Want to know what Ketone Esters are and whether you should use them? This article covers all things Ketone Esters. It examines what the research shows so far and what it doesn’t have answers for. It also outlines who may benefit from Ketone Ester supplementation, and for which goals (athletics, cognitive, weight loss or therapeutic).

Read on to learn about:

What Are Ketone Esters?

There is a lot of talk about Ketone Esters at present, with increasing anecdotes of both HVMN (said like: Human) and KetoneAid’s Ester (called KE4). Ketone Esters fall under the category of exogenous ketones along with ketone salts. Exogenous ketones are substances that contain ketones and lead to the state of ketosis. Esters differ from ketone salts since they’re developed by binding an alcohol molecule to a ketone body. Salts are bound to Sodium, Potassium or Calcium.

Not being bound to a salt allows for Ketone Esters to contain a greater amount of Beta-Hydroxybutyrate (BHB). Beta-Hydroxybutyrate is one of the three ketones bodies produced in the body. It is seen in greater quantities than other ketone bodies. This means that Esters can increase ketone levels more than commercially available ketone salts.

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

A History of Ketone Esters – Timeline

What Ketone Esters Are on The Market?

There are two commercially available Ketone Esters on the market at present, HVMN and KetoneAid. Whilst KetoneAid and HVMN are individual products, the type of ketone used is identical in both.

There is a lot of talk about these products, with the two companies raising huge sums of money in pre-sales. Interest in Ketone Esters is mainly focused on sports performance and neurological therapies. There’s also ongoing discussion about the potential role of Ketone Esters for longevity as well as productivity. This stems from the role of BHB in these areas, however, these are beyond the scope of the present article.

Whilst HVMN and KetoneAid are the only commercially available Esters, a recent publication used a different type of Ester 1 (1,3-butanediol acetoacetate diester (AcAc Diester)). This offers an interesting comparison to KetoneAid and HVMN’s BHB monoester. A key difference is that this Ester was an Acetoacetate.

Acetoacetate is another of the ketone bodies, which is typically converted into BHB, although it can be used for fuel itself. It promotes comparatively higher levels of acetoacetate rather than BHB 2 3. The AcAc diester also did not increase ketones to the same extent as the BHB monoester. The AcAc diester reached 1 mmol, compared to up to 5 mmol with the ketone monoester.

The AcAc diester has been researched extensively in rats. They have shown promising results and may have anti-seizure properties 4. However, much of the interest from a general health and performance standpoint surrounds the BHB monoester. This has therefore been the subject of human trials to date.

What is the Difference Between Ketone Esters?

What Are the Side Effects of Ketone Esters?

Side effects have been commonplace in research using Ketone Esters. Most commonly, reports of gastrointestinal (GI) distress are reported. These have been markedly reduced in some studies, and are likely dependant on the amount of Ester consumed. For example, research has shown taking beyond the recommended dose is a key predictor of GI distress 5.

In research with the AcAc diester, every participant experienced side effects during an exercise test. These are shown below:

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

A response to this paper was published questioning the use of a fizzy drink alongside the Ester 6. They pointed out that this combination would likely increase the chance of GI discomfort. As a result, we don’t know how much of this was a result of the ketone itself, and we don’t know whether the AcAc diester is less tolerable than BHB.

Luckily more data exists around the BHB monoester. Previously, comparable side effects were shown using the ketone monoester used in KetoneAid and HVMN. For example, flatulence, nausea, diarrhoea and dizziness were reported in five out of twenty-four participants in a low dose, and in all participants when the dosage was increased 7.

A similar finding was reported in a study using KetoneAid. Here there were reports of nausea (7/11), cramps (6/11), belching (4/11), heartburn (3/11), flatulence (3/11) and vomiting (1/11) 8.

It is likely these symptoms would be reduced, by ensuring participants had experience with the Ester, or by taking a lower dose. Saying this, using lower doses may reduce any potential performance benefit.

Furthermore, other recent publications have shown considerably less side effects. This may be attributed to improving formulations, and smarter use of the supplement. For example, recent papers have shown minimal side effects when combining the Ester with flavoured water 9.

What do Ketone Esters Taste Like?

Historically Ketone Esters were thought to taste pretty bad. From this, they earned a reputation of tasting like ‘jet fuel’, after being mentioned online with podcasters such as Peter Attia and Tim Ferriss.

Manufacturers have made big efforts since then to make them more palatable. It seems taste is rapidly improving. KetoneAid’s Ester is now described as tasting ‘not too bad’, with the flavour described as ‘Very Scary Cherry’. HVMN describe their Ester as tasting similar to an alcoholic spirit, with berry and lemon nodes.

