By: Robert Schinetsky

The usage of exogenous ketone supplements (particularly BHB salts) is greater than ever as interest in the ketogenic diet has reached fever pitch-like status.

Bolstered by claims of “enhanced weight loss”, “increased fat burning, and “heighted cognitive function”, more and more individuals continue to seek out the alternative fuel source as a way to power their day.

And while it may be an efficient form of fuel for both mind and body, there’s still a great deal left to learn about the effects of regular consumption of exogenous ketones as well as some unintended consequences that you may not be considering.

In this article we’ll discuss the potential health risks involved with using exogenous ketone salts, particularly in regards to your cardiovascular health. 

First let’s start by recapping a brief history of ketone supplements

Exogenous Ketones: A Brief History

In the “early” days of ketone supplements, the only viable option for providing the body with an exogenous form of ketone bodies were ketone esters.

These esters are created by linking an alcohol group to a ketone body. The problem with ketone esters is that they were both incredibly expensive and extremely unpalatable. 

This lead to the development of ketone salts whereby a mineral salt (calcium, magnesium, potassium, or sodium) is bound to BHB, the most abundant and well-studied of the ketone bodies. In contrast to ketone esters, the ketone salts are cheaper to produce, easier to blend in water, and don’t taste like you just licked a wet dog on a hot summer day.

BHB salts vs Ketone Esters

Now, there’s a few other big differences between these two types of ketone supplements than just cost and taste, a few of which we’ve discussed before in our Keto Wars article.

For starters, ketone esters tend to create a larger surge in BHB levels in the blood compared to an equivalent dose of BHB salts; however, BHB salts tend to result in a longer lasting elevation of blood BHB levels than ketone esters.[1,2,3]

Additionally, ketone esters raise blood levels of D-BHB, while BHB salts result in an increase in the L-isoform of BHB.

This is worth noting as D-BHB is the form naturally produced by the body. This means that while the two molecules (L-BHB and D-BHB) are similar they act differently in the body.  

And, studies have shown as much. The L-isomer is metabolized via different pathways than D-isomers, and the L-BHB form has been shown to be a weaker antioxidant and less potent energy source than D-BHB.[1,4,5] Scientists are also unsure if our bodies are capable of converting the L-isomer into the more potent (and naturally occurring) D-isomer. 

Finally, the majority of the research conducted to date has investigated the possible prophylactic properties of BHB are using D-BHB, not L-BHB.

Now, all that being said, BHB salts do offer the advantage of supplying the body with additional electrolytes, such as sodium, magnesium, potassium, and calcium. Typically though, only calcium, magnesium and sodium are used as the binding mineral due to the fact that ketone-potassium supplements aren’t that stable.

This is important because dehydration and loss of valuable electrolytes (particularly potassium and magnesium) are two of the main reasons many people experience “keto flu” during their initial transition from a sugar-burning machine to a fat-burning one.

However, while supplementing with some electrolytes is beneficial, too much can lead to potential health complications, particularly in regards to the cardiovascular system. 

When considering whether or not to purchase a ketone supplement, most people tend to look at the sodium content for fear that too consuming too much of the mineral might result in high blood pressure.

Yet, they pay little to no attention to the calcium content of the product.

Why is calcium a concern?

After all, weren’t we always told to drink milk as kids in order to get our calcium and vitamin D to make strong bones?

Indeed we were, but there’s a difference between naturally occurring calcium (like the kind in dairy, beans, and leafy greens) and supplemental calcium with regards to its effects on the health of the human body.

When you take into consideration that the RDI for dietary calcium is 1,000 mg per day for young to middle-aged adults (women over age 50 and all individuals age 70+ are recommended to get 1,200 mg per day) and most people tend to be not get in enough calcium (or magnesium) daily, using a supplement that contains calcium (such as BHB salts) should seem all well and good.

Right?

Maybe not as we’re about to discuss.

Ketone Supplements and Inflammation

Inflammation is a natural (and essential) part of the body’s immune response where it helps our bodies recognize microscopic ne’er-do-wells and defend the body from injury and infection. Inflammation also plays an important role in helping the body recover from exercise and grow bigger, stronger muscles.

However, as with most things in life, more is not always better, especially in the case of inflammation.

Having too large of an immune response, or one that lasts too long increases our risk for certain chronic diseases such as type 2 diabetes, cardiovascular disease, various cancers, and neurodegenerative diseases like Alzheimer’s.

