Ketone Esters: What They Are, Benefits Of Use and How They Work

What are the research supported benefits of Ketone Esters? This article explains where the applications of esters may be. It also outlines who may benefit from Ketone Esters.

What Are Ketone Esters?

There is a lot of talk about Ketone Esters. Esters fall under the category of exogenous ketones along with ketone salts. These are substances that contain ketones and lead to the state of ketosis. However, esters differ from ketone salts since they’re formed by binding an alcohol molecule to a ketone body. Salts are bound to Sodium, Potassium or Calcium.

Not being bound to salt means Esters can contain more Beta-Hydroxybutyrate (BHB). BHB is one of the three ketones bodies that we produce. It is present in greater quantities than other ketone bodies, and is the main ketone based fuel source. This means that Esters can increase ketone levels more than ketone salts.

As a result, they are sparking interest in people looking into potential health and performance benefits of ketones.

A History of Ketone Esters – Timeline

What Ketone Esters Are on The Market?

Two esters are on the market at present, HVMN and KetoneAid (KE4). Whilst these are different products, the type of ester is identical.

There is a lot of talk about these products, with the two companies raising huge sums of money in pre-sales. With interest mainly focused on sports performance and neurological therapies.

Types of esters

Whilst HVMN and KE4 are the only available Esters, a recent publication used a different type of ester [note]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. , 8, 806.[/note] (1,3-butanediol acetoacetate diester (AcAc Diester)). This offers a comparison to KE4 and HVMN’s ester.

A key difference is that this Ester was an Acetoacetate (AcAc). AcAc is another of the ketone bodies. It converts into BHB, although it is also used for fuel itself. It promotes higher levels of AcAc rather than BHB[note]Cox, P.J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., Murray, A.J., Stubbs, B., West, J., McLure, S.W. and King, M.T. (2016).Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell metabolism, 24(2), 256-268.[/note],[note]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. Frontiers in physiology, 8, 806.[/note].

What Are the Side Effects of Ketone Esters?

Side effects have been commonplace in research using esters. Most commonly, reports of gastrointestinal (GI) distress are seen. These have been reduced in some studies, and are likely dependant on the amount of Ester consumed. For example, research has shown taking beyond the standard dose is a key predictor of GI distress[note]Clarke, K., Tchabanenko, K., Pawlosky, R., Carter, E., King, M. T., Musa-Veloso, K., … & Veech, R. L. (2012).Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regulatory Toxicology and Pharmacology, 63(3), 401-408.[/note].

In research with the AcAc ester, every participant experienced side effects during an exercise test. These are shown below (n=11):

• 5 – Moderate Nausea
• 2 – Dry Retching and Nausea
• 2 –  Minor Gut Discomfort
• 1 – Moderate Reflux
• 1 – Prolonged Vomiting and Dizziness

Do Esters Improve Performance?

Background

There’s a lot of talk about esters right now with regards to exercise performance. Due to the relative lack of research on these new products, most of the feedback has come from elite athletes.

Esters gained a huge amount of publicity when it was found out that Team Sky had been using them. Following this, it was also found out that six other teams were using esters. Thus, there was much hype around esters. Soon, other athletes began using esters, such as combat sport athletes.

Theory

The aim of this section is to move away from the hype and look into the theory and research on esters. We will look at why esters may impact exercise, and if this stands up in the research to date.

A key research paper by Cox et al.[note]Cox, P.J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., Murray, A.J., Stubbs, B., West, J., McLure, S.W. and King, M.T. (2016).Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell metabolism, 24(2), 256-268.[/note] carried out the most comprehensive study of esters on exercise to date. The Oxford University research group used esters to see the effect of them on cycling performance. They found a 2% improvement. Whilst this is a notable finding, the study also took extensive blood and muscle measures. Thus, these tests allow us to better understand why performance improvements may occur.

Why Did These Performance Improvements Occur?

It’s clear that many factors were at play in seeing these performance improvements. Notable changes in substrate use occurred after ester ingestion. This means changes in the use of fat, carb and ketones were evident. One change is a decrease in glycolysis. With glycolysis being the breakdown of glucose.

