Exogenous ketones have become a popular nutritional supplement since their introduction in 2014.

Like with any new supplement, though, there tends to be a lot of misinformation that you have to sift your way through to find the reliable data. So, this article does the hard work for you and gets right to what the true benefits and drawbacks of exogenous ketones are.

We also cover what forms of ketones to consider, how they function in the body, and their role in future research.

What Are Ketones?

Ketones are fuel for the energy-generating mitochondria within the cells of our bodies. They are an alternative fuel source to glucose.1

Ketones are simple compounds because of their small molecular structure and weight. Specifically, they are organic (carbon-based) compounds that contain a central carbon atom double-bonded to an oxygen atom and two carbon-containing substituents, denoted by “R” (see chemical structure below) 2 3.

generic ketone
Generic Ketone Structure

In humans, there are 3 different ketones produced by the mitochondria of the liver. These are also often referred to as ketone bodies 2.
The three ketones are:

  1. Acetone
  2. Acetoaceate ( also know as Acetoacetic Acid)
  3. Beta-Hydroxybutyric Acid (also known Beta Hydroxybuyrate or BHB). Other chemical names include 3-hydroxybutyric acid or 3-hydroxybutyrate.

BHB is not technically a ketone since it contains a reactive OH-group in place of where a double-bonded oxygen normally would be as you can see in the diagram below. Yet, BHB still functions like a ketone in the body and converts into energy much like acetoacetate and acetone.

Ketone Bodies
Structures of Ketone Bodies

Ketogenesis is the metabolism of fatty acids by β-oxidation. 4 This process gives acetyl CoA which then leads to β-hydroxy-β-methyglutaryl-CoA (HMG-CoA) as seen below5. HMG-CoA converts into Acetoacetone which can switch back and forth to BHB. Acetoacetone to Acetone conversion is irreversible (on the left below). Acetoacetate and BHB (via acetoacetate) are used to produce energy when converted back into acetyl-CoA within a cell’s mitochondria whilst Acetone is excreted in the breath and urine.4

Formation of Ketone bodies
Formation of Ketone bodies from acetyl-CoA2

Exogenous Ketone Bodies Explained

Exogenous ketone bodies are just ketone bodies that are ingested through a nutritional supplement. Ketone bodies produced in the liver are more properly referred to as endogenous ketone bodies.

Exogenous = Originates from a source external from the body.
Endogenous = Originates from a source internal to the body.

Most supplements rely on BHB as the source of their exogenous ketone bodies. BHB is converted to acetoacetic acid with a small quantity converted to acetone through a acetoacetate decarboxylase waste pathway. Some of the acetoacetic acid will enter the energy pathway using beta-ketothialase, which converts acetoacetic acid to two Acetyl-CoA molecules (see diagram below2).

 

Ketosis pathway
Ketosis pathway before entering the the Krebs (energy) pathway2

The Acetyl-CoA enters the Krebs cycle and generates ATP. Exogenous ketone body supplements provide users with an instant supply of ketones. Even if you’re not in a state of ketosis before ingestion (such as when eating a higher-carb diet). They raise blood ketones even in the presence of insulin (which inhibits ketogenesis).6

Important note: Research is in its early stages and we need more data to understand the long-term effects of combining high blood ketone levels with high or moderate carbohydrate based diets.

We don’t yet fully understand what the long term effects of combining a non ketogenic diet with exogenous ketone supplements are. Research is in its early stages and more data is needed.

A common question is why BHB is the go-to ketone body for exogenous ketone supplements. The likely reason is a combination of its efficient conversion into energy and its ease of formulation. In other words, that it is easier to formulate BHB into a nutritional supplement. And the body efficiently converts BHB to acetoacetic acid, which effectively raises blood ketone levels.

Are “Raspberry Ketones” the Same as “Ketone Bodies”?

Raspberry ketones have become an increasingly popular ingredient used in fat-loss supplements. But, despite their name, they have no relation to ketone bodies. This has created some confusion for people interested in exogenous ketone supplements.

Raspberry ketones are in fact phenolic compounds that give raspberries their pleasant smell. They are structurally similar to the stimulant synephrine. Despite the marketing, raspberry ketones also don’t appear to have much effect on fat loss.7

Takeaway: Ignore information and products related to raspberry ketones. These have nothing to do with exogenous ketones and beta-hydroxybutyrate.

