Exogenous: “introduced from or produced outside the organism or system” - Merriam-Webster

Ketone Salts and Ketone Esters

Exogenous ketones are a synthetic form of ketone bodies. They come in two forms: ketone esters and ketone salts (Harvey et al., 2019).

Ketone salts have a sodium (Na+) molecule attached while ketone esters have a double bond (ester) to oxygen (O). They are then bound to another ketone precursor/molecule, avoiding the salt or acid load. Ketone esters can be further divided into B-Hydroxybutyrate esters and Acetoacetate esters. These different esters could give different physiological effects.

See image for comparison. Both forms of exogenous ketones can increase levels of B-Hydroxybutyrate (BHB) in the blood.

There are also important differences in structure between the same type of ketones (isoforms) that are discussed at the end of the article.

The first study published in humans using ketones was in 2012 (Clarke et al., 2012). However, ketone esters were first used in a performance study in 2016 (Cox et al., 2016) (the authors currently own a patent for ketone esters in the US).

Since then, multiple studies have used ketone esters and ketone salts. There are currently fewer brands of ketone esters. The main form of ketone salts used in studies is KetoForce which is made by KetoSports (Stubbs et al., 2017, O’Malley et al., 2017, Rodger et al., 2017).

Ketone salts are generally bought in powder form and mixed with liquid, while ketone esters are packaged in liquid form (Scott and Deuster 2017).

Read Scientific Quotes

“Ketone bodies, acetoacetate (AcAc) and D-β-hydroxybutyrate (βHB), are respiratory fuels that can be oxidised by most body tissues [21] and are formed in large quantities (up to 150 g/day) by the liver in response to low blood glucose and insulin [23,24].” - Cox and Clarke 2014 “Ketone esters are not commercially available to date, but ketone salts represent a cheaper, more readily-available exogenous ketone supplement. These salts comprise of the free acid form of βHB buffered with sodium, potassium, and/or calcium salts but are less effective at elevating plasma βHB concentrations compared to the ketone monoester (Stubbs et al., 2017). ” - Evans et al., 2018 “... two prominent ketone esters in the published literature are the R,S-1,3-butanediol acetoacetate diester (Kesl et al., 2016) and the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester (Clarke et al., 2012; Cox et al., 2016). Acute ingestion of either ester can result in short-term (~0.5 to 6 h) nutritional ketosis indicated by [βHB] >1 mM (Clarke et al., 2012; Kesl et al., 2016). For the ketone monoester, ingestion at a dose 573 mg/kg body mass (BM)resulted in [βHB] of ~3 mM after 10 minutes and rising to ~6 mM 30 min after ingestion (Cox et al., 2016).” - Evans et al., 2017

Will Exogenous Ketones get you into ketosis?

Exogenous ketones can rapidly increase the level of ketones in the blood (Clarke et al., 2012). The increase occurs within 30–45 minutes after drinking the supplement. Blood ketone levels can remain elevated for ~2–3 hours after ingestion. Some studies use multiple doses of exogenous ketones to keep blood levels elevated (Leckey et al., 2017, Stubbs et al., 2017).

Ketones are frequently measured by looking at B-Hydroxybutyrate (BHB) levels in blood. In the graph below you can see examples of human studies that use exogenous ketones. Ketone esters are better at increasing BHB levels and act in a dose-response manner (Shivva et al., 2016; Stubbs et al., 2017).

Ketone esters also elevate BHB levels higher, for those who have not eaten a meal beforehand (Stubbs et al., 2017). Lower ketone levels in a fed state could be due to reduced ketone uptake or reduced gastric emptying (Pinckaers et al., 2017).

Higher ketone levels aren’t necessarily better. Some scientists think there might be a “goldilocks zone” where performance can be improved (Egan 2017). The idea is that high ketone levels could cause a negative feedback loop where uptake by skeletal muscle is reduced (Pinckaers et al., 2017). High levels could also potentially inhibit glycolysis (anaerobic energy system).

Some scientists speculate that BHB levels above 2 mmol/l is needed to get performance benefits (Stubbs et al., 2018). We need more research to see if there are optimal ketone levels for performance.

Read Scientific Quotes

“... while skeletal muscle is able to extract ~50 % of circulating ketone bodies when concentrations are low (0.1–0.5 mmol/L), this uptake capacity is reduced to only ~5 % when concentrations reach ~6–7 mmol/L. However, exercise may increase ketone body uptake, as recent pilot data [58] and preliminary reports [67] suggest that exercise increases the absolute rate of ketone body uptake and oxidation by skeletal muscle [58, 67].” - Pinckaers et al., 2017 “Reaching blood ketone concentrations >2 mM is likely a key mediator of any potential ergogenic effect” - Stubbs et al., 2018

Timeline of Exogenous Ketone Studies

The use of exogenous ketones dates back to the 1980s (Fery et al., 1988, Fery et al., 1986, Fery et al., 1983). If they have been studied for so long, then why are they becoming popular now?

A string of studies from 2016 to 2018 have brought keto supplementation to the forefront of endurance exercise. Starting with Cox et al., in 2016 a new study was published almost every other month. The last study used in our analysis was published in early 2018.