Ketone Supplement Fundamentals

It can be difficult to reach a state of ketosis (blood ketones >0.5 mM). Adherence to a ketogenic diet is challenging in today’s carb-centered society. Carbohydrate and protein intake must be monitored to keep the body in a 'ketogenic' state. Sometimes side effects mean that people decide not to continue with the diet. The alternative to achieve 'ketosis' is to fast, which triggers a 'ketogenic' state. However, prolonged fasting is not practical or appealing to many people.  

Ketones could directly cause some of the health benefits of the ketogenic diet and fasting. There are many changes within the body triggered by fasting or a ketogenic diet, but ketones are an important fuel and signal1. Therefore, researchers have explored different tools for 'ketosis' without dietary changes. Ketones themselves are not usually found in high concentrations in food. However, there are now several different ketone supplements that can be consumed like food that raise blood ketone levels.  

Taking ketone supplements means the body can be in 'ketosis' without being ‘ketogenic,’ and may deliver some of the benefits of 'ketosis.' Here it is important to note that exogenous ketones don’t trigger natural ketone production, they don’t put you in a ‘ketogenic’ state. They do put you into ‘ketosis’ which simply means that your blood ketone levels are elevated.   

Endogenous vs Exogenous Ketones

Exogenous ketone bodies are ketones that are consumed through a nutritional supplement. They can result in ketosis without changing the diet. Ketones produced by the liver during a ‘ketogenic’ state (when fasting or following a ketogenic diet) are called endogenous ketones.

Exogenous = ‘Exo’ = external. ‘Genous’ = origin. Originates from a source external from the body.

Endogenous = ‘Endo’ = within. ‘Genous’ = origin. Originates from a source internal to the body.

Different Types of Ketones: Beta hydroxybutyrate and Acetoacetate. 

Most forms of exogenous ketones deliver beta hydroxybutyrate (BHB) rather than acetoacetate (AcAc). This is due to a combination of factors:

  1. BHB is the ketone that is present in the blood at the highest level when produced naturally2
  2. BHB can be readily converted to AcAc inside the cells, and then be used to generate ATP.
  3. BHB is more ‘reduced’ than AcAc. This means when it is used inside the mitochondria, its conversion to AcAc generates NADH. NADH is needed for ATP production in the mitochondria. By contrast, when consuming an AcAc based supplement, some of the AcAc will be converted to BHB because the interconversion is an equilibrium. This uses up NADH and produces NAD, which is not helpful for mitochondrial ATP production.  
  4. BHB is more stable and therefore easier to formulate into a consumable product.

Optical Isomerism of BHB

There are two optical isoforms of BHB: D- and L- BHB. ‘Optical isomerism’ refers to slight differences in the organization of the bonds of the BHB molecule. To illustrate, think of our left and right hands: they have identical components, put together in the same order, but they can’t overlay perfectly.  

FIGURE 1:

Hands illustrating optical isomerism

The subtle differences between D- and L- BHB mean than the body cannot use the two forms in the same way. The body releases D- BHB and uses it for energy. The body does not release significant amounts of L-BHB3. Furthermore, it is unclear how the human body uses L-BHB. Studies in rats suggest that it is not readily used as fuel, and is mainly used to synthesize fats4,5. Overall, L-BHB appears to be a ‘weaker’ form of D-BHB both regarding its ability to provide energy, but also in its ability to act as an antioxidant6

There are two main classes of exogenous ketone supplements that deliver BHB: ketone esters and ketone salts. Medium Chain Triglycerides (MCTs) are also used to artificially raise blood ketone levels. They contain a fat that is easily converted into BHB, but there is no BHB in MCT itself. 

Ketone esters:

Ketone esters are liquids that contain BHB or AcAc bound to another ketone precursor (such as butanediol or glycerol) by 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.

Advantages of Ketone Esters

  • Ketone esters deliver BHB or acetoacetate without a high salt or acid load.
  • Levels of D-BHB achieved are high after D-BHB ketone ester drinks  (up to 6 mM)7,8.
  • The D-BHB ester in HVMN Ketone is approved as a food by the FDA and not prohibited for use in sport by WADA. 