The keto diet is often lauded for its anti-inflammatory properties.[6,7,8]

In particular, the ketone body β‐hydroxybutyrate (βHB) has received the bulk of the praise due to some research indicating that it can directly inhibit the NLRP3 inflammasome, a key regulator of inflammation.[10]

Additional research indicates that BHB suppresses inflammation by inhibiting NF-kB activation (and subsequent IL-1 secretion) and histone deacetylases (HDACs), which improves memory encoding. In case you weren’t aware, NF-kB is a key signaling pathway involved in inflammation and is considered by researchers as the “holy grail” upon which anti-inflammatory drugs can act.[11]

Scientists also believe that BHB may play a role in reducing other types of pain, including neuropathic pain, inflammatory pain, and thermal pain due to the ketone body’s ability to increase adenosine which exerts analgesic (pain-relieving) effects.[12]

All of this is in addition to the fact that ketone bodies create less oxidative stress during the production of ATP than glycolysis (the process by which the body breaks down glucose to create ATP).

So it would seem that if we could further increase our BHB levels (via ketone supplements), we should see a greater reduction in markers of inflammation.

But, that’s not the case according to some recent research.

While the ketogenic diet itself may be useful for reducing oxidative stress and improving markers of systemic inflammation, the same effects may not be conferred by exogenous ketone supplements.

A recent study documented that oral ketone supplementation activates the innate immune system which can cause inflammation.[10]

10 healthy males took part in the study in which researchers were investigating the effects of a ketone salt supplement (0.3 g/kg body mass) vs a flavour-, sodium- and potassium-matched placebo with regards to its ability to suppress NLRP3 inflammasome activation.

(Note: for a 170lb male this equates to roughly 23.2 grams of BHB salts. The typical dose of BHB salts included in one serving of most ketogenic supplements is ~11-12g)

Markers of NLRP3 inflammasome activation tracked by the researchers included:

- Active caspase-1

- Secretion of mature IL-1

- NLRP3 mRNA

- IL1B mRNA

Furthermore, researchers also measured circulating glucose, insulin, and non-esterified free fatty acids (FFAs), insulin, and glucose to trace metabolic changes in response ketone supplements consumption.

As expected, ingestion of BHB salts led to elevations in blood BHB levels (0.2+/-0.1 mM to 0.9+/-0.2 mM 30 minutes following ingestion of ketone salts). Interestingly, BHB salt consumption also led to increases in active caspase-1 as well as insulin.

Caspase-1 is an enzyme that transforms pro-IL-1B into mature IL-1B to be secreted to carry out the inflammatory response. These effects fly counter to animal and cell culture studies noting that BHB limits the inflammatory response by suppressing IL-1B secretion.

Researchers observed no changes in IL-1B mRNA or NLRP3 mRNA, which they believe indicates that the increased IL-1B secretion was due to increased active caspase-1.

As a follow up to the ketone salt study, researchers also tested the effects of ketone ester supplements on a group 20 individuals, though only 18 volunteers completed the trial. 

Similar to ketone salt ingestion, consumption of ketone esters led to increases in caspase-1 activation, and subsequently IL‐1β secretion, as well as insulin.

Based on these results, it appears that not only do ketogenic diets differ in their effects on inflammation in the body but it also induces a different metabolic state. More specifically, ketogenic diets lower inflammation and decrease insulin levels. Administration of ketone supplements increases BHB levels (similar to ketogenic diets), but also increases markers of inflammation and insulin.

Therefore, based on these findings, it seems that BHB salts and ketone esters actually result in the exact opposite metabolic state that an individual is trying to attain on a ketogenic diet.

It’s important to note that this is but one study demonstrating the potentially adverse effects of exogenous ketones on healthy humans subjects, and further research is needed to identify and explore why ketone supplements increase inflammation and insulin levels, but for the time being, if you want to take advantage of the potential health benefits associated with being in a state of nutritional ketosis, do it via a ketogenic diet, not ketone supplements.

As if elevated markers of inflammation and insulin wasn’t enough, there’s more to unravel with the potential risks of using ketone supplements...

Ketone Supplements and Cardiovascular Risks

Researchers have established a link between elevated circulating calcium and cardiovascular disease morbidity and mortality.[15,16,17] More recently, scientists have also identified a link between calcium supplements and an increased risk of cardiovascular disease.[18]

Most recently, a new study published in the Journal of Clinical Hypertension reviewed the medical records of 641 participants and found an association between high serum calcium levels and increased risk of cardiovascular disease using the Framingham risk score.[13]

In case you weren’t aware, the Framingham risk score is a method for predicting an individual’s risk of severe cardiovascular events up to 10 years after estimation.[13]

The reason elevated calcium levels are concerning is that they can lead to changes blood coagulation mechanisms as well as endothelial dysfunction. Additionally, elevated intracellular free calcium level leads to greater secretion of catecholamines (epinephrine, norepinephrine, etc), which leads to vasoconstriction and increased arterial blood pressure.[19,20]

And, as you may or may not know, Vitamin D plays a crucial role in cardiovascular health and calcium absorption. Specifically, bones can only effectively absorb calcium if there is sufficient vitamin D.

When you consider the fact that significant portions of the population are deficient in vitamin D, coupled with the fact that vitamin D deficiency can lead to increased vascular inflammation and adverse cardiovascular-related events[20], and the

So, what does this have to do with ketone supplements?