Ketone Salts vs. Ketone Esters

Exogenous ketones of beta-hydroxybutyrate are available in two forms:

  1. Ketone Salts: Naturally-derived compounds that simply mix sodium (and/or potassium, or calcium) with BHB to improve absorption. Commercially available supplements are all made from ketone salts currently (includes KetoForce, KetoCaNa and Keto OS). These are also sometimes called “Ketone Mineral Salts” of “BHB Mineral Salts”.
  2. Ketone Esters: Synthetically-made compounds that link an alcohol to a ketone body, which is metabolised in the liver to a ketone. Ketone esters are used primarily in research for testing their efficacy in elevating ketone body levels (below is a generic structure of a BHB ester). Yet, the first commercial Ketone ester drink will be available in 2018 by HVMN. Research esters are reportedly very unpleasant tasting which HVMN hopes to change.
Structure of a BHB Ester
Structure of a beta-hydroxybutyrate Ester

The Ketone esters raise blood levels of beta-hydroxybutyrate to higher levels than the Ketone salts. There is also strong evidence that ketone esters are more effective than ketone salts as far as their physiological benefits go. It is not clear why this happens, but could be because of a difference in the absorption rate in the GI tract.

However, esters tend to be a little tougher to tolerate (due to gut distress after ingestion) and don’t have the most pleasant taste (as mentioned earlier).

Figure 1 6 below shows a comparison ingesting equal amounts of BHB in the form of a Ketone ester and Ketone salts on blood BHB.
The supplements included:

  • BMS (Beta-hydroxybutyrate Mineral Salt) – sodium/ potassium based (KetoForce)
  • KE (Ketone Ester) – (R- 3-hydroxybutyl-R-1,3-hydroxybutyrate) (HVMN)

    Graph to show Ketone ester vs salt
    Figure 1: Blood BHB level after consuming a Ketone Ester vs Ketone Salt drink6

Why use Exogenous Ketones?

Exogenous ketone supplements may provide a multitude of benefits.

These include athletic performance enhancement, more efficient weight loss, cancer prevention, cognitive improvement and anti-inflammatory properties.

Weight Loss Goals

  • Appetite suppression: Appetite was measured in 10 males and 5 females after consuming a ketone ester (KE) or a dextrose (DEXT) drink . Desire to eat and perception of hunger dropped after both drinks, but the KE was 50% more effective for 1.5-4hrs. Insulin levels rose for both drinks but were 3x less with the KE drink after 30mins (Fig 2). The hunger hormone, ghrelin, was significantly lower between 2 to 4 hours after drinking the KE (Fig 2). In conclusion Ketone esters delay the onset of hunger and lower the desire to eat. 8

Ketone ester hunger, satiety, fullness
Figure 2: Perceived hunger, fullness and satiety after consuming a dextrose or ketone ester drink over time. Effects of Ketone ester or dextrose drink on plasma insulin and ghrelin levels over time8.
  • The fate of excess ketones: In the event someone has an excessive amount of ketones in the blood, the body (specifically the kidneys) will work as quickly as possible to filter out ketones via urine rather than converting them to adipose tissue.9 This is not to say that you can’t gain fat if you consume an exorbitant amount of exogenous ketones, but that they are less prone to be converted to fat than other nutrients.
  • More tolerable than MCT oil: MCT oil has been known to cause gastrointestinal distress in users, especially when taken in higher amounts. Exogenous ketones in the form of ketone salts, in comparison, are well-tolerated. Thus they enable one to avoid adverse GI events while providing the body with similar types of benefits. Figure 2 shows Ketone esters can be effective at reducing appetite. A combination of MCT oil and exogenous ketones may aid weight loss and allow a lower loading of ketone supplements, without the GI distress seen with MCT oil.

Performance Goals

  • Athletic enhancement: The improvement of energetic efficiency and fuel sparing mechanisms. Exogenous ketone supplementation could enhance both of these components of athletic performance. There is a promising outlook in this area for a variety of reasons:
    • Exogenous ketones induce acute ketosis, lasting for several hours. This is without needing to have depleted muscle glycogen stores. (Low muscle glycogen is well known to impair sustained physical performance).10.
    • The ‘carb-sparing’ effect from BHB suppresses the break down of muscle glycogen. This leads to lower lactate levels. When increasing exercise intensity, fat oxidation (burning) reaches a limit. At that point the muscle burns carbohydrates as fuel. But when consuming Ketone esters, the body does not make this switch. This suggests Ketones are being used instead. 11
    • Exogenous ketones cause the body to rely less on fat as fuel (see Fig 3). Fat takes longer to metabolise for energy than muscle glycogen. This is why fatty acids are not the preferred fuel under heavy exercise. This could be useful for keto-adapted athletes performing high-intensity cardiovascular or strength training.12 This is particularly useful for the Keto-adapted athlete who wants to undergo high-intensity cardiovascular or strength training.
    • Ketone esters increase free carnitine whilst exercising (which seems to improve physical performance)13
    • Exogenous ketones reduce the use of Branched-chain amino acids (BCAAs) as fuel (deamination). Consumption of a ketone ester drink reduced the rise in muscle BCAAs by 50% during exercise. 6