Disadvantages of Ketone Esters

  • Ketone esters have a bitter taste that is difficult to mask.
  • Ketone esters are more expensive to make than ketone salts. 
  • Some studies have reported mild GI side-effects of ketone ester drinks (BHB ester8,9. AcAc-Diester10). Side-effects include nausea or a feeling of dizziness. However, other studies report little to no side-effects of ketone ester drinks 7,11

Overview of clinical research

Ketone esters aren’t a recent discovery. The first ketone ester was developed in the late 1970’s (a glycerol and acetoacetate ester) (Birkhahn1978) and more were developed in the mid-1990’s (RS-1,3-butanediol-acetoacetate mono- and di-esters)4. 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 NIH received funding from the US Military to develop one of these ketone ester compounds: R-1,3-butanediol-R-3-hydroxybutyrate (BD-BHB, See Figure 2A). This is the ketone ester in HVMN KETONE. When taken as a drink, the ester bonds are broken by gut esterase enzymes, releasing butanediol and D-BHB into the blood. Butanediol is metabolized by the liver to form D-BHB. Both molecules of D-BHB reach the circulation, as the liver is unable to use ketones. Consumption of this ketone ester elevates blood ketone levels in humans with few GI and systemic side effects8. This ester has been approved by the FDA for use as food, cleared for use in athletes by the World Anti Doping Agency. The HVMN Ketone product will be batch tested as part of the NSF ‘safe for sport’ program. There are seven published studies human studies of 128 people that have shown:

  • This ester is safe and well tolerated at several doses. There are minimal side effects8
  • This ester raises blood ketones reliably, and in a dose-dependent way12 .
  • In a case study of one patient with Alzheimer’s Disease, daily ketone ester consumption improved cognitive impairment13
  • This ester improved endurance performance in a 30-minute cycling test by 2-3% (400m) when taken before exercise with carbohydrate7
  • When taken after exercise along with IV glucose, this ketone ester improved glycogen re-synthesis11 .
  • When taken after exercise with carbs and protein, this ketone ester activated pathways controlling muscle protein synthesis9.
  • This ester raises BHB levels higher than ketone salts and works even when taken with a carbohydrate-rich meal14
  • This ketone ester decreases appetite and also the levels of the hunger hormone, ghrelin15.  

FIGURE 2:

The second ketone ester compound was developed at the University of South Florida. This is a di-ester of acetoacetate and butanediol (See Figure 2B). In rodents, this ketone ester raises blood D-BHB to 1 - 4 mM and blood AcAc to up to 5 mM 16. There is one published study of this ketone ester in humans; results showed a 2% decrease in 31km cycling time trial performance10. 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.

Ketone salts

Ketone salts are a powder containing BHB bound to a mineral salt (such as sodium or calcium) or an amino acid (such as lysine or arginine). The powdered salts are dissolved into a liquid to make it easier to consume. Published human clinical trials report blood BHB levels of 0.6 - 0.8 mM after ketone salt drinks17,18

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 recommended daily allowance. High salt intake is linked to conditions such as hypertension, cardiovascular disease and stomach cancer19. In the first 1-2 weeks of following a ketogenic diet, there is a higher requirement for electrolytes due to increased excretion in urine. This has led to suggestions that regular ketone salt consumption might compensate for these losses. However, electrolyte imbalances do not persist after the adaptation period of ~28 days20. Therefore, excess salt consumption may have long-term health implications, even for those on a  ketogenic diet. 
  • Salts can cause gastrointestinal symptoms, 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-BHB14
  • Many of the ketone salts currently available on the are not approved as GRAS (generally recognized as safe) by the FDA. 

Overview of clinical research

The effects of ketone salt consumption were tested in a small number of clinical studies21,22. In these children with inborn defects in metabolism,  maximal BHB levels were  0.4 - 2.5 mM and doctors noticed improvements in their clinical symptoms. 

