The benefits of Exogenous ketones for athletes: the evidence base

Exogenous ketones are marketed as a “fourth fuel” for athletes, capable of boosting endurance and accelerating recovery. The editorial team analyzed key randomized studies and meta-analyses to separate the proven from hypotheses and marketing.

Where the expectations came from

The theoretical rationale looked convincing. Ketone bodies are an efficient fuel that tissues can oxidize in parallel with glucose and fats. If muscles are given an additional energy source, it would be possible to preserve limited glycogen stores and delay fatigue in prolonged work.

The impetus for the interest was the work of Cox and colleagues (2016) in the journal Cell Metabolism. The researchers showed that after taking a ketone ester, muscles partially switch to oxidizing ketones, lactate formation decreases, and in one of the experiments trained cyclists managed to cover, on average, a slightly greater distance in 30 minutes than after a carbohydrate drink.

It is important to understand the conditions of this work. The participants were well trained, they took the ketone ester together with carbohydrates, and the test was conducted after prior prolonged exercise. This is not the scenario in which store-bought salt supplements are usually used.

After publication, a number of laboratories tried to reproduce the result in different protocols. It is precisely these subsequent data, not the first striking work, that shape the current understanding of the effectiveness of ketones.

Endurance: what subsequent studies showed

As early as the following year, the group of Leckey and colleagues (2017) published the opposite result: in professional cyclists, taking a ketone diester worsened performance in a time trial of about 31 km. Participants complained more often of nausea, stomach discomfort and reflux, which the authors considered a significant explanation for the deterioration.

The study by Poffé and colleagues (2020) tested whether ketones affect the use of muscle glycogen during prolonged work with sufficient carbohydrate intake. It turned out that neither performance nor glycogen breakdown changed significantly. That is, the idea of “glycogen sparing” was not confirmed under realistic conditions.

Systematic reviews summarized this picture. The meta-analysis by Valenzuela and colleagues (2020), which included randomized controlled studies of acute intake of ketone supplements, found no significant effect on physical performance overall. The review by Margolis and O’Fallon (2020) came to a similar conclusion: the overwhelming majority of works showed no benefits, and some recorded a deterioration.

So, at the level of aggregate data, acute intake of ketones before or during training does not provide a reliable increase in endurance. Isolated positive results are not reproduced consistently and probably depend on the specific protocol, product and individual tolerability.

Short and intense exercise

For short high-intensity efforts, the prospects of ketones are theoretically even more modest. Such exercise largely depends on rapid glycolysis, while ketones, on the contrary, can inhibit the use of glucose by muscles and reduce the formation of lactate, which here is a sign of the required speed of energy supply.

The study by O’Malley and colleagues (2017) with ketone salts showed that they enhance fat oxidation during work, but at the same time worsen performance in a high-intensity test. The authors explained this by a shift of metabolism toward less “fast” energy sources.

There are few data on strength sports, bodybuilding or team disciplines. There is no direct evidence in the peer-reviewed literature that ketones increase strength, power or muscle mass. Therefore, for athletes whose result is determined by explosive strength, ketones have no grounds for use as an ergogenic aid.

Recovery, glycogen and overtraining

The most interesting current data concern not acute performance but recovery. In the work of Holdsworth and colleagues (2017), a ketone ester taken together with glucose after exhausting exercise was associated with higher muscle glycogen synthesis compared with the control.

However, these results are not unambiguous. Vandoorne and colleagues (2017) found that taking a ketone ester during the recovery period enhanced mTORC1 signaling, associated with protein synthesis, but did not accelerate glycogen resynthesis. The difference in conclusions is probably related to the amount of carbohydrates and the design of the studies.

The work of Poffé and colleagues (2019) became notable. For three weeks the participants performed a very large volume of training, and after sessions and before bed they received a ketone ester or placebo. In the ketone group, fewer signs of functional overreaching, a better appetite and greater power in the final test were observed than in the control.

These data give grounds to believe that ketones can be useful precisely in periods of excessive exercise, in particular through the effect on energy balance and, possibly, on hormonal and sympathetic responses. However, this is about a few small studies, and it is too early to turn them into a practical standard.

Limitations of the evidence base

The first limitation is the heterogeneity of products. Most positive results were obtained with ketone esters, whereas salts with lower bioavailability and a significant amount of minerals predominate on sale. Transferring conclusions from one type of product to another is incorrect.

The second is small samples. A typical study includes 8–15 participants, mostly trained men. There are very few data on women, amateurs, adolescents and older people, and the statistical power of the works is often insufficient to detect small effects.

• Different products: salts, monoesters, diesters with different kinetics.
• Different protocols: with and without carbohydrates, fasting and after meals, acute and chronic intake.
• Difficulty of blinding: participants often recognize the characteristic taste of the ester.
• Funding: some works are connected with the developers of commercial products.

The third limitation is the difficulty of blind control. Ketone esters have a distinct bitter taste and cause noticeable effects, so participants often guess that they received the active product. This creates a risk of a placebo effect in both a positive and a negative direction.

Finally, international consensus documents on athletes’ nutrition, in particular the IOC statement on dietary supplements (Maughan et al., 2018), do not include ketones in the group of agents with a reliable evidence base for an ergogenic effect.

Editorial conclusions

Acute intake of exogenous ketones to increase endurance or intense performance currently has no convincing scientific confirmation. Isolated positive results are not reproduced, and some studies record a deterioration due to gastrointestinal symptoms and a shift in metabolism.

The most promising direction appears to be the use of ketone esters in periods of very high training loads to support recovery, but these data are still limited to a few small studies.

Athletes considering ketones should remember: carbohydrates, sufficient caloric intake, sleep and competent load planning have a much larger evidence base.

We also recommend reading our articles “Exogenous ketones: what they are and how they work,” “Myths about exogenous ketones” and “How to take exogenous ketones: dosage, timing, duration.”

References

1. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24(2):256–268.
2. Leckey JJ, Ross ML, Quod M, Hawley JA, Burke LM. Ketone diester ingestion impairs time-trial performance in professional cyclists. Front Physiol. 2017;8:806.
3. Valenzuela PL, Morales JS, Castillo-García A, Lucia A. Acute ketone supplementation and exercise performance: a systematic review and meta-analysis of randomized controlled trials. Int J Sports Physiol Perform. 2020;15(3):298–308.
4. Margolis LM, O'Fallon KS. Utility of ketone supplementation to enhance physical performance: a systematic review. Adv Nutr. 2020;11(2):412–419.
5. O'Malley T, Myette-Cote E, Durrer C, Little JP. Nutritional ketone salts increase fat oxidation but impair high-intensity exercise performance in healthy adult males. Appl Physiol Nutr Metab. 2017;42(10):1031–1035.
6. Holdsworth DA, Cox PJ, Kirk T, et al. A ketone ester drink increases postexercise muscle glycogen synthesis in humans. Med Sci Sports Exerc. 2017;49(9):1789–1795.
7. Poffé C, Ramaekers M, Van Thienen R, Hespel P. Ketone ester supplementation blunts overreaching symptoms during endurance training overload. J Physiol. 2019;597(12):3009–3027.
8. Maughan RJ, Burke LM, Dvorak J, et al. IOC consensus statement: dietary supplements and the high-performance athlete. Br J Sports Med. 2018;52(7):439–455.