Ketone Supplement Fundamentals

Authored by Nate MartinsDr. Brianna Stubbs and Brady Holmer • 
November 10, 2019
 • 15 min read
exogenous-ketonesresearchketosis

Evolution is likely the reason for ketosis

This process evolved to enable humans to survive long periods of time without food. Ketosis was a necessity, since without an external source of energy in the form of food, humans would have eventually starved. An evolutionary “work-around” maintained energy stores in the face of deprivation by producing molecules called ketones from the body’s own internal fat stores. 

These molecules are now known to have more benefits than just survival.

But today, we rarely encounter anything close to nutrient deprivation. Our food-plenty society and high-carb food options ensure many of us are well-fed. We never force our bodies to become “ketogenic”—meaning that it’s actively producing ketones. What a shame, since ketones have a variety of beneficial effects for cell signaling and metabolism.

How then, can we gain the benefits of ketosis? One way is to eat a low-carbohydrate ketogenic diet, a.k.a the “keto diet”, or to fast

Other avenues into ketosis exist, ways to “hack” evolution and enter ketosis without having to eat a low-carb diet or fast for days on end. 

This method involves the use of exogenous ketones (“exo” meaning “from outside”) in the form of supplements. Furthermore, these exogenous ketones and keto supplements can be used to deepen levels of ketosis and provide a fuel source under certain metabolic conditions like fasting.

What is Ketosis?

First, let’s talk about ketones. 

Ketones are the products of the breakdown of fats in the body. Under a state of carbohydrate depletion, blood sugar is reduced, insulin levels fall, glucagon and cortisol rise, and fatty acids (FFAs) are liberated into the blood through a process called lipolysis. The increase in blood levels of FFAs is then sensed by the body, and FFAs are then transported to the liver and used in the production of ketone bodies. Three ketones exist: Acetoacetate (AcAc), Beta-hydroxybutyrate (BHB), and Acetone. 

Being in ketosis simply means that you have elevated levels of ketones in your blood, usually agreed upon at 0.5mM. Typically, this means elevated AcAc or, more commonly and in greater amounts, BHB. 

BHB and AcAc are the ketones mostly referred to when talking about ketosis and, as we will see later on, ketone supplements

BHB is the ketone present at the highest levels in the blood of a body in ketosis.1 This is significant for two reasons. For one, BHB is more stable than AcAc, and can be transported through the blood to other organs and tissues much more effectively. AcAc can be spontaneously broken down when it’s in the blood, where it forms acetone—a metabolic “waste product” that we excrete in the breath. We can’t use much acetone for energy.

But this doesn’t make AcAc any less important. 

In fact, AcAc is the “parent” ketone body—it’s what the body produces first, when the body is entering ketosis, and serves as the precursor for BHB. AcAc produced in the liver is converted to BHB, and then shuttled out and delivered elsewhere. A small amount of AcAc does travel through the circulation to be used as a fuel source, just to a lesser extent than BHB.

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Endogenous vs. Exogenous Ketosis

“Am I in ketosis?” This question has a straightforward answer. As mentioned, typically a blood ketone level >0.5mM signifies that the body is producing ketones (or is in ketosis, depending on the route taken).

Route taken? Correct. There are two ways to achieve ketosis—endogenously or exogenously. 

Endogenous ketosis (“endo” meaning within”) is achieved through a low-carb high-fat diet (i.e. ketogenic diet) or fasting, in which the body produces its own ketones. The stimulus is dietary carbohydrate restriction, and the response is that we start to burn fat, leading to (eventually) an outflow of ketones from the liver. Since diverse signaling pathways are activated in order to activate endogenous ketosis and in response to it, diverse physiological benefits also occur. 

In contrast, exogenous ketosis (“exo” meaning outside) is achieved through the use of dietary ketone supplements and/or intake of certain types of dietary fats. These supplements can boost ketone levels either directly (ketone supplements) or indirectly (MCTs) but either way, elevate levels of blood ketones. Ketosis achieved exogenously can occur even in the absence of a ketogenic diet or prolonged fast. Sounds too good to be true. 

Ketosis might be ketosis, but the profiles used to achieve endogenous and exogenous ketosis vary drastically, and therefore have different benefits. There is something to be said about triggering the body to naturally produce ketones vs. “artificial” induction of ketosis. In the former, you’re forcing the body to be “ketogenic” whereas in the latter, you’re in ketosis, but not “ketogenic.” There are benefits to both.

Exogenous ketones are an alternative to physiological ketosis, and can be used in diverse ways to achieve certain mind and body states, almost like ketosis on cue.

While supplements are only chemically synthesized versions of ketones, the structure and function are essentially the same.

But, structural similarities aside, exogenous and endogenous ketosis have varying effects on the body. For instance — exogenous ketone supplementation is likely best for those trying to meet the needs of a ketogenic diet, improve sport performance, or further increase ketone levels on a ketogenic diet or a fast. However, the health benefits of ketosis like increased fat metabolism, weight loss, and some of the other metabolic benefits might only come from lifestyle changes like fasting or a ketogenic diet.

