The Growing Evidence Behind Exogenous Ketones in Performance & Health

I have been reading and writing a lot about exogenous ketones recently. This is an exciting area of research, and I’m hearing great things from applied practice, too. There’s increasing evidence that exogenous ketone supplements may improve training outcomes (1–4). However, recently as I’m personally not training as much anymore, I have become interested in the use of exogenous ketones from a health perspective. The research is quite fascinating. In this blog, I’ll describe how they might have broader application to health, too.

What are exogenous ketones?

We know that by consuming a diet very low in carbohydrates – less than 50 grams per day or so – we can enter ketosis or increase the circulating concentration of ketones in the blood. That’s why these diets are called ‘ketogenic’ (5, 6). In some instances, such diets are known a “therapeutic ketogenic diets” due to the positive effects they have had on chronic diseases. However, in recent years, supplements have been developed that allow us to increase our circulating ketone concentrations independently of our habitual diet. These are the so-called ‘exogenous ketone supplements’ (7).

As talked about in previous blogs, there are various types of exogenous ketone supplements, including ketone esters, ketone salts, and ketone precursors (that are converted into ketones in the body). Ketone salts combine ketones with sodium, potassium, calcium, or magnesium, and, predictably have the potential to provide a very high salt load. Ketone salts tend to provide a modest elevation in blood ketone, specifically D-βHB, concentrations. Ingestion of the ketone precursor butanediol produces similarly modest elevations in blood D-βHB concentrations without the salt load. Ketone ester ingestion produces much larger increases in circulating ketones (7). The metabolism of the various ketone supplements is complicated, but the point I am trying to illustrate here is that ketone supplements are not all the same, and therefore different supplements may have different effects. Ketone esters are showing the greatest promise, and are what researchers are now focusing on (12).

In brief: What the literature says about exogenous ketones and performance and training outcomes

After an exciting study was published by researchers from the University of Oxford in the journal Cell Metabolism back in 2016, there was some fanfare about exogenous ketones having the potential to spare glycogen during exercise (8). Unfortunately, subsequent literature hasn’t really borne that out (9–11), and it now seems unlikely that exogenous ketone supplementation during exercise has a large or consistent glycogen-sparing effect.

However, researchers investigating exogenous ketone supplementation in athletes are now focusing on how it might benefit recovery and adaptation, with promising results (12). This research was kick-started by a study led by Chiel Poffé that was published in the Journal of Physiology in 2019 (1).

In that study, Poffé and colleagues put 18 male subjects through a block of overload training. The subjects, who were fit but certainly not elite athletes, trained twice per day, six days per week, for three weeks. The goal of the training programme was to blast the subjects, such that they were overreached by the end of the three weeks, simulating a period of very heavy training or even competition. Half of the subjects received a ketone ester drink during recovery from each session, and half received a placebo.

The researchers found pretty strong evidence that ingestion of the ketone drink during recovery blunted symptoms of overreaching, including boosting power output, maintaining maximum heart rate (this typically drops when you’re overreached), and reducing stress hormones. These are pretty awesome outcomes for those of us taking training seriously.

Subsequently, researchers found that this post-training ketone supplementation regimen improves sleep (4), which can be impaired during periods of heavy training load (13). Perhaps improved sleep is one mechanism through which ketone supplementation improved recovery in the 2019 study.

Data has also shown post-exercise ketone supplementation increases circulating erythropoietin (EPO) concentrations (2, 3). This is another exciting finding, as EPO is a hormone involved in red blood cell production. This may translate into a very favourable adaptive response over time, although we’ll need to wait to see that data emerge.

So, there is quite a bit of evidence emerging that suggests ketone supplementation might enhance recovery and improve the training process. More data is being published every month, so let’s continue to follow it to determine if and how we might use ketones to get the most from our training.

Health effects: Do exogenous ketones promote health?

The positive effects with ketone supplementation described above are great for athletes and their performance. We all know how important sleep is, and it’s probably also true that many people don’t get enough. Sleep is critical for recovery and restoring our physiology to where it needs to be; for example, during sleep we restore the balance of neurotransmitters in the brain, and this may be one of the reasons why we make poor decisions when sleep deprived (14, 16, 18). If taking exogenous ketones improves sleep quality, I think that’s likely to not only improve our training, but improve our health too.

Figure: Some exogenous Ketone companies have sub-brands specifically targeted towards health and immunity. The potency of these sub-brands is typically lower than those aimed at specifically exercise performance.

I think you can make a similar case for the data showing erythropoietin release following exogenous ketone supplementation (2, 3), given maintaining adequate red blood cell mass is important for health as well as performance, and the data showing ketone supplementation improves our ability to deal with training stress (1). Whilst I’m speculating here, and it depends on the mechanisms involved, it seems possible that this benefit might translate into improved ability to manage heavy work, family, or lifestyle stress, or at least cope when these stresses are combined with training.