The decrease in glycolysis may be an issue in high-intensity exercise. This is because carbs are the main fuel source in this domain[note]Romijn, J. A., Coyle, E. F., Sidossis, L. S., Gastaldelli, A., Horowitz, J. F., Endert, E., & Wolfe, R. R. (1993). href=”http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.503.9239&rep=rep1&type=pdf”>Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. American Journal of Physiology-Endocrinology And Metabolism, 265(3), E380-E391.[/note].

The authors suggest that the effect of the Ketone Ester in impairing glycolysis was counteracted by the oxidation of ketones. Thus, glycogen was spared, meaning it was not depleted at the end of the exercise bout.

Comparisons to Performance Impact of Keto Diet

This is similar to that of the keto diet[note]Carey, A. L., Staudacher, H. M., Cummings, N. K., Stepto, N. K., Nikolopoulos, V., Burke, L. M., & Hawley, J. A. (2001). Effects of fat adaptation and carbohydrate restoration on prolonged endurance exercise. Journal of Applied Physiology, 91(1), 115-122.[/note], but instead of becoming a fat burner, you are using ketones as an added fuel source to spare glycogen stores. Glycogen sparing is of interest to endurance athletes as glycogen stores are finite (with 300-600g in the muscle, and 80-110g in the liver). It is therefore only large enough to fuel approximately up to 3 hours of exercise[note]Jeukendrup, A. (2014). A step towards personalized sports nutrition: carbohydrate intake during exercise. Sports Medicine, 44(1), 25-33.[/note].

This is the reason so many athletes, experience the ‘hitting the wall’ phenomenon. As glycogen stores are depleted they are unable to burn the vast quantity of fat that should be available to them from their fat stores. Thus, during glycogen depleting exercise, being able to burn an alternative fuel source such as fat, may be beneficial.

What other changes occurred?

Another change noted was the increase in burning of fat stored in the muscle, despite the high intensity of the exercise. This was a noteworthy discovery since the ability to use fat stored in the muscle is greatly diminished at high intensities[note]Powers, S. K., & Howley, E. T. (2007). Exercise physiology: Theory and application to fitness and performance.[/note]. The finding is both interesting and unexpected. This is because exogenous ketones are known to reduce the ability to burn fat[note]Hellman, D. E., Senior, B., & Goodman, H. M. (1969). Anti-lipolytic effects of β-hydroxybutyrate. Metabolism-Clinical and Experimental, 18(11), 906-915.[/note]. Bein able to burn fat at a high intensity has large performance implications.

What has further research shown?

A recent study, for example, showed the ability to burn fat at high intensity explained the difference between recreational and elite athletes [note]Hetlelid, K. J., Plews, D. J., Herold, E., Laursen, P. B., & Seiler, S. (2015). Rethinking the role of fat oxidation: substrate utilisation during high-intensity interval training in well-trained and recreationally trained runners. BMJ open sport & exercise medicine(1), e000047.[/note].

Increased lactate impairs the muscle’s ability to use fat stored in the muscle[note]Gorski, J. (1992). Muscle triglyceride metabolism during exercise. Canadian journal of physiology and pharmacology, 70(1), 123-131.[/note].The ability to maintain lower lactate may be one reason that fat stored in the muscle is burnt at high intensities. This is one potential reason for improved performance.

These improvements in performance are notable. Yet, researchers have noted the difficulty in blinding participants to the ester. This opens the door to the placebo effect which improves performance[note]Ross, R., Gray, C. M., & Gill, J. M. (2015). Medicine and science in sports and exercise (8), 1672-1681.[/note][note]Clark, V. R., Hopkins, W. G., Hawley, J. A., & Burke, L. M. (2000). “Medicine and Science in Sports and Exercise, 32(9), 1642-1647.[/note]. Thus, research must ensure blinding to the ketone to ensure the placebo effect is not an issue.

The findings discussed raise two important questions:

• Do ketone esters themselves improve performance?
• Do different Ketone Esters have different levels of effectiveness?