As we mentioned at the beginning of this piece, when creating BHB salts, the BHB molecule is bound to one of 4 minerals -- sodium, potassium, magnesium, and calcium.

In fact, ketone supplements on average contain anywhere from 260-600mg of calcium (from calcium BHB) per serving.[14] Just two servings of BHB salts may put individuals well over the RDI of calcium and potentially increase their risk of kidney stones and/or cardiovascular disease.

And when you couple this with the fact that most ketone supplements do not provide any vitamin D and a significant percentage of the population is deficient in vitamin D, you can see why this becomes somewhat alarming -- individuals are supplementing with calcium, yet lacking a key nutrient that helps drive the mineral from the blood and into the bone, which may lead to potential cardiovascular related issues.

Again, this drives home the point that caution must be exercised before using any type of dietary supplement, particularly ketone supplements with high calcium contents.

Ketone Supplements, Performance, and Fat Loss

The list of reasons to limit (or avoid) ketone supplements continues to grow.

We’ve discussed at length in previous articles that ketone supplement do not enhance fat burning, weight loss, athletic performance or cognitive function according to recent research.[21]

Suffice it to say the science behind ketone supplements is severely lacking. Not only are they unproven in their ability to confer any sort of benefit, they may actually lead to overwhelming side effects.

Until further research is conducted demonstrating the safety and efficacy of exogenous ketones in healthy human subjects, they cannot (and should not) be recommended for daily use.

This is why AML ThermoHeat Fat Burning Protein does not contain added ketone salts. Instead, AML ThermoHeat Fat Burning Protein incorporates MCT and Paradoxine, ingredients that work to stimulate the body’s natural ketone generation mechanisms and activate brown fat thermogenesis (fat burning).

AML ThermoHeat Fat Burning Protein does NOT contain calcium BHB either. It does supply valuable electrolytes commonly missing in ketogenic diets, ThermoHeat Fat Burning protein includes potassium citrate and magnesium.

Potassium citrate is a approved supplement for kidney stones, which are more prevalent in people on ketogenic diets due to the combination of water loss and low electrolyte levels on Keto diets.

Don’t fall for the marketing hype of ketone supplements. They’re unproven and ineffective at best and potentially hazardous at worst.

References

1. Stubbs, B. J., Cox, P. J., Evans, R. D., Santer, P., Miller, J. J., Faull, O. K., Clarke, K. (2017). On the Metabolism of Exogenous Ketones in Humans . Frontiers in Physiology . Retrieved from https://www.frontiersin.org/article/10.3389/fphys.2017.00848
2. Rodger, S., Plews, D., Laursen, P., & Driller, M. (2017). The effects of an oral β-hydroxybutyrate supplement on exercise metabolism and cycling performance. Journal of Science and Cycling; Vol 6, No 1 (2017).
3. 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 = Physiologie Appliquee, Nutrition et Metabolisme, 42(10), 1031–1035. https://doi.org/10.1139/apnm-2016-0641
4. Lincoln BC, Des Rosiers C, Brunengraber H. Metabolism of S-3-hydroxybutyrate in the perfused rat liver. Arch Biochem Biophys. 1987; 259:149-56.
5. 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.
6. Pinto A, Bonucci A, Maggi E, Corsi M, Businaro R. Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer's Disease. Antioxidants (Basel). 2018;7(5):63. Published 2018 Apr 28. doi:10.3390/antiox7050063
7. Hallberg, SJ., McKenzie, AL., Williams, PT., et al. Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study. Diabetes Ther. 2018; 9:583–612
8. Athinarayanan SJ., Adams , RN., Hallberg, SJ.,et al. Long-Term Effects of a Novel Continuous Remote Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-year Non-randomized Clinical Trial. 2018. BioRxiv. doi: https://doi.org/10.1101/476275
9. Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21(3):263–269. doi:10.1038/nm.3804
10. Neudorf, H., Durrer, C., Myette‐Cote, E., Makins, C., O'Malley, T., Little, J. P., Oral Ketone Supplementation Acutely Increases Markers of NLRP3 Inflammasome Activation in Human Monocytes. Mol. Nutr. Food Res. 2019, 1801171. https://doi.org/10.1002/mnfr.201801171
11. Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1(6):a001651. doi:10.1101/cshperspect.a001651
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13. Park, B, Lee, Y‐ Borderline high serum calcium levels are associated with arterial stiffness and 10‐year cardiovascular disease risk determined by Framingham risk score. J Clin Hypertens. 2019; 00: 1– 6. https://doi.org/10.1111/jch.13532
14. https://shop.perfectketo.com/products/exogenous-ketones-keto-supplement
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18. Wang L, Manson JE, Sesso HD. Calcium intake and risk of cardiovascular disease: a review of prospective studies and randomized clinical trials.
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21. 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 = Physiologie Appliquee, Nutrition et Metabolisme, 43(7), 711–717. https://doi.org/10.1139/apnm-2017-0724