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 rats 23,24,25, with blood BHB levels after salt drinks being relatively low (> 0.5 mM). Similarly, in humans ketone salts gave a peak D-BHB of 1 mM, whereas the same amount of BHB as a ketone ester  (BD-BHB) raised blood BHB to 2.8 mM14. It was also noted 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)17,18. 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 MCT, caffeine, and carbohydrate. It is unknown if adding these extra ingredients will help or hinder the effects of the ketone salt consumed. Many ketone salt supplements do not currently have FDA “Generally Recognised as Safe” status. 

Medium Chain Triglycerides (MCTs):

Medium chain triglycerides are fat molecules; they are made up of glycerol joined to 3 medium length fatty acids. In this case, ‘medium’ chain length means that there are 6-12 carbons in the fatty acid chain. They do not contain ketones themselves, but ketones are formed as a result of their breakdown by the body.  Coconut oil is a natural source of medium chain triglycerides, but they can also be taken as synthetically purified MCT oils.

Due to structural differences, medium chain triglycerides are processed differently to long-chain fats. Long-chain fats are absorbed and are released into the blood via the lymphatic system, bypassing the liver. However, medium-chain triglycerides are transported straight to the liver in the blood. There, they are either used directly as a source of energy or turned into ketones. 

Advantages of MCTs

  • ‘Natural’ sources of MCT exist in food, such as coconut oil.

Disadvantages of MCTs

  • Many people get gastrointestinal symptoms following high levels of  medium chain triglyceride consumption.
  • High amount of calories.
  • Comparatively low blood ketone levels.

Overview of clinical research

There are a large number of research papers demonstrating that MCTs are safe to consume. However, gastrointestinal side-effects (such as diarrhea) are common, especially when consuming high amounts26. This presents a problem, as high amounts of MCT are required to raise blood BHB. In general, studies of MCTs supplements report that blood ketone levels are low (0.5-1 mM)26

There is not a clear answer as to which chain length of fatty acids that make up an MCT is best at raising blood BHB levels. The available research suggests that C6 (caproic) and C8 (capric) fatty acids have the greatest effects on blood BHB27,28 .

Data for the ketone ester and ketone salt BHB are from14,7 

Butanediol

1,3-butanediol (BD) is an alcohol that is structurally similar to BHB. Because of this similarity, the liver easily converts it into BHB and creates a non-fasted ketosis.

Advantages of Butanediol

  • Approved by the FDA as a food.

Disadvantages of Butanediol

  • Comparatively low ketone levels.
  • Risk of intoxication.

Overview of clinical research

Animal experiments showed29 that drinking BD elevates BHB levels up to 1mM. However, there was lethargy and sedation following high doses of BD. If the elevation of blood BD were to have the same effects in humans, this might manifest as cognitive and neuromotor symptoms. Chronic consumption of BD as a food additive has been deemed to be safe by the FDA. However, high doses (> 50 g) of BD may be required to elevate blood ketone bodies sufficiently. The risk of side-effects means that supplementation of BD alone is unlikely to be an acceptable strategy to achieve ketosis.

Choosing the best ketone supplement

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. Keep an eye out for human studies of exogenous ketones and ketone supplement reviews as they become more widely available. 

Considerations for Athletes

Elite athletes have to take extra precautions with sports foods (e.g., energy bars and drinks) and supplements (e.g., caffeine, creatine) to ensure that they do not violate anti-doping rules. Firstly, the specific compound itself must not be prohibited by the World Anti Doping Agency (WADA). Furthermore, an independent laboratory must test each batch of the food/supplement to confirm no contamination with a banned substance. In the USA the major independent testing laboratory is NSF ‘Safe for Sport.’  ‘Informed Sport’ or ‘Informed Choice’ offer testing, and are more popular outside the USA. 

44% of failed drugs tests in the UK in 2012  were caused by contaminated supplements (Source: UKAD website). 

Ketone supplements are not currently banned by WADA, although as far as we are aware, the only ketone product to have been explicitly cleared by WADA is the ketone ester in HVMN Ketone. Some  (but not all) of the commercially available ketone salts are tested by ‘Informed Sport, ’ and HVMN Ketone is tested by NSF ‘Safe for Sport.’   

