By: Robert A. Schinetsky

Recent estimates indicate that roughly 75% of the population (~244 million individuals) in the United States consumes dietary supplements.[1]

Why do so many people choose to use supplements?

Simple -- as a species, we like to support, optimize, enhance, and improve anything and everything about ourselves as much as possible.

And, if there’s even a small chance that popping a pill or chugging a powder can make just just a little bit better, we’re willing to try it.

Due to the rampant surge in popularity in all things ketogenic these days, it’s no surprise that keto supplements are some of the best-selling products around.

After all, the ketogenic diet has been noted in clinical trials to[2,3,4]:

        - Improve blood sugar regulation

        - Be neuroprotective

        - Support treatment of various chronic conditions

Plus, when you factor in that the ketogenic diet, by definition, is fairly restrictive (essentially no starchy carbohydrates, including fruits), forcing many to seek snacks and meal replacements (MRPs) to help maintain the diet, it’s easy to see why supplements that are advertised to “instantly put you into ketosis” or enhance the keto lifestyle are so alluring.

But, when you really start to drill down and understand the different ways in which the ketogenic diet and keto supplements impact the body, you begin to see that the two are very different beasts.

And that brings us to the topic of today’s article -- are ketone supplements a “breakthrough” supplement that enhances fat loss, performance, focus, and the overall human condition, or are they another in the long line of overhyped supplements that under deliver on the fancy marketing claims?

To answer that question, let’s start with a quick rundown of what keto is, and why anyone would want to follow a ketogenic diet.

What is Keto?

Keto is short for ketosis -- a metabolic state where the body is essentially burning fat for fuel. Ketosis is a naturally occurring process in times when the body does not have sufficient amounts of glucose (the body’s primary and preferred source of fuel). 

One can enter a state of nutritional ketosis whenever the body is starved of glucose (i.e. carbohydrates, such as during periods of fasting or when following a very low-carb diet (~50 grams of carbohydrates per day).[5,6]

In this state of glucose deprivation, the liver starts pumping out ketones which provide the body with an alternative fuel source. The two main ketone bodies used to power the body’s cells are beta-hydroxybutyrate (BHB) and acetoacetate (AcAc). 

Researchers estimate that a keto-adapted adult can produce 150 or more grams of ketones daily after adapting to complete fast, and between 50-100 grams per day on a properly constructed ketogenic diet.[7]

However, in the early hours, days, and even weeks of switching to a ketogenic lifestyle, your body (for lack of a better, more sophisticated term) “freaks out” and has a hard time transitioning into a state of nutritional ketosis where its burning stored fat and generating ketone bodies, such as BHB. This process is more difficult and time-consuming for the body the more unbalanced your diet is (i.e. consuming way too many carbohydrates and sugar).

In these instances, keto proponents advertise keto supplements as a means to ease the transition and reteach the body how to burn fat for fuel (though this “reteaching” period is heavily debated in the research community).

A more likely explanation for the pangs of transitioning to a ketogenic state is due to the rapid loss of essential mineral, water, and various other nutrient stores. 

For a more specific example, people often complain of brain fog, lethargy, and muscle cramps when during the keto transition. Each of these can be explained by the rapid, abrupt loss in water, electrolytes, and low blood glucose that comes with suddenly cutting off the body’s primary source of fuel. 

The reason for this is that when you adopt a very-low carbohydrate diet, you starve the body of glucose. When this initially happens, the body relies on its carbohydrate stores (glycogen) to provide the glucose your brain, muscles, and other tissues need.

When those stores get depleted, the body starts searching for an alternative fuel source, which in this case is ketone bodies, specifically BHB which accounts for roughly 78% of the total ketones in the blood.[8]

To help “prime your body’s keto pump” and facilitate the transition into ketosis that much quicker, a number of keto supplements have been developed to provide individuals with exogenous ketone bodies while their body “figures” things out again.

So, what’s in these keto supplements to support and enhance the keto experience?

Inside Keto Supplements

The first question to ask yourself is -- why would you want to supplement with ketones in the first place?

