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.
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.
Most forms of exogenous ketones deliver beta hydroxybutyrate (BHB) rather than acetoacetate (AcAc). This is due to a combination of factors:
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.
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 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.
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:
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 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.
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 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.
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 .
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.
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.
When considering ketone supplements, you should consider factors such as:
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.
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.’
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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.
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.
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.
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.
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.
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.
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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.
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