      Free Fatty acid and glycogen plasma levels after Ketone ester consumption
      Figure 3: Plasma Free Fatty Acid (FFA) and glycerol concentrations after consuming high fat, carbohydrate or ketone ester drink6
  • Improved cognition: Elevated plasma ketone concentrations divert the brain to utilize ketone bodies for synthesis of phospholipids, which drives growth and myelination. Normally, glucose would be the preferred substrate, which is much less efficient.14 BHB seems to act as a signal for neuronal pathways. These enhance synaptic plasticity, cognition and neuronal stress resistance. 15 In rat studies, ingestion of a ketone ester for 5 days improved their spatial learning and memory. 16.

Health & Longevity

  • Anti-carcinogenic properties: Data seems to suggest that exogenous ketones are an effective anti-carcinogen. The reason behind this is that cancer cells are unable to use ketone bodies effectively, unlike most healthy tissues in the body. In fact, dietary ketone supplementation has been shown to increase survival rates of mice with systematic cancer by as much as 70%.17
  • Neuroprotection: As humans age, the brain becomes more susceptible to neurodegeneration and subsequent conditions such as Alzheimer’s and Parkinson’s disease. Exogenous ketone supplementation appears to ameliorate the typical decline in cognitive function that comes with aging. The likely mechanism for this neuroprotective property is that ketone bodies reduce the inflammation and hyperexcitability that is normally exhibited as glucose metabolism declines in the brain.18, 19
  • Anti-Inflammatory properties: There is evidence that ketone bodies play a crucial role in reducing inflammation by inhibiting a specific class of proteins called inflammasones.20
  • Gene regulation profile change. There is evidence that gene sets can be up regulated or down regulated. Still early days but an example of this is a change in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) in rats on a ketogenic diet.

Mechanisms: How Exogenous Ketones Work

Exogenous ketones have a variety of physiological effects shortly after ingestion:

  • For starters, ingesting ketones (especially ketone esters) is an efficient way to elevate BHB in the blood by upwards of 2 mMol for nearly 8 hours (see Ref. 2). Ketone salts don’t appear to elevate BHB in the blood as efficiently (or significantly) as ketone esters do, though.
  • Exogenous ketone supplementation causes blood glucose to decrease significantly, likely due to the acute increase in insulin sensitivity. Therefore, exogenous ketones may present a potential therapy for type-2 diabetics via regulation of blood glucose.
  • Exogenous ketones also improve oxygen utilization, especially in the central nervous system (CNS).21 This effect decreases the likelihood of oxygen reaching potentially toxic levels in the CNS, which in turn has a number of other positive health ramifications (such as those discussed in the previous section).

Possible Downsides to Ketone Supplementation

As with almost any nutritional supplement, side effects and downsides are possible after consuming exogenous ketones. That being said, they tend to be rather benign and will most likely improve as exogenous ketone supplementation becomes more prominent. The most common side effects to be aware of when using exogenous ketones include:

  • Electrolyte Imbalance – The physiological reasoning behind electrolytes becoming depleted during a state of ketosis is due to lack of water retention and frequent urination. When supplementing with exogenous ketones, the acute state of ketosis will likely increase the frequency of urination, but it won’t deplete glycogen stores. Therefore, it may be useful to drink an electrolyte solution if you are urinating a lot after taking exogenous ketones, but it’s dependent upon how you feel.
  • Halitosis (bad breath) If you’re on a ketogenic diet you are probably aware that as the body starts to metabolize fat, ketones can cause poor breath. There is very little one can do about this, it’s just the nature of the beast. Unfortunately, this can also arise when using exogenous ketones, but it’s not as lasting as when on a ketogenic diet. Chewing gum or mints is about the best option if it becomes a noticeable issue. This maybe caused by over consumption of the ketone supplement, tailoring the quantity consumed may prevent excess BHB being converted to acetone, which is likely excreted by the lungs.
  • Possible GI distress (flatulence) at exceptionally high doses –  In the studies referenced in this article, exogenous ketones taken in large doses occasionally resulted in GI distress, especially flatulence. However, the cause of this is hypothesized to be due to the fact that ketones were mixed in a milky fluid that wasn’t very palatable. If you’re taking a nominal dose of exogenous ketones the likelihood of GI distress is rather low. Moreover, if some GI distress is prevalent, it should improve as you become accustomed to taking ketones.
  • Hypoglycemia: why not to be concerned – Taking exogenous ketones can drive blood glucose levels quite low, but you are not likely to feel the typical symptoms of hypoglycemia. This is because when ketone levels are high enough, they dominate as fuel in the brain; hence, you will feel just fine despite having low blood glucose. A highly-cited study by George Cahill, found elevated ketone levels could protect fasted participants when they were administered insulin to induce hypoglycemia.

Future Applications & Research

Most current research on exogenous ketones focuses on the health and longevity applications of their use. Much of Dominic D’Agostino’s current work is on the cancer prevention aspect of exogenous ketones.

Another area that is targeted, is the psychological benefits of exogenous ketones, especially with how they can help protect brain tissue from degradation. As mentioned earlier, this has implications for the prevention of conditions like Alzheimer’s disease, Parkinson’s disease, and epileptic seizures.

Hopefully, in the not-too-distant future research will also focus more on the athletic performance benefits of exogenous ketones, specifically with regards to resistance training and cardiovascular exercise. The data on each of these applications is very limited at this time.

Further Reading & Recommended Resources

There are a limited group of individuals we recommend you follow to keep up with current findings on exogenous ketones. See the links below:

  • Dominic D’Agostino, Ph.D has does research focusing on cancer prevention with exogenous ketones. Dominic’s research and his lab at the University of Southern Florida has led the way in the area of exogenous ketones in the U.S. We interviewed Dominic here.
  • Peter Attia, M.D. is a surgeon who studied at Stanford Medical School and did his residency at Johns Hopkins University. He has a passion for helping others lose weight, increase their longevity, and improve their performance (physically and mentally). He has experimented heavily with ketosis, exogenous ketones and ketogenic diets.
  • Dr. Richard Veech is the senior investigator at the Laboratory of Metabolic Control in Rockville, MD, USA. His research focuses heavily on the role of ketone bodies in regards to preventing metabolic diseases, such as type-2 diabetes.
  • Patrick Arnold is an organic chemist who is notorious for being the creator of several performance-enhancing steroids. He is arguably one of the strongest influencers on the advancement of sports supplementation. Currently he is focused on developing products under the KetoSports brand, which includes two exogenous ketone products – KetoForce and KetoCaNa.
  • Kieran Clarke is a researcher at Oxford University in the UK, and has authored research around their use in athletic performance most notably.

Quality Interviews and Blog Posts

  • STEM-Talk Interview discussing “Ketone esters and their application in sport” featuring Dr. Brianna Stubbs
  • The Eating Academy: Blog post from Dr. Peter Attia on “My Experience with Exogenous Ketones”
  • Quantified Body Podcast: 2 hour long interview discussing the safety, effectiveness and status of ketone mineral salts featuring Dr. Dominic D’Agostino.
  • Dominic D’Agostino has two in-depth interviews on The Tim Ferriss Show (Part 1, Part 2). Discussion includes exogenous ketones for mitigating the onset of neurodegenerative diseases, using ketones in place of fasting for chemo-protection, benefits of ketone supplementation when consuming carbohydrates, the risks and potential toxicities of ketones.
  • KetoVangelist: Dr. Dominic D’Agostino discusses his work with exogenous ketones

Takeaways

Exogenous ketones are becoming a popular topic of research. Importantly, research aims to validate their various uses (physical performance, weight loss, neuroprotective effects etc.). While there is good research on many of these, more data is needed to provide conclusive evidence.

Exogenous ketones, especially Ketone esters, achieve ketosis without following a ketogenic diet.  But they must be consumed regularly to maintain ketosis. If Ketones are readily available then they may be used preferential over carbohydrates and fats when exercising. Even in highly glycolytic (carbohydrate) activities, such as sprinting.

Exogenous ketones certainly appear to have strong health and longevity properties at this point, especially for reducing the risk of cancer and possibly preventing/reversing type-2 diabetes. We recommend reading more from the resources listed above as they are the foremost authorities on research on exogenous ketones.

