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 speeding recovery. The editorial team analyzed the 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 effective fuel that tissues can oxidize in parallel with glucose and fats. If muscles are given an additional energy source, one could preserve the limited glycogen stores and delay fatigue in prolonged work.

The impetus for interest was the work of Cox and colleagues (2016) in the journal Cell Metabolism. The researchers showed that after taking a ketone ester the 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, the ketone ester was taken together with carbohydrates, and the test was conducted after prior prolonged exertion. 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 various protocols. It is precisely this subsequent data, rather than the first striking work, that shapes 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 more often complained of nausea, stomach discomfort, and reflux, which the authors considered a significant explanation for the worsening.

The study by Poffé and colleagues (2020) tested whether ketones affect the use of muscle glycogen during prolonged work with adequate carbohydrate intake. It turned out that neither performance nor glycogen breakdown changed substantially. 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 trials of acute ketone supplement intake, found no significant effect on physical performance overall. The review by Margolis and O'Fallon (2020) reached a similar conclusion: the vast majority of works showed no benefits, and some recorded a worsening.

Thus, 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 exertion

For short high-intensity efforts, the prospects of ketones are theoretically even more modest. Such exertion depends largely on rapid glycolysis, and ketones, on the contrary, can inhibit muscles' use of glucose and reduce the formation of lactate, which here is a sign of the required rate 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 is little 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 results are determined by explosive strength, there are no grounds to use ketones 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 exertion was associated with higher muscle glycogen synthesis compared to 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 study designs.

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 received a ketone ester or placebo. In the ketone group, fewer signs of functional overreaching, better appetite, and greater power in the final test were observed than in the control.

These data give grounds to believe that ketones may be useful precisely during periods of excessive loads, particularly through their effect on energy balance and, possibly, on hormonal and sympathetic responses. However, this concerns isolated 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 in retail. Transferring conclusions from one product type to another is incorrect.

The second is small samples. A typical study includes 8–15 participants, mostly trained men. There is very little 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, fasted and after eating, 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 athlete nutrition, in particular the IOC statement on dietary supplements (Maughan et al., 2018), do not include ketones among 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 worsening due to gastrointestinal symptoms and a shift in metabolism.

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

Athletes considering ketones should remember: carbohydrates, adequate caloric intake, sleep, and sensible 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.