This is important since much lower BHB levels are present following AcAc Ester use (<1 mmol vs. >5 mmol). This may be the reason for impairment. As well as this, the paper reported GI issues for subjects taking the AcAc Ester. Thus it’s not clear whether the Ester itself impaired performance, or if it was the nausea felt by all subjects.

Ketone Esters for Cognition and Repeated Sprint Exercise

A recent study looked at the effect of esters on repeated sprints and cognitive performance after exercise. The key finding from this paper was enhanced cognition with esters after sprints. An important part of performance is the ability to think when fatigued. Being able to function well, and make good decisions can be the difference between winning and losing. The team from Dublin City University tested this.

This study design involved a Loughborough Intermittent Shuttle Test. This entailed 5 sets of 15 minutes of running, with 3 minutes break between (part A). Then, participants changed every 20 metres between easy and hard running until fatigue (part B). Cognitive tests before and after the exercise trials looked at changes in this respect.

The results showed no difference in any exercise type. It was not expected that performance would improve here. This is due to the impairment in the pyruvate dehydrogenase (PDH) complex following ester ingestion.

What is PDH?

PDH is an enzyme that plays a key role in glycolysis. It does this by helping turn pyruvate into Acetyl CoA. This is then used in the body to deliver an acetyl group to the Krebs cycle. This is how we all produce energy. Thus an impairment of PDH will impair the burning of carb for fuel.

This impairs carb use, which is essential for high-intensity exercise. Suggesting esters may not improve performance of this kind.

Study Synopsis

The highlight of this study, was the improvement in cognition when taking the ester.

This is an interesting finding that offers an alternative use for esters. With the authors concluding:

‘Despite the lack of benefit to performance, the novel finding of preserved executive function after exercise suggests that there remains a chance that ketones could enhance sport performance in team sport athletes’.

This opens the door for future research in the area of cognition and esters.

Takeaways

Research is still in the early stages, with two endurance trials and one sprint trial. Future studies on the role of BHB and performance are much needed. Evans et al. addressed many reasons for improvement in this paper[note]Evans, M., Cogan, K. E., & Egan, B. (2017). Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. The Journal of physiology, 595(9), 2857-2871.[/note], as well as mechanisms that may impair performance.

Key factors contributing to improved performance

• Glycogen Sparing
• Reduced Lactate
• Increased Intramuscular Triglyceride Use
• Improved Executive Function

As well as this, a factor known to affect performance is the inhibition in the PDH complex. This complex is also affected by following a keto diet[note]Evans, M., & Egan, B. (2018). Intermittent Running and Cognitive Performance after Ketone Ester Ingestion. Medicine and science in sports and exercise.[/note]. This could impair performance in sprint activities. Yet, research so far suggests rather than impairing performance, there is no change.

Ketone Esters to Improve Recovery from Exercise

Theory

Ketosis is common after exercise, even in people not on keto. This is called Post-Exercise Ketosis (PEK). A response that improves the uptake of glycogen, and supports protein synthesis[note]Evans, M., Cogan, K. E., & Egan, B. (2017). Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. The Journal of physiology, 595(9), 2857-2871.[/note]. Thus there may be a role for increasing ketones post-exercise. This could spare protein and carb stores when carb stores are low.

This area is another that is still in the very early stages of research. There are two studies using esters. The two areas studied are glycogen replenishment and protein synthesis. The findings of these are of interest and provide a rationale for further study.

Early recovery research

Protein Synthesis

High levels of ketone bodies may have protein sparing effects in skeletal muscle. Before the use of Esters, ketone infusions showed a 10% increase in protein synthesis. This occurred when BHB levels reached 2 mmol[note]Nair, K. S., Welle, S. L., Halliday, D., & Campbell, R. G. (1988). Effect of beta-hydroxybutyrate on whole-body leucine kinetics and fractional mixed skeletal muscle protein synthesis in humans. The Journal of clinical investigation, 82(1), 198-205.[/note]. Ester use has shown similar results[note]Vandoorne, T., De Smet, S., Ramaekers, M., Van Thienen, R., De Bock, K., Clarke, K., & Hespel, P. (2017). Intake of a ketone ester drink during recovery from exercise promotes mTORC1 signaling but not glycogen resynthesis in human muscle. Frontiers in physiology, 8, 310.[/note].

