Exogenous Ketones: What They Are, Benefits of Use and How They Work

Exogenous Ketones: What They Are, Benefits of Use and How They Work

Exogenous ketones have become an increasingly popular nutritional/ dietary supplement since they were introduced in 2014. Like with any new supplement of interest, though, there tends to be a lot of misinformation that you have to sift your way through to find the reliable data.

Therefore, this article will do the hard work for you and get right into what the true benefits and drawbacks of exogenous ketones are. We will 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 used by our bodies (our mitochondria) to generate energy. They are an alternative fuel source to glucose.

Biochemically speaking, ketones 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).  Ketones are considered simple compounds because they don’t contain chemical groups that are readily reactive.

generic ketone

Generic Ketone Structure

In humans, there are 3 different ketones (referred to as ketone bodies) produced in mitochondria of the liver: acetone, acetoacetic acid, and beta-hydroxybutyric acid (BHB).

Beta-Hydroxybutyric Acid
Also commonly referred to as Beta Hydroxybutyrate or just 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.

However, BHB still functions like a ketone in the body and can be converted to energy (via acetyl-CoA), much like acetoacetate and acetone can (though the acetone conversion to acetyl-CoA is not efficient).

Ketone Bodies

Structures of Ketone Bodies

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 (oxidized) via BHB dehydrogenase into acetoacetic acid; the majority of the acetoacetic is then decarboxylated via acetoacetate decarboxylase into acetone.

Essentially, exogenous ketone body supplements provide users with an instant supply of ketones to utilize, even if you’re not necessarily in a state of ketosis prior to ingestion (such as when eating a higher-carb diet).

A common question is why BHB is the go-to ketone body for exogenous ketone supplements. The reason is that BHB is the most efficient ketone body in terms of either being utilized directly by tissues or being oxidized to acetoacetate and then utilized.

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

Raspberry ketone has become an increasingly popular ingredient used in fat-loss and general health supplements. However, despite its name, it has no relation to ketone bodies. This has created some confusion for people interested in exogenous ketone supplements.

Raspberry ketone is in fact a phenolic compound that gives raspberries their pleasant smell. It is structurally similar to the stimulant synephrine. Despite the marketing it doesn’t appear to have much effect on fat loss.1

Takeaway: Ignore information and products related to raspberry ketones, they 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 metabolized in the liver to a ketone. Ketone esters are used primarily in research (at the moment) for testing their efficacy in elevating ketone body levels (below is a generic structure of a BHB ester). They also are reportedly very unpleasant tasting, according to those who have experimented with them.
Structure of a BHB Ester

Structure of a BHB Ester

Currently, the commercially available supplements for personal use are all made from the ketone salts. Ketone esters are only used in research at this time.

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.

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 (see ref.3) below shows a comparison of the effects of various ketone supplements on body weight changes, in rats, over 4 weeks (note how ketone ester was the most effective at reducing weight gain over the 4 week period):

Effect of Exogenous Ketone Supplements on Body Weight

Figure 1: Effect of Exogenous Ketone Supplements on Body Weight

The supplements included:

  • BMS (Beta-hydroxybutyrate Mineral Salt) – sodium/ potassium based (similar to KetoForce)
  • MCT (medium chain triglyceride oil)
  • BMS + MCT (1:1 mixture of beta-hydroxybutyrate mineral salt and MCT oil)
  • KE (Ketone Ester – 1,3 butanediol acetoacetate diester)
  • BD (1,3-butanediol)

Benefits of Exogenous Ketone Use

Exogenous ketone supplements may provide a multitude of benefits, ranging from athletic performance enhancement, more efficient weight loss, cancer prevention, cognitive improvement, anti-inflammatory properties, and more.

Weight Loss Goals

  • Appetite suppression: As shown above in figure 1, a 4-week trial done on rats showed that exogenous ketones were effective at reducing weight gain. It is likely that this reduction in weight gain was the result of the exogenous ketones reducing the overall food intake.
  • 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.2 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 generally well-tolerated. Thus they enable one to avoid adverse GI events while providing the body with similar types of benefits.3

Performance Goals

  • Athletic enhancement: Exogenous ketone supplementation has a promising outlook for enhancing athletic performance for a variety of reasons. Firstly, ingested ketone bodies induce an acute ketosis that lasts for several hours and mimics the physiology of starvation. Secondly, exogenous ketones present a way to elevate ketone levels without having depleted muscle glycogen stores (low muscle glycogen is well known to impair sustained physical performance).4 This being said, at this time there is little direct data that shows performance enhancements after ingesting exogenous ketones. The hypothetical premise behind their use is sound nevertheless.
  • 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.5

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%.6
  • 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.7, 8
  • 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.9

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.3) 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).10 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.
  • 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.