Next read Part II in our exogenous ketone series, on exogenous ketone supplements to understand the current ketone supplements available.

QUESTION(S): What questions do you have about exogenous ketones that haven’t been answered in this article? Let us know by adding to the in the comments.

References:

  1. Sato, Kiyotaka, et al. Insulin, ketone bodies, and mitochondrial energy transduction. The FASEB Journal 9.8 (1995): 651-658.
  2. Stryer, Lubert. “Biochemistry, 1995.” H Freeman & Co.,, New York (1995) pp. 510–515, 581–613, 775–778. ISBN 0 7167 2009 4.
  3. Zupec-Kania, Beth A., and Emily Spellman. “An Overview of the Ketogenic Diet for Pediatric Epilepsy.” Nutrition in Clinical Practice, vol. 23, no. 6, 2008, pp. 589–96, doi:10.1177/0884533608326138.
  4. Veech, Richard L., et al. Ketone bodies, potential therapeutic uses. IUBMB life 51.4 (2001): 241-247.
  5. Nelson, David L., Albert L. Lehninger, and Michael M. Cox. Lehninger principles of biochemistry. Macmillan, 2008.
  6. Stubbs, Brianna J., et al. (2017) On the Metabolism of Exogenous Ketones in Humans. Frontiers in Physiology, vol. 8, no. OCT, 2017, pp. 1–13, doi:10.3389/fphys.2017.00848
  7. I.F. Gaunt, M. Sharratt, J. Colley*, A.B.G. Lansdown, P. Grasso (1970). Acute and short-term toxicity of p-hydroxybenzyl acetone in rats. Food and Cosmetics Toxicology, 8(4), 349-358.
  8. Stubbs, Brianna J., et al. A ketone ester drink lowers human ghrelin and appetite. Obesity (2017).
  9. Clark, V. L., & Kruse, J. A. (1990). Clinical methods: the history, physical, and laboratory examinations. JAMA, 264(21), 2808-2809.
  10. Cox, P. J., & Clarke, K. (2014). Acute nutritional ketosis: implications for exercise performance and metabolism” Extreme Physiology & Medicine, 3, 17. http://doi.org/10.1186/2046-7648-3-17.
  11. Cox, Pete J., et al. (2016) Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metabolism, vol. 24, no. 2, Elsevier Inc., pp. 256–68, doi:10.1016/j.cmet.2016.07.010.
  12. Burke, Louise M., et al. (2017)Low Carbohydrate, High Fat Diet Impairs Exercise Economy and Negates the Performance Benefit from Intensified Training in Elite Race Walkers. Journal of Physiology, vol. 595, no. 9, pp. 2785–807, doi:10.1113/JP273230.
  13. Wall, Benjamin T., et al. (2011) Chronic oral ingestion of l‐carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans. The Journal of physiology 589.4 (2011): 963-973.
  14. Yeh, Y. Y., & Sheehan, P. M. (1985, April). Preferential utilization of ketone bodies in the brain and lung of newborn rats. In Federation proceedings (Vol. 44, No. 7, pp. 2352-2358).
  15. Hood, David A., et al. (2016) Unravelling the mechanisms regulating muscle mitochondrial biogenesis. Biochemical Journal 473.15 : 2295-2314.
  16. Murray, Andrew J., et al. (2016) Novel ketone diet enhances physical and cognitive performance. The FASEB Journal 30.12: 4021-4032.
  17. Poff, A. M., Ari, C., Arnold, P., Seyfried, T. N., & D’Agostino, D. P. (2014). Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. International journal of cancer, 135(7), 1711-1720.
  18. Hashim, S. A., & VanItallie, T. B. (2014). Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester. Journal of lipid research, 55(9), 1818-1826.
  19. Hertz, L., Chen, Y., & Waagepetersen, H. S. (2015). Effects of ketone bodies in Alzheimer’s disease in relation to neural hypometabolism, β‐amyloid toxicity, and astrocyte function. Journal of neurochemistry, 134(1), 7-20.
  20. Youm, Y. H., Nguyen, K. Y., Grant, R. W., Goldberg, E. L., Bodogai, M., Kim, D., … & Kang, S. (2015). The ketone metabolite [beta]-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nature medicine, 21(3), 263-269.
  21. D’Agostino, D. P., Pilla, R., Held, H. E., Landon, C. S., Puchowicz, M., Brunengraber, H., … & Dean, J. B. (2013). Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 304(10), R829-R836.