They showed improved protein synthesis when consuming a ester. This further validates the potential use of esters in recovery from exercise.

Glycogen Replenishment

The role of esters on glycogen resynthesis is more mixed. Recent research on glycogen resynthesis showed a 50% increase in glycogen after 2 hours recovery[note]Holdsworth, D. A., Cox, P. J., Kirk, T., Stradling, H., Impey, S. G., & Clarke, K. (2017). A ketone ester drink increases postexercise muscle glycogen synthesis in humans. Medicine and science in sports and exercise, 49(9),1789.[/note]. This is not supported by the latter Vanboorne study. They showed no effect in increasing glycogen.

Following these papers, a landmark study was recently published to see whether chronic ester use could help performance, with the results discussed below.

Ester use to prevent overreaching

A recent study[note]Poffé, C., Ramaekers, M., Van Thienen, R. and Hespel, P., (2019). Ketone ester supplementation blunts overreaching symptoms during endurance training overload. The Journal of physiology.[/note] looked to further develop the use of esters as a recovery tool. Using the rationale of the above studies, as well as the fact that ketones can reduce inflammation and oxidative stress, they suggested that esters could reduce overreaching symptoms.

The study was the first to test esters when taken over a long (3 week period). The findings were that the negative symptoms associated with over-training were reduced when taking the ester. This translated into a 15% improvement on an endurance test after 3 weeks on the ester.

Practical Relevance

This suggests using the ester to prevent overreaching symptoms can help endurance performance. This was an impressive study, and has great practical relevance for athletes that may go through heavy training blocks.

The athletes were training twice per day and taking ester after every session. Thus athletes in this situation may benefit from ester use.

Takeaways Relating To Ketone Esters and Performance/Recovery

From current research, there are a few things that are clear about esters and performance:

Ketone Esters for Performance and Recovery

What Do We Know From the Research	Growing Areas of Research	Negative Impacts of Ketone Esters on Performance
Using esters can prevent symtpoms of overreaching, and with chronic use this can improve endurance	Esters may Improve Cognition During Exercise	Reduced Ability to use carbs through the reduction in PDH
During Exercise, esters Result in a Lower Lactate levels	Using esters in Recovery May increase Glycogen Resynthesis	GI Distress.
Post Exercise, esters Increase Protein Synthesis	Esters May Enhance Endurance Performance	Not enough evidence to Recommend Esters for Exercise Performance

What Will We See From Future Research?

It is not yet known whether this can lead to esters helping performance. However, it is likely there is, at best there’s no improvement in sprinting. In longer exercise, more research is needed to see the effect of esters.

Areas Warranting Further Investigation

More research will help understand the impact of esters on performance

Research at present cannot state that performance will improve. The current body of research is inconclusive. The theory behind the ketones is sound. With only a handful of current papers, the role of esters in performance is an exciting area.

Many athletes would benefit from improved condition. In particular, combat sports and team sport athletes. This provides an area of future study following the work of Egan and Evans[note]Evans, M., & Egan, B. (2018). Intermittent Running and Cognitive Performance after Ketone Ester Ingestion. Medicine and science in sports and exercise.[/note].

Esters for keto athletes?

There has yet to be a paper looking at if esters can impact keto-adapted individuals.

The fact that keto athletes are not dependant on carbs may mean they benefit further. This is because the impairment in glycolysis may be less of a issue in this group.

More research on certain types of activity would be useful. For example, different work rates and different durations of activity. This will help see what sports may benefit from ester.

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Matt Carpenter MSc.

I am a PhD student researching the efficacy of carbohydrate for living and performance, alongside methods to optimise exercise performance in keto-adapted athletes. I joined the Ketosource team in July 2018 as a Research Analyst, and in December 2018 took on the role of Nutrition Analyst. My role entails keeping up to date with the latest research within the realm of health and well-being, as well as working on experiments to run, addressing some key questions present in the keto community.