There are other potential health benefits of exogenous ketones. For example, a 2017 study published by researchers from the University of Oxford in the journal Obesity found that consumption of a ketone supplement may be useful for suppressing appetite (17). After an overnight fast, participants consumed either a ketone supplement or an isocaloric dextrose drink (that is, an equal number of calories were consumed), and blood samples and subjective measures of hunger and appetite were recorded in the following four hours. Participants had lower hunger and desire to eat, and reduced concentrations of the hunger hormone ghrelin after consuming the ketones. These responses have been replicated elsewhere (21, 23). This has obvious implications for those seeking to lose weight, although I will add the caveat that acute studies measuring appetite responses to an intervention in a laboratory setting may not translate to free-living conditions, in the long term. It’s also not as though most of us seeking to lose weight and suppress appetite would have a sugar drink for breakfast! In fact, a study published this year found that consumption of exogenous ketones – albeit ketone salts – did not suppress 24-h appetite (22).

Appetite-suppressive effects of exogenous ketones appear to contradict the data in the 2019 overreaching study I cited above, which found that the exogenous ketones group maintained energy balance, whereas the control group slipped into negative energy balance; that is, they consumed less calories than they expended, which may be one of the mechanisms through which ketones improved recovery (1). Perhaps, then, ketones help us regulate our energy intake, rather than have strictly appetite-suppressing effects?

Where does that land us for using exogenous ketones to help control appetite when looking to lose weight? The data isn’t conclusive, so this literature is one to keep an eye on.

There is also some suggestion that ketones have positive effects on brain health. Ketones are an important during brain energy crisis, as might be seen with chronic glucose hypometabolism or after a concussion (15). Ketones may help protect brain cells against damage due to reactive oxygen species production after a brain injury (19), and ketones may even have some merit for people with Alzheimer’s disease (20). Like with the appetite literature I mentioned above, we don’t have much certainty here, but the myriad settings ketones are showing promise does support the contention that they do have positive brain-related benefits.

Summary

So, my take on the literature as it stands now is that ketone supplementation has a lot of potential, for endurance performance and training, and for health. I’ll caveat that by saying we don’t yet have conclusive evidence – we rarely do – and we always need to see if things work for us on an individual level when trying anything new.

Exogenous ketones of course come with a bit of a price tag, but my advice is that if your take on the literature is that they’re worth trying – which is where I am – consider getting hold of a relatively small quantity to start with to see how you go.

Endure on!

References

1. Poffé C, Ramaekers M, Van Thienen R, Hespel P. Ketone ester supplementation blunts overreaching symptoms during endurance training overload. Journal of Physiology 597: 3009–3027, 2019. doi: 10.1113/JP277831.
2. Evans E, Walhin JP, Hengist A, Betrts JA, Dearlove DJ, Gonzalez JT. Ketone monoester ingestion increases postexercise serum erythropoietin concentrations in healthy men. Am J Physiol Endocrinol Metab 324: E56–E61, 2023.
3. Poffé C, Robberechts R, Van Thienen R, Hespel P. Exogenous ketosis elevates circulating erythropoietin and stimulates muscular angiogenesis during endurance training overload. Journal of Physiology 601: 2345–2358, 2023. doi: 10.1113/JP284346.
4. Robberechts R, Albouy G, Hespel P, Poffè C. Exogenous ketosis improves sleep efficiency and counteracts the decline in REM sleep following strenuous exercise. Med Sci Sports Exerc 55: 2064–2074, 2023. doi: 10.1249/MSS.0000000000003231.
5. Burke LM. Ketogenic low CHO, high fat diet: The future of elite endurance sport? Journal of Physiology 599: 819–843, 2021. doi: 10.1113/JP278928.
6. Shaw DM, Merien F, Braakhuis A, Maunder E, Dulson DK. Effect of a ketogenic diet on submaximal exercise capacity and efficiency in runners. Med Sci Sports Exerc 51: 2135–2146, 2019.
7. Shaw DM, Merien F, Braakhuis A, Maunder E, Dulson DK. Exogenous ketone supplementation and keto-adaptation for endurance performance: Disentangling the effects of two distinct metabolic states. Sports Medicine 50: 641–656, 2020. doi: 10.1007/s40279-019-01246-y.
8. Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab 24: 256–268, 2016. doi: 10.1016/j.cmet.2016.07.010.
9. Dearlove DJ, Harrison OK, Hodson L, Jefferson A, Clarke K, Cox PJ. The effect of blood ketone concentration and exercise intensity on exogenous ketone oxidation rates in athletes. Med Sci Sports Exerc 53: 505–516, 2021. doi: 10.1249/mss.0000000000002502.
10. Poffé C, Ramaekers M, Bogaerts S, Hespel P. Exogenous ketosis impacts neither performance nor muscle glycogen breakdown in prolonged endurance exercise. J Appl Physiol 128: 1643–1653, 2020. doi: 10.1152/japplphysiol.00092.
11. Margolis LM, Pasiakos SM, Howard EE. High-fat ketogenic diets and ketone monoester supplements differentially affect substrate metabolism during aerobic exercise. Am J Physiol Cell Physiol 325: C1144–C1153, 2023.
12. Robberechts R, Poffé C. Defining ketone supplementation: the evolving evidence for post-exercise ketone supplementation to improve recovery and adaptation to exercise. Am J Physiol – Cell Physiol. 2023.
13. Jürimäe J, Mäestu J, Purge P, Jürimäe T. Changes in stress and recovery after heavy training in rowers. J Sci Med Sport 7: 334–339, 2004.