Well, research into ketone bodies has noted that they beneficially impact gene expression and cellular functions in a variety of ways.

More specifically, studies have shown that BHB can inhibit histone deacetylase (HDAC), instigating a torrent of metabolic activity that leads to better resiliency, metabolic health, and longevity.[8] 

And, it also has been noted to impart anti-aging effects via upregulation of hnRNP A1-induced Oct4-mediated Lamin B1 pathway in vascular cells.[9]

Ketones can even cross the blood-brain barrier, providing the brain with a readily useable form of energy that’s described by many as somewhat stimulatory and offer a measure of neuroprotection too.

Continuing with the cognitive benefits of ketones, they support conversion of glutamate (an excitatory neurotransmitter) to GABA (the body’s primary inhibitory neurotransmitter) via upregulation of GABA-mediated inhibition.[11,12] And to top it off, when the brain takes up ketone bodies, cerebral blood flow is also increased (bringing more oxygen and nutrients to the brain).[13]

Researchers estimate that ketones can provide the brain with ~70% of its energy requirements, the rest would have to come from glucose either obtained from the diet or produced endogenously via gluconeogenesis.[10]

Given the plethora of benefits that come along with increased levels of ketone bodies in the blood, it’s easy to understand why individuals would want to supplement with them in the form of exogenous ketones.

So, what types of exogenous ketones are available?

Keto supplements typically supply exogenous ketones in the form of BHB. This is due primarily to two factors:

        - BHB accounts for the vast majority of ketone bodies in the blood

        - Acetoacetate (AcAc) is chemically unstable. AcAc will slowly break down  over time to form acetone.

As a result, every keto supplement you find on the market is delivering only BHB as opposed to the naturally occurring mix of BHB and Acetoacetate. (hint, hint: here’s problem #1 with keto supplements.)

Additionally, the form of BHB found in most supplements is a mixture of “D” and “L” isomers.

The difference here, is that when produced naturally by the body (endogenously), BHB only appears in the D-isomer form.

Why does this matter?

Well, from a metabolic standpoint, the two isomers (while similar) act differently in the body. Furthermore, the current body of scientific research extolling the benefits of BHB are in regards to the D-isomer of BHB, not the L-isomer.

Is this a big deal?

Possibly so, as the L-isomers are not metabolized via the same pathways as the D-isomers are.[14,15]. Studies indicate the L-form is weaker than D-BHB in its ability to provide energy as well as its antioxidative capacity.[18]

It’s also worth noting that researchers aren’t really clear what benefits (if any) can be derived from L-isomers of BHB or if our bodies can even convert them to the D-isomer.

Which form of BHB am I getting? 

Complicating this issue is the fact that most exogenous ketone supplements do NOT list which isoform of BHB they are including. You might be getting all D-BHB, a mix of D-BHB and L-BHB, or all L-BHB. You just don’t know with most products.

So, at best your getting a product that may contain all D-BHB; however, given the high cost of exogenous ketones, it’s far more likely you are getting a mix of D-BHB and L-BHB (or just L-BHB).

What this means, if all things go in your favor your exogenous ketone supplement may be bioavailable and confer some of the benefits of endogenous BHB. At worst, you’re shelling out huge chunks of cash for a product that may have little to no beneficial effects whatsoever outside of giving you very expensive urine.

But, let’s assume that every keto supplement manufacturer on the market has the consumers best interest at heart (which they don’t) and use only the D-isomer and include it at an efficacious dose (typically 5-6 grams of BHB). 

The research into the effects of exogenous ketones on sports performance and fat loss aren’t all that encouraging.

Let’s see the areas where ketone supplements pale in comparison to a ketogenic diet.

Ketogenic Diets vs Keto Supplements

Transient Effects

Exogenous ketones (in the form of BHB salts and ketone esters) only provide a temporary increase in blood ketone levels. These sharp, temporary elevations in blood ketone levels typically only last a few hours, which means that you can experience a short decline in energy, mental clarity, and focus if you’re not following a properly formulated diet.