Do Ketone Esters Improve Exercise Performance?

Background

There’s a lot of talk about Ketone 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.

Ketone Esters gained a huge amount of publicity when it was discovered by Team Sky. They had been using them with stories of riders becoming furious if they missed their drink, which at the time cost about $2000 each. Following ,this it was discovered that six other teams were using Ketone Esters. This increased the hype around Ketone Esters. Soon, other areas of sport began using Ketone Esters such as combat sports.

Theory

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

A key research paper by Cox et al. 10 carried out the most comprehensive study of Ketone Esters on exercise performance to date. The Oxford University research group used Ketone Esters to improve cycling performance by 2%. This is a notable finding, and more interestingly, the study took extensive blood and muscle measures. This allows us to better understand why performance improvements may occur.

Why Did These Performance Improvements Occur?

It’s clear that a number of factors were at play in seeing these performance improvements. Notable changes in substrate use occurred after Ketone Ester ingestion. This means changes in the use of fat, carbohydrate and ketones were evident. One change is a decrease in glycolysis, with glycolysis simply being the breakdown of glucose. This is one factor that reduces lactate. This is a molecule that increases during exercise and coincides with a build up of hydrogen ions which contributes to fatigue.

Thus, lower lactate may be a mechanism for performance improvements. This may be an issue in high-intensity exercise since carbohydrates are the predominating fuel source 11.

The authors suggest that the effect of the Ketone Ester in impairing glycolysis pathways was counteracted by the preferential oxidation of ketones. This allowed for the sparing of glycogen meaning glycogen was not depleted at the end of the exercise bout.

This is similar to that of the ketogenic diet 12, 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). Glycogen is therefore only large enough to fuel approximately up to 3 hours of exercise 13.

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.

Another change noted was the increase in burning of fat stored in the muscle. This occurred 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 14. This finding is both interesting and unexpected. This is because exogenous ketones are known to be anti-lipolytic (meaning they should reduce the ability to burn fat) 15. The ability to burn fat at a high intensity has significant performance implications.

With a recent study showing that rates of fat oxidation at high intensities are the difference between recreational and elite athletes 16.

Increased lactate impairs the muscle’s ability to oxidise fat stored in the muscle 17. The ability to maintain lower lactate may be one mechanism by which intramuscular triglycerides are oxidised at high intensities. This is one potential mechanism for improved exercise performance.

Summary

These improvements in performance and physiological changes are encouraging. However, researchers have noted the difficulty in blinding participants to the Ketone Ester. This opens the door to the placebo effect which has been unequivocally shown to improve exercise performance 18 19. Thus research must ensure full blinding to the ketone in order to enhance the validity of future studies.

Following this landmark study and to this day, just one paper has addressed endurance performance. In 2017, a group of researchers at the investigated the role of the AcAc Diester on 31 km cycling performance in elite cyclists 20. This showed a 2% performance impairment, concluding that Ketone Esters do not enhance exercise. These findings 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 shown following AcAc diester ingestion (<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 Diester. It’s not clear whether the Ester itself impaired performance, or whether it was the increased feelings of nausea felt by all subjects.

Ketone Esters for Cognitive Performance and Repeated Sprint Exercise

A recent study looked at the effect of Ketone Esters on repeated sprints and cognitive performance after exercise. The key finding from this paper was improved cognition with Ketone Esters after repeated sprints. One often underappreciated part of exercise performance is the ability to be cognitively astute in the face of fatigue. Being able to function well, and make good decisions could be the difference between winning and losing. The researchers from Dublin City University tested this. They used a Ketone Ester to determine whether they could improve cognitive performance after a repeated sprint trial.

This study design involved a Loughborough Intermittent Shuttle Test. This entailed 5 sets of 15 minutes of running, with 3 minutes break in between (part A). Following this, participants alternated every 20 metres between 55% VO2max (this being the maximum rate at which oxygen can be taken up and utilised by the muscles) and 95% VO2max until they couldn’t continue (part B). Cognitive tests were performed before and after the exercise trials.

The results showed no difference in any exercise modality. This was expected due to impairment to the pyruvate dehydrogenase (PDH) complex following Ketone Ester ingestion.

PDH is an enzyme that plays a key role in glycolysis. It does this by contributing to turning pyruvate into Acetyl CoA. This is then used in the body to deliver acetyl group to the Krebs cycle, which is how we all produce energy. This means that an impairment of PDH will impair glycolysis, which represents the burning of carbohydrate for fuel.

This impairs carbohydrate use, which is essential for high-intensity exercise. This suggests Ketone Esters may not improve exercise performance of this kind.