Future Applications & Research

Current research on exogenous ketones is heavily focused towards the health and longevity applications of their use. Much of Dominic D’Agostino’s work is currently focused 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. – Dr. D’Agostino has his Ph.D. in neuroscience, molecular pharmacology, and physiology; he currently does research focusing on cancer prevention with exogenous ketones. Dominic’s research has largely led the way in the area of exogenous ketones. We interviewed Dominic here.
  • Peter Attia, M.D. – Dr. Attia 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.
  • Richard Veech – Dr. 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 – Patrick 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.

Quality Interviews and Blog Posts

  • Super Human Radio Interview: Interview discussing “Best Practices For Using Ketone Salts For Dieting, Performance And Therapeutic Purposes” featuring Dr. Dominic D’Agostino and Patrick Arnold
  • 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.
  • Tim Ferriss Show Interview with Dominic D’Agostino 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 likely to be a popular topic of research in the coming years to validate their various uses (physical performance, weight loss, neuroprotective effects). While there is good research about many of these, more data is needed to provide conclusive evidence.

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 current research and findings with regards to 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 in the comments.

References:

  1. 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.
  2. Clark, V. L., & Kruse, J. A. (1990). Clinical methods: the history, physical, and laboratory examinations. JAMA, 264(21), 2808-2809.
  3. Shannon L. Kesl,corresponding author Angela M. Poff, Nathan P. Ward, Tina N. Fiorelli, Csilla Ari, Ashley J. Van Putten, Jacob W. Sherwood, Patrick Arnold, and Dominic P. D’Agostino (2016). Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats. Nutrition & Metabolism, 13(9).
  4. 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
  5. 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).
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  • Michelle Eddington

    Can a 13 year old 205-10 lb boy take these ketones?

  • Patrick Taylor

    Can you suggest a MCT powder product that is high in C8 and has c10 without having the C12?

    • Hi @disqus_aYb48x7b8b:disqus,
      The only powder that currently refines the MCT and eliminates the C12, is the Bulletproof Instamix. It uses the Brain Octane (Caprylic Acid). However, it also includes ghee, so it isn’t a pure MCT powder product.

      We have an in depth article looking at MCT powders and the current products available here: https://ketosource.co.uk/mct-powder/

  • Mtcclark

    Can you cite any studies that evidence how the presence of exogenous ketones in the body actually induce or trigger the process of Ketosis (burning fat)? I have read that the presence of exogenous ketones in the body actually “blocks” the body’s process of Ketosis (burning fat) because the body thinks it already has enough ketones for fuel energy and doesn’t need anymore.

    • Hey @maryteresaclark:disqus

      That’s not how ketones or ketosis works so you won’t find studies on that.

      “Nutritional ketosis” comes with a well formulated ketogenic diet, and is simply the state of ‘raised ketones’ in the body as they are created through fat conversion to ketones via ketogenesis in the liver.

      The mechanism for weight loss through “ketosis” (raised blood ketones/ ketone based metabolism) is thought to be “Satiety” and appetite regulation.

      Here’s a quote from Dominic D’Agostinto on this from a recent interview I did with him: “It allows for effortless weight loss because when you’re in a state of nutritional ketosis the ketones function to control appetite. It prevents your appetite from controlling you. We don’t really know the mechanisms that regulate appetite control, are incredibly complex. But we think that the ketones are essentially telling the brain it’s in a fed state, that’s the simplistic way to put it.” -> rest of interview here: https://thequantifiedbody.net/ketone-bodies-dominic-dagostino/

      There are studies on improved ‘body composition’, Dominic noted one that is due for publication soon for athletes – as ketones preserve lean body mass, and thus tend towards biased ‘fat loss’ vs. muscle loss.

      • Mtcclark

        Thank you for your reply! So, regarding exogenous ketones and weight loss, I definitely understood that it is the process of Ketosis that burns fat and that exogenous ketones trigger or put the body into a state of Ketosis (fat burning) in a person who is not otherwise achieving nutritional Ketosis by way of their diet. Am I correct in now understanding that the only benefit that exogenous ketones have on weight loss or fat loss is in the fact that they tend to curb the appetite which presumably results in a lower caloric intake which should result in weight loss. So, as relates to weight loss only, they act like an appetite suppressant. Period. I definitely understood that exogenous ketones were somehow directly connected to promoting the process of Ketosis in the body which is directly connected to burning fat. This is where my misunderstanding came from:
        Ketosource.co.uk, “Ketone Supplements: Review Of Current Products And Future Developments,” …”How Strong Is The Blood Ketone Impact”
        “……Power : The products impact on BHB levels in the blood. The stronger the product, the more effective it is as putting the body into ketosis and the longer the effect lasts……” I also asked Pruvit whether or not exogenous ketones trigger (or put the body into) Ketosis which burns more fat and I was told “yes.” Thanks for clarifying this for me!!

        • Ketosis is a state of raised ketones in the body – so yes, exogenous ketones do raise ketones as explained in the excerpt you quoted – and can put you into ketosis as a result.