BHB monoester and AcAc diester chemical compounds

Why Use Exogenous Ketones?

Before diving into the specific forms of exogenous ketones and the nuances of each, let’s discuss some of the general reasons one might choose to use exogenous ketone supplements in the first place. 

One of the primary reasons to use exogenous ketones may be to enhance the effects of your low-carb ketogenic diet or intermittent fasting regimen. These practices will likely have you in a ketogenic state already. To further enhance the benefits many people claim to feel when ketogenic/fasting— like mental clarity, sharpness, lower fatigue—exogenous ketones can be superimposed, which essentially means going “deeper” into ketosis. 

Exogenous ketones might also be a helpful aid to transition into ketosis when starting out on a ketogenic diet. 

Many cite the “keto flu” as a badge of honor one must experience when entering into ketosis. When the body is first adapting to a diet very low in carbohydrates, and not yet fully adapted to burning fat/utilizing ketones, you may experience symptoms like nausea, headache, weakness, irritability, muscle soreness, difficulty sleeping, and irritability. Using an exogenous ketone supplement during your transition into keto may mitigate some of these symptoms by ramping up the level of ketones in your blood to use as an energy source for brain and body. It may also improve energy levels early on in ketosis before adaptation occurs.  

And finally, whether endogenously produced or not, ketones have diverse signaling roles in the body that could benefit mental and physical health, metabolism, and longevity, as well as serving as a cellular energy source.

Medium-Chain Triglycerides (MCTs)

MCTs aren’t ketones, but rather a type of fat molecule comprised of a glycerol bonded to three medium-length fatty acids (FAs) that are 6 - 12 carbons in length. 

Why are we talking about these then, if they aren’t ketones? 

Well, MCTs are actually pretty good sources for the body to breakdown and turn into ketones. When it comes to ketone production, not all fats are created equal, and longer isn’t always better. Size matters. 

The source of fat in MCT oil and other MCT containing fats (like coconut oil) is the most efficient type for producing ketone bodies. The medium chain fats go right to the liver, where they require less work to break down compared to long- and short-chain fatty acids. 

You can get your MCTs in two ways: through an MCT oil or powder, or by consuming a rich (and tasty) source of MCTs such as coconut oil. 

The MCTs include caproic acid (C6), caprylic acid (C8), capric acid (C10), and lauric acid (C12). Of these, caprylic acid (C8) is preferred for ketone production, and optimally what you should look for when purchasing an MCT oil supplement. Lauric acid is the MCT found most abundantly in coconut oil (about 50% of the total MCTs). 

Because of its efficacy, pure C8 should be considered as part of the base of your MCT Oil Powder of choice.

Benefits of MCTs: What Does the Research Say?

Though marketed as a supplement, one benefit of MCTs is that they’re derived from all natural food sources. For those who are “anti-synthetic,” you have nothing to fear from MCTs. 

A powerful benefit of MCT ingestion, like ketone supplements, might be appetite suppression.

MCTs might help blunt hunger and help with calorie and portion control, thereby indirectly helping you adhere to a diet and thus meet your body composition goals.

One study demonstrated that acute intake of MCTs led to reduced food consumption at lunch while also reducing the blood glucose and triglyceride response to the meal.2 Interestingly, MCT oil also has a “satiating” effect that is not observed with coconut oil.3

MCTs might directly aid in weight loss as well, outside of general satiety. 

This action might be due to the fact that MCT oil supplementation can increase energy expenditure, fat oxidation, metabolism, and thermogenesis (body heat production) which leads to a lower body weight and more fat loss over time.4,5 Furthermore, MCT supplementation might have metabolic benefits like lowering LDL cholesterol and increasing lipoprotein particle size.6

Disadvantages of MCTs: What Does the Research Say?

Large amount of MCTs, like any supplement, have been reported to cause gastrointestinal side effects.7,8 

This might be an issue, since in order to raise blood BHB to adequate levels to reach ketosis, a high amount of MCTs (and even more coconut oil) must be consumed. Remember, MCTs must be metabolized first before they become ketones—they don’t directly elevate blood ketone levels. Most studies show that MCT consumption elevates blood BHB to levels around 0.5 - 1mM.

Let’s not forget about calories. One downside to coconut oil and MCTs is that they’re fairly calorie-dense, so it’s important to keep track of your macros and calories when using supplements. Compared to ketone salts and ketone esters, MCTs result in much lower levels of ketosis, but they may be a more cost-effective and approachable option for new keto dieters. 

Coconut Oil vs. MCT Oil for Ketosis

MCT oils and powders are the most concentrated sources of MCTs and thus might be your best option if you’re hoping to get into ketosis. MCT oil also has different proportions and types of MCTs compared to coconut oil; with a bit more C8 (caprylic acid) and a bit less C12 (lauric acid). 

There is evidence that the satiating effect of MCTs might be more potent when they come in the form of a concentrated MCT oil compared to coconut oil.3 If you’re looking for something to help with appetite suppression or a small snack that will “tide you over” more effectively, search for a high-quality MCT oil or powder.

However, in terms of taste and versatility, coconut oil takes the keto