The highlight of this study, however, was the improvement in cognition noted when taking the Ketone Ester compared to the placebo. Breaking these results down, multi-tasking ability was preserved in the Ketone Ester group and decreased in the placebo. However, other cognitive tests addressing reaction time and sustained attention were non-significant.

This is an interesting finding that offers an alternative use for Ketone Esters, with the authors concluding:

‘Despite the lack of benefit to physical performance, the novel finding of preserved executive function after exhausting exercise suggests that there remains a possibility that exogenous ketones could enhance sport-specific performance of team sport athletes via other mechanisms’.

This opens the door for future research in the area of cognition and Ketone Esters. Particularly with maintaining cognitive function being such an important aspect of team sports.

Takeaways

Research is still in the early stages, with just two performance trials complete to endurance and one on repeated sprints.

Future studies are warranted on the effect of BHB and exercise performance. Many mechanisms for improvement are discussed in research by Evans et al. 21, as well as mechanisms that may impair performance. The key factors that may contribute to improved performance seem to be:

  • 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 is inhibited when following a ketogenic diet and is also thought to occur following ketone supplementation 22. This theoretically could impair performance in sprint activities. However, 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 non-keto individuals. This is called Post-Exercise Ketosis (PEK). It is thought to be a response that improves the replenishment of muscle glycogen and enhanced protein synthesis 23. This would suggest that there may be a role for increasing ketones post-exercise. This could spare protein and carbohydrate stores during times of low carbohydrate availability.

This area is another that is still in the very early stages of research. There are two published papers directly using Ketone Esters. The two areas studied are the role of Ketone Esters on glycogen replenishment and protein synthesis. The findings of these are of interest and certainly provide a rationale for the topic to be researched further.

Protein Synthesis

It is known that ketone bodies have protein sparing effects in skeletal muscle. Prior to the use of Ketone Esters, ketone body infusion showed a 10% increase in protein synthesis which occurred when BHB levels reached 2 mmol 24. This was shown with Ester supplementation, by Vanboorne et al 25. They showed improved protein synthesis when consuming a Ketone Ester. This further validates the potential use of Ketone Esters in recovery from exercise.

Glycogen Replenishment

The role of Ketone Esters on glycogen resynthesis is more mixed at present. A 2016 study on glycogen resynthesis reported a 50% increase in muscle glycogen content after 2 hours of recovery 26. This, however, is not supported by the subsequent Vanboorne study. They showed no effect in improving glycogen resynthesis, so more research is needed to confirm such findings.

Takeaways Relating To Ketone Esters and Performance/Recovery

From current research, there are a few things that are clear about Ketone 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 Ketone Esters Encourages Muscle Glycogen Sparing Using Ketone Esters may Improve Cognition During Exercise Impaired Ability to Use Carbohydrate Through the Downregulation of PDH
During Exercise, Ketone Esters Result in a Lower Exercising Lactate Concentration Using Ketone Esters in Recovery May increase Post-Exercise Glycogen Resynthesis Gastrointestinal Distress. (Although this is not directly related to performance, it would be crazy to think this isn’t an issue when it comes to performing at your best)
Post Exercise, Ketone Esters Increase Protein Synthesis Ketone Esters May Enhance Endurance Performance Insufficient Evidence at Present to Recommend Ketone Esters for Exercise Performance
Source: Ketosource Analysis.

What Will We See From Future Research?

It is not yet known whether Ketone Esters can improve performance through these mechanisms. It is likely there is, at best, no improvement in repeated sprint performance, due to the changes in PDH and glycolysis noted. In continuous exercise, more research is needed to explain the true performance effect of Ketone Esters.

Areas Warranting Further Investigation

    • More research needs to be conducted to further understand the impact of Ketone Esters on performance

Research at present cannot conclusively state that performance will improve. The current body of research is mixed and inconclusive.
The theory behind the ketones is sound. With only a handful of current papers, the role of Ketone Esters for performance is an exciting and growing area.

    • Improvements in cognition suggest the Esters may be useful in sports that may benefit from enhanced cognition

A plethora of sports, such as combat sports and team sports may provide fascinating areas of future study following the work of Egan and Evans 27.

    • Added to this, the area of recovery has a lot of work yet to do, but with encouraging results to date
    • There has yet to be a paper evaluating how Ketone Esters can impact keto-adapted individuals. This would be a fascinating study as the Ketone Esters impairment in glycolysis may show to be less problematic. This may result in performance improvements in keto-adapted athletes

The fact that ketogenic athletes are not dependant on carbohydrate may mean they benefit further 28. This is because the impairment in glycolysis may be less of a hindrance in this population.

More research and more specificity relating to different types of activity, different work rates and different durations are needed to determine the true performance effect.