          • Mtcclark

            So Ketosis is “a state of raised ketones” NOT actually “the process by which fat is burned and ketones are produced?” … A “state” or “condition” of the blood? versus “a metabolic process?” You mention that this “state” or “condition” of raised ketone levels (via ingestion of exogenous ketones) can INDEED “put you into Ketosis as a result?”…. This was my original question (when I asked for studies) on the premise that the presence of exogenous ketones in the body actually induces or triggers the process of Ketosis (burning fat)? The original response above led me to believe “that is not how ketones and Ketosis work.” Meaning they don’t trigger or put you into Ketosis? but here … elevating your ketone levels by ingesting exogenous ketones “can put you into Ketosis” (means the process of your body burning fat versus carbs for fuel, resulting in fat loss, even without the Keto die, correct?) So then … for weight loss purposes, exogenous ketones are NOT ONLY about suppressing the appetite, after all (as I thought above, after your first response)? They are ALSO about the ability to trigger, induce or put the body into Ketosis which means your body is burning fat, even without your appetite being suppressed or being on a Keto diet? So …. how do exogenous ketones help with weight loss!? Do they help by suppressing appetite? Or by promoting Ketosis (without appetite suppression or Keto diet) which burns fat? Or both?

          • I’ve actually already answered in the first response.

            The reason you’re still asking questions is because you’re trying to combine information you’ve taken from elsewhere with the information here/ responses.

            It seems you have learned elsewhere that “ketosis means fat burning”. Which is an over simplification, and not directly related to the use of exogenous ketones.

            The takeaway is this.. If you are using exogenous ketones with the goal of losing weight, you should do so by using them as substitutes for your food intake, not on top of your normal diet. A good approach is to take them in the morning for breakfast for example, thus making use of the appetite suppressant effect as a good start to the day.

          • LeighLeigh

            That is the information I was looking for! Thanks Damien. Exogenous ketones are wonderful, but nobody has told me HOW they work in relation to losing weight. I am currently researching if EK’s will help me stay in ketosis longer so that I lose weight. But I never knew that you use them as a supplement instead of on top of what you are eating! Since I do a 8:16 fast each day, I will use them in my coffee in the morning. Cool.

          • Glad to hear it was helpful Leigh

          • It’s still not clear to me either. Yes, I am sorting through info from many sources, a lot of which is contradictory and/or not very well explained. Please be patient with my confusion!

            My takeaway is that:

            1) The keto diet promotes fat loss because you are actually burning fat to make the ketones.

            2. Exo. ketones promote weight loss by suppressing appetite. You are losing weight via calorie restriction.

            Is that correct?

            If so, this leads to a couple of other questions.

            The marketing for exo. ketones claims that it promotes fat loss and preserves muscle, even when not on a keto diet.

            Does this mean the body will not be taking calories from muscle?

            Does that mean the weight that comes off will be fat? What is the mechanism for that, please? I understand the mechanism for fat-burning when on a keto diet. I understand that taking exo. ketones puts you in ketosis… does BEING in ketosis cause your body to burn fat?

            Right now, taking exo. ketones sounds like taking a diet pill or drinking a glass of water before a meal to cut appetite. It’s very likely healthier and more effective, but not necessarily putting your body in any kind of an enhanced fat-burning state.

            Thank you for your time and very good article.

          • A recent study by Cox (google it) showed that using exogenous ketones will tell your body to prioritize ketones for fuel (and fat) instead of glycogen. If I could over simplify it, once your body is burning a fuel, it wants to keep burning that fuel. This is why getting off a high carb diet sucks right off the bat, our body just wants more carbs amd doesn’t switch to fat burning right away (as opposed to once fat adapted).

  • Mary Jo Bonifas

    My husband had Parkinson’s. What would you recommend as a supplemental dose along with his carbidopa/levodopa?

  • Super excited to have found this site this morning. Keep sharing the knowledge Damien. Many thanks for all you do!

  • Sean Micheal Mclean

    I, my wife and three kids ages 19,16,14 have been using exogenous ketones for 12 months. we Absolutely love them. the energy, mental clarity and better sleep was the first things that we experienced. My two youngest split a serving before their swim meets. The last 6 meets they BOTH broke personal best EVERY meet. Ketones provide 30-35% more ATP(cellular energy) than glucose. In the gym my wife and I are killing our workouts. We threw away all the stimulant pre-workouts and barely use protein powder anymore. Ketones are muscle sparring and new research is showing that they may also help to grow muscle. Point is we love being in ketosis and having the ability to have some carbs. Exogenous ketones keep us in ketosis even when we eat carbs.

    There are some side effects though. I’ve posted a link to the side effects.
    https://www.facebook.com/That-Keto-Life-1196669157046515/
    http://www.nutritionalketones.com/25-2/

  • Matthew Saxon

    If you are already Keto adapted, are exogenous Ketones of any benefit?
    Will you get the benefits of hormone regulation with exogenous Ketones?
    Is there any health risks from regularly switching from one energy system to another via exogenous Ketones?
    What naturally regulates the body’s level of Ketones and is this affected by exogenous Ketones?

    Cheers