketone levels and the resulting level of ketosis
  • The quality of the supplement and what impurities it may contain (like sugar, MCT powder or caffeine)
  • The importance of your overall experience. Do you care about price, taste, side effects, etc.?

Exogenous ketones are a new and exciting technology. 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 fully understand how exogenous ketones affect performance, recovery and cognitive ability–but the early results are promising.

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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.Yue Qiao, Zhaohua Gao, Yong Liu, et al., “Breath Ketone Testing: A New Biomarker for Diagnosis and Therapeutic Monitoring of Diabetic Ketosis,” BioMed Research International, vol. 2014, Article ID 869186, 5 pages, 2014. doi:10.1155/2014/869186
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.Murray, A.J., Knight, N.S., Cole, M.A., Cochlin, L.E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M.K., Atherton, H.J., Schroeder, M.A., et al. (2016). Novel ketone diet enhances physical and cognitive performance. FASEB J.
16.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.
17.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.
18.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.
19.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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