Are all Exogenous Ketones Created Equal?

There is increasing interest in the effect that ketones might have on athletes' performance. 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’ (1, 8). 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’ (9).

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.

Ketone esters, on the other hand, are bound to a ketone precursor (like butanediol) via an ester bond. There are three ester bonds: monoester (one), diester (two), or triester (three). All esters will raise ketone levels beyond baseline values. Ingestion of the ketone precursor butanediol produces similarly modest elevations in blood D-βHB concentrations without the salt load. Ketone ester (monoester, diester, and triester) ingestion produces much larger increases in circulating ketones (9). Most commercially available Ketone Esters on the market today are monoesters, with brands such as Delta G, for example. Figure 1, below, shows the time course of 3 different salt ketones versus a monoester. As you can see, there is quite a difference in terms of effect.

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.

Anyway, the main rationale for ingesting exogenous ketones during endurance exercise is two-fold. Firstly, exogenous ketones may provide an alternative fuel source – probably not to a significant extent (3) - or modulate fuel metabolism in a manner favorable for performance (2), such as stabilizing blood glucose and preventing fatigue from hypoglycemia. Secondly, ketones are an ‘efficient’ fuel source, producing higher energy yields per carbon unit than carbohydrates (11). Thus, exogenous ketone supplementation has often been hypothesized to benefit performance via metabolic mechanisms.

Our R,S-1,3-butanediol study did not show benefits for endurance performance

I was involved in a study published back in 2019 that investigated the impact of ingesting the exogenous ketone supplement R,S-1,3-butanediol on time-trial performance in cyclists (10). This supplement is absorbed across the gut after ingestion, where it is converted into the ketone βHB in the liver. In the study, we had a group of well-trained male cyclists ride at 85% of VT2 for 85 min – which is probably somewhere around half-Ironman power – before completing a fixed amount of work, 7 kJ.kg-1, as quickly as possible. The time-trial was designed to last ~25-30 min.

The cyclists did these performance tests twice; once with a dose of the butanediol ingested 30 min before exercise and after 60 min of the preload phase, and once with a placebo. We measured a range of physiological and perceptual variables throughout the trials, alongside performance.

We were testing the hypothesis that ingesting butanediol prior to and during exercise would improve subsequent endurance performance, via a glycogen-sparing effect during the steady-state phase, leaving more carbohydrate fuel available for the high-intensity time-trial phase. Unfortunately, our data did not show this effect – time-trial performance was similar in the butanediol and placebo trials, with no difference in time-to-completion or average power output. The supplement did increase blood D-βHB concentrations, though only to ~1 mmol.L-1 during exercise, which is not particularly high. Interestingly, there was some evidence of reduced efficiency during the steady-state phase of the butanediol trial, with greater rates of oxygen consumption at the 20 min timepoint of the steady-state phase compared to the placebo trial.

It was also notable that around half of the participants reported moderate or severe gastrointestinal symptoms in the ketone trial, with a couple even reporting low-level dizziness, nausea, and euphoria, a bit like feeling a little drunk! When you consider that the supplement, a ketone precursor, is essentially an alcohol, metabolized by the liver enzyme alcohol dehydrogenase, these effects are not surprising. Perhaps these negative perceptual effects of the butanediol supplement masked any benefits it may have had metabolically.

Where the literature is now headed: Ketone esters

So, our study seems to suggest that ingesting the butanediol supplement prior to and during endurance exercise does not have a beneficial impact on endurance performance. However, ketone supplementation has certainly not run out of road, and plenty of studies have been conducted since 2019 exploring the impact of ketone supplements in a range of endurance sport settings. These studies have tended to use ketone esters, which have much greater effects on circulating ketone concentrations. That means we can ingest less and get larger rises in circulating ketones.

For example, ketone ester ingestion during recovery from exercise has been shown to boost circulating erythropoietin concentrations (4). As erythropoietin – or EPO – is the hormone that stimulates red blood cell production, this may translate into a very favorable adaptive response over time, although we'll need to wait to see that data emerge. Another study found that ingestion of a ketone ester supplement as part of post-exercise recovery nutrition during a period of intensified training blunted symptoms of fatigue and overreaching, which are useful effects during training camps or busy racing periods, especially considering this translated to improved performance (5).

A series of studies also from the same group – led by Peter Hespel from KU Leuven in Belgium – found that ketone ester ingestion during exercise does improve endurance performance, although seemingly only when co-ingested with bicarbonate (6, 7). Bicarbonate is a handy buffer of the fatiguing acid that is produced during exercise, and ketone ester intake can itself generate an acidosis. Therefore, by ingesting ketone esters alongside bicarbonate, you can harness the benefits of the raised ketone concentrations, whilst mitigating any negative effects of the acid-producing effects of the ketone supplement. That’s if you can handle the bicarbonate, which is known for producing stomach issues in some athletes.

Conclusions and practical applications

Exogenous ketone supplements are increasingly available, and increasingly studied for their potential benefits in endurance sport. Not all ketone supplements are the same, and it seems that ketone esters hold the most promise, particularly in recovery from exercise. If you are considering using ketone supplements, my advice would be to get a small quantity to try first, and see how well you tolerate them and adapt. It's starting to look like the use of Ketone monoesters may be more beneficial in terms of day-to-day use, aiding training adaptation. And perhaps not something that is saved for only race day.

References

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