Anecdotally, even those who do follow a well-formulated ketogenic diet have remarked on occasion of experiencing this “hazy” feeling from an overload of ketones slamming the body at once.

In order to prevent the subsequent drop in ketone levels, it’s commonly recommended to consume exogenous ketones alongside MCT oil (or powder) which stimulates the liver to continue producing ketones. BHB salts DO NOT stimulate ketogenesis.

Therefore, once your body has processed the ingested ketones and it’s searching for more energy, if you’re not keto-adapted (or following a ketogenic diet at all), it’s very likely you’ll experience an energy crash of sorts.

Instead of wasting money on overpriced BHB salt formulations that offer short-lived effects, you’d be better served to restrict carbohydrate intake and supplement with MCT oil, which is considerably cheaper than BHB salts and ketone esters and stimulates the production of ketone bodies.[19]

Reduces Endogenous Ketone Production

There is one “side effect” of consuming exogenous ketones that many people interested into keto don’t realize. Supplementing with exogenous ketones temporarily reduces your body’s natural production of ketones. 

How so?

Exogenous ketone supplements increase blood levels of ketones by providing your body with an external source of BHB. Similar to ingesting carbohydrates or injecting anabolic steroids, what the body receives from the outside, it produces less of on its own.

For example, when you run a cycle of testosterone, your body naturally downregulates endogenous production of testosterone. Likewise, when you consume sufficient amounts of dietary carbohydrate, your body does not need to perform gluconeogenesis to create the required glucose it needs to power the various cells that only rely on glucose. 

The same holds true for supplemental ketone bodies. If you’re giving your body a readily accessible form of BHB (i.e. keto supplements), it takes the path of least resistance and uses those first and foremost for energy, instead of wasting time and more energy to break down stored fat, oxidize the liberated fatty acids, and generate ketones. 

Once the exogenous ketones are all used, the body will then resume ketone production (assuming you are following a ketogenic diet and not a high-carbohydrate one).

The reason for this is that the body has several feedback mechanisms that restrict ketone production if ketone levels get too high to prevent your blood from getting too acidic.[20,21,22,23]

Sports Performance

Since skeletal muscle can use ketone bodies for energy, sports performance is one of the big areas keto supplements are marketed towards. And when you consider the fact that BHB is capable of delivering more energy per unit of oxygen consumed than either glucose or fatty acids, consuming something that would increase BHB concentrations makes sense.[24]

However, the majority of research assessing the effects of exogenous ketones on sports performance don’t paint a very pretty picture.

We’ve gone into great detail before explaining why keto supplements do not enhance sports performance, so click here to read all the gory details, but as a brief refresher for those that haven’t read (or don’t remember) our previous explanation.

But to recap, studies investigating the effects of exogenous ketone supplementation on sports performance researchers observed:

        - Subjects had a 7% drop in average power output[25]

        - Ketone supplementation inhibits the use of glycogen[26]

        - No improvement in cognitive performance following exercise[29]

        - Ketone esters do NOT improve heart rate, rating of perceived exertion, 15 meter sprint times or shuttle run time to exhaustion.[27]

        - Ketone supplementation reduces free fatty acid availability, indicating exogenous ketone ingestion impedes the body’s ability to burn its own fat for fuel during exercise as well as the pro-lipolytic effects of exercise[28] 

Taken together, this has led some researchers to say:

“...there is currently no evidence to support the use of ketone bodies as an ergogenic aid under conditions where optimal evidence based nutritional strategies are applied.”[28]

What has yet to be fully teased out in the literature is whether or not a period of adaptation is required to extract any performance-enhancing benefits from exogenous ketones administration and what (if any) dosing strategy should be used, 

Based on the current body of literature, we know that using ketone supplements reduces lipolysis as well as the availability of fatty acids -- the exact opposite of what occurs when a person follows a proper keto diet.