‘More research and more specificity relating to different types of activity, different work rates and different durations are needed to determine true performance effect’.

Ketone Esters for Neurological Conditions, Other Health Issues and Emerging Research

Ketones act like an alternative fuel for the brain, providing up to 60% of the brains energy during starvation 29. Thus there is great interest in ketogenic diets and methods of increasing ketone availability for neurological conditions.

This may present a case for the ketone ester. Ketogenic diets have been used for years treating conditions such as refractory epilepsy and have shown potent anti-seizure effects 30. In Glut1 deficiency syndrome, in particular, glucose metabolism is impaired and ketogenic diets are the treatment of choice.

Whether exogenous ketones can benefit neurological conditions relies on the mechanism that is behind the promising results, and whether the ketone bodies themselves mediate this. Growing evidence is showing BHB to be at least partly responsible for the neuroprotective effects elicited 31 32.

Alzheimer’s disease (AD) is sometimes referred to as type 3 diabetes. One early feature of AD is impaired glucose utilisation by the brain. Thus providing an alternative fuel source in the form of ketone bodies may be beneficial to those with AD. Unfortunately, most studies have been carried out on rodents, and very little research has used a Ketone Ester specifically.

However, research has alluded to neuroprotective effects of ketone bodies through the use of MCT oils. This has led to improvements in cognition in AD patients 33 34.

As a result of this research, interest surrounds the role of Ketone Esters for neurological conditions. There has been little research directly on the use of Esters. Yet the ability to increase ketones dramatically provides a utility that will be subject to much more research in the coming years.

A recently published case study showed improvements in an individual with AD following Ketone Ester supplementation. The report showed clear improvements in behaviour, cognition and activity performance 35. The case study can be found here. This highlights the remarkable effect observed through a ketone ester supplementation protocol.

Animal studies and human case studies in this area are compelling, so this is certainly one area where future research looks promising. Ketogenic diets, MCT oil and Ketone Esters all look like they will have some degree of benefit. Saying this, especially with the research mentioned, there’s a need for a controlled trial to further assess the roles and mechanisms of Ketone Esters. With more research, it would not be surprising if this area became the main use for Ketone Esters.

Do Ketone Esters Aid Weight Loss?

People may be interested in using Ketone Esters and other exogenous ketones to support weight loss. A recent research paper showed reduced appetite following ingestion of a Ketone Ester 36. This would suggest consuming Ketone Esters can reduce food consumption.

Saying this, the Ketone Esters in this study were compared to maltodextrin, a type of sugar. From this, we can conclude that Ketone Esters curb appetite over simple carbohydrates such as types of sugar. The question now is can Ketone Esters curb hunger compared to other foods, and create meaningful changes in body mass?

Currently, there is insufficient evidence to support using Ketone Esters for weight loss. It also isn’t the most exciting area for using the Ester. Whether future research shows any potential role for Esters here remains to be seen.

What is most exciting in the remit of weight loss and weight management, are changes in metabolic rate associated with Ketone Ester ingestion. Research has shown that ketones increase metabolic rate in rats 37. This is as a result of increased adipose thermogenesis.

This is the process of thermogenesis that occurs from uncoupling of proteins and may result in greater energy expenditure. There is a potential for the Ketones Ester to increase total energy expenditure. Unfortunately, these studies on Ketone Esters have only been carried out on rodents. They showed significant increased resting energy expenditure and total energy expenditure 38. Whether this applies to humans and elicits an effect meaningful enough to alter body mass remains to be seen.

Whilst this is encouraging, controlled trials are needed to monitor changes in metabolic rate and overall weight loss through Ketone Ester supplementation. It is likely that any changes in metabolism are far too minor to represent a useful case for the Ketone Ester.

Where Can I Buy Ketone Esters?

Ketone Esters are not yet available in the UK. Esters can only be purchased directly from the manufacturers within the US. For more information check out their websites here:

Summary: The Takeaways

  • Much of the discussion around Ketone Esters is based upon theory and anecdote at present, as opposed to strong research data
  • Claims of direct performance improvements are not currently supported by research to date. Research is still in its early stages and Ketone Esters may be shown as a performance or recovery enhancer in future
  • Much more research is to come and we eagerly await this, with a great deal of hype around Esters and ketones for neurological conditions. This represents possibly the most exciting area for Ketone Esters, with a sound rationale, research in rodents and a compelling case study
  • Only time and future research will tell if Ketone Esters have a clear and research-based purpose within the health and exercise fields
QUESTION(S): What questions do you have about Ketone Esters that haven’t been answered in this article? Let me know by adding to the in the comments.

Study References:

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