  1. Newman, J.C., and Verdin, E. (2017). Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25, 42-52.

  2. Cahill, G.F., Jr. (2006). Fuel metabolism in starvation. Annu Rev Nutr 26, 1-22.

  3. Reed, W.D., and Ozand, P.T. (1980). Enzymes of L-(+)-3-hydroxybutyrate metabolism in the rat. Arch Biochem Biophys 205, 94-103.

  4. 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.

  5. Webber, R.J., and Edmond, J. (1977). Utilization of L(+)-3-Hydroxybutyrate, D(-)-3-Hydroxybutyrate, Acetoacetate, and Glucose for Respiration and Lipid-Synthesis in 18-Day-Old Rat. J Biol Chem 252, 5222-5226.

  6. Haces, M.L., Hernandez-Fonseca, K., Medina-Campos, O.N., Montiel, T., Pedraza-Chaverri, J., and Massieu, L. (2008). Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Exp. Neurol. 211, 85-96.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  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. Newport, M.T., VanItallie, T.B., Kashiwaya, Y., King, M.T., and Veech, R.L. (2015). A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 11, 99-103.

  14. 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.

  15. A Ketone Ester Drink Lowers Human Ghrelin and Appetite Stubbs, Brianna J., Cox, Pete J., Evans, Rhys D., Cyranka, Malgorzata, Clarke, Kieran, de Wet, Obesity, November 2017

  16. 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.

  17. Rodger, S., Plews, D., Laursen, P., and Driller, M. (2017). The effects of an oral β-hydroxybutyrate supplement on exercise metabolism and cycling performance.

  18. 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.

  19. 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.

  20. Rabast, U., Vornberger, K.H., and Ehl, M. (1981). Loss of weight, sodium and water in obese persons consuming a high- or low-carbohydrate diet. Ann. Nutr. Metab. 25, 341-349.

  21. Plecko, B., Stoeckler-Ipsiroglu, S., Schober, E., Harrer, G., Mlynarik, V., and Gruber, S. (2002). Oral beta-hydroxybutyrate supplementation in two patients with hyperinsulinemic hypoglycemia: monitoring of beta-hydroxybutyrate levels in blood and cerebrospinal fluid, and in the brain by in vivo magnetic resonance spectroscopy. Pediatr Res 52.

  22. Van Hove, J.L.K., Grunewald, S., Jaeken, J., Demaerel, P., Declercq, P.E., Bourdoux, P., Niezen-Koning, K., Deanfeld, J.E., and Leonard, J.V. (2003). D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD). Lancet 361, 1433-1435.

  23. Kesl, S.L., Poff, A.M., Ward, N.P., Fiorelli, T.N., Ari, C., Van Putten, A.J., Sherwood, J.W., Arnold, P., and D’Agostino, D.P. (2016). Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats. Nutr. Metab. 13, 9.

  24. 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.

  25. 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.

  26. Henderson, S.T., Vogel, J.L., Barr, L.J., Garvin, F., Jones, J.J., and Costantini, L.C. (2009). Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond) 6, 31.

  27. McGarry, J.D., and Foster, D.W. (1971). The Regulation of Ketogenesis from Octanoic Acid: THE ROLE OF THE TRICARBOXYLIC ACID CYCLE AND FATTY ACID SYNTHESIS. J Biol Chem 246, 1149-1159.

  28. Schultz, L.H., Smith, V.R., and Lardy, H.A. (1949). The Effect of the Administration of Various Fatty Acids on the Blood Ketone Levels of Ruminants. J. Dairy Sci. 32, 817-822.

  29. Desrochers, S., Dubreuil, P., Brunet, J., Jette, M., David, F., Landau, B.R., and Brunengraber, H. (1995). Metabolism of (R,S)-1,3-Butanediol Acetoacetate Esters, Potential Parenteral and Enteral Nutrients in Conscious Pigs. Am J Physiol-Endoc M 268, E660-E667.

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