Fat Loss

In addition to explaining in detail how exogenous ketone supplements do not enhance performance, we’ve also extolled the many ways in which keto supplements do not aid the process of fat loss (impaired lipolysis, fat burning, etc), save one -- appetite suppression.

A 2018 study published in the journal Obesity found that ingestion of a ketone ester supplement reduced ghrelin, the hormone that signals hunger, stimulates appetite, and increases food intake.[30]

This led researchers to conclude that exogenous ketones may exert appetite suppressing effects in the body.

However, ketogenic diets by nature are very satiating, with most people stating they feel less hungry when transitioning to a ketogenic diet. What’s unclear at this stage is whether the use of exogenous ketones provides any more appetite suppression than just following a proper keto diet.

GI Issues

In addition to all of the other drawbacks to exogenous ketones, there’s one more you can add to the list -- GI distress.

Research has shown that consuming large quantities of ketone salts (the kind found in most keto supplements) results in gastrointestinal distress.[31] Additional research into ketone esters using acetoacetate as the ketone body base noted that subjects became nauseous after ingestion and had to reduce performance output.[21]

It should be mentioned that ketone esters using D-BHB as their “base” report relatively few side effects[32], but again the average supplement consumer is purchasing ketone supplements using BHB salts, not esters due to the high cost (and deplorable taste) of ketone ester products.

The Bottom Line on Keto Supplements

Based on the current body of evidence, there is a substantial lack of proof that their use confers any significant benefits in regards to performance, fat loss, or cognitive function above and beyond that which can be obtained by following a well-formulated ketogenic diet.

Keto supplements simply do not provide any substantial benefit that can justify their cost or potential drawbacks. 

If you want to get the benefits of ketones, consider reducing your carb intake, experimenting with intermittent fasting, and supplementing with MCT oil. This trifecta won’t inhibit endogenous ketone formation (it actually supports it) and it’s a heck of a lot cheaper!

References:

1. "2018 CRN Consumer Survey on Dietary Supplements | Council for Responsible Nutrition." Home | Council for Responsible Nutrition, crnusa.org/CRNConsumerSurvey.
2. Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr. 2013;67(8):789-96.
3. Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease-modifying effects of the ketogenic diet. Behav Pharmacol. 2006;17(5-6):431-9.
4. Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev. 2008;59(2):293-315.
5. Owen OE , et al. "Liver and Kidney Metabolism During Prolonged Starvation. - PubMed - NCBI." National Center for Biotechnology Information, ncbi.nlm.nih.gov/pubmed/5773093/.
6. Fukao T , et al. "Pathways and Control of Ketone Body Metabolism: on the Fringe of Lipid Biochemistry. - PubMed - NCBI." National Center for Biotechnology Information, ncbi.nlm.nih.gov/pubmed/14769483.
7. Féry F, Balasse EO. Ketone body production and disposal in diabetic ketosis. A comparison with fasting ketosis. Diabetes. 1985; 34:326-32
8. Sena, S. F. (2010). Beta-hydroxybutyrate : New Test for Ketoacidosis. Department of Pathology and Laboratory Medicine.
9. Rojas-Morales, P., Tapia, E., & Pedraza-Chaverri, J. (2016). β-Hydroxybutyrate: A signaling metabolite in starvation response? Cellular Signalling, 28(8), 917–923.
10. White H, Venkatesh B. Clinical review: ketones and brain injury. Crit Care. 2011;15(2):219. Published 2011 Apr 6. doi:10.1186/cc10020
11. Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease modifying effects of the ketogenic diet. Behav Pharmacol. 2006;17:431–439. doi: 10.1097/00008877-200609000-00009.
12. Yudkoff M, Daikhin Y, Nissim I, Lazarow A. Ketogenic diet, amino acid metabolism, and seizure control. J Neurosci Res. 2001;66:931–940. doi: 10.1002/jnr.10083.
13. Hasselbalch SG, Madsen PL, Hageman LP, Olsen KS, Justesen N, Holm S, Paulson OB. Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia. Am J Physiol. 1996;270:E746–E751
14. Lincoln BC, Des Rosiers C, Brunengraber H. Metabolism of S-3-hydroxybutyrate in the perfused rat liver. Arch Biochem Biophys. 1987; 259:149-56.
15. Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, M Stirling M, Clarke K. On the Metabolism of Exogenous Ketones in Humans. Front. Physiol. 2017.
16. Desrochers, S., David, F., Garneau, M., Jette, M., and Brunengraber, H. (1992). Metabolism of R-1,3-Butanediol and S-1,3-Butanediol in Perfused Livers from Meal-Fed and Starved Rats. J. 285, 647-653
17. Webber, R.J., and Edmond, J. (1977). Utilization of L(+)-3-Hydroxybutyrate, D(-)-3-Hydroxybutyrate, Acetoacetate, and Glucose for Respiration and Lipid-Synthesis in 18-Day-Old Rat. J Biol Chem 252, 5222-5226
18. Haces, María L., et al. "Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions." Experimental Neurology, vol. 211, no. 1, 2008, pp. 85-96.
19. Vandenberghe C, St-Pierre V, Pierotti T, Fortier M, Castellano CA, Cunnane SC. Tricaprylin Alone Increases Plasma Ketone Response More Than Coconut Oil or Other Medium-Chain Triglycerides: An Acute Crossover Study in Healthy Adults. Curr Dev Nutr. 2017;1(4):e000257. Published 2017 Mar 22. doi:10.3945/cdn.116.000257
20. Balasse & Neef (1975) Balasse EO, Neef MA. Inhibition of ketogenesis by ketone bodies in fasting humans. Metabolism: Clinical and Experimental. 1975;24(9):999–1007. doi: 10.1016/0026-0495(75)90092-X
21. 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. Published 2017 Oct 23. doi:10.3389/fphys.2017.00806
22. Evans M, Cogan KE, Egan B. Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol. 2016;595(9):2857-2871.
23. Taggart, A. K. P., Kero, J., Gan, X., Cai, T.-Q., Cheng, K., Ippolito, M., Waters, M. G. (2005). (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. The Journal of Biological Chemistry, 280(29), 26649–26652. https://doi.org/10.1074/jbc.C500213200
24. Murray AJ, Knight NS, Cole MA, et al. Novel ketone diet enhances physical and cognitive performance. FASEB Journal. 2016; 30: https://doi.org/10.1096/fj.201600773R
25. O’Malley, T., Myette-Cote, E., Durrer, C., & Little, J. P. (2017). Nutritional ketone salts increase fat oxidation but impair high-intensity exercise performance in healthy adult males. Applied Physiology, Nutrition, and Metabolism, 42(10), 1031–1035. https://doi.org/10.1139/apnm-2016-0641
26. https://www.medicalnewstoday.com/articles/319742.php
27. Evans, M., & Egan, B. (2018). Intermittent Running and Cognitive Performance after Ketone Ester Ingestion. Medicine and Science in Sports and Exercise. https://doi.org/10.1249/MSS.0000000000001700
28. Pinckaers PJM, Churchward-Venne TA, Bailey D, van Loon LJC. Ketone Bodies and Exercise Performance: The Next Magic Bullet or Merely Hype? Sports Medicine (Auckland, N.z). 2017;47(3):383-391. doi:10.1007/s40279-016-0577-y.
29. Waldman, H. S., Basham, S. A., Price, F. G., Smith, J. W., Chander, H., Knight, A. C. McAllister, M. J. (2018). Exogenous ketone salts do not improve cognitive responses after a high-intensity exercise protocol in healthy college-aged males. Applied Physiology, Nutrition, and Metabolism, 43(7), 711–717. https://doi.org/10.1139/apnm-2017-0724
30. Stubbs, Brianna J., et al. "A Ketone Ester Drink Lowers Human Ghrelin and Appetite." Obesity, vol. 26, no. 2, 2017, pp. 269-273.
31. Veech RL (2004). The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 70, 309–319.
32. Clarke K, Tchabanenko K, Pawlosky R, et al. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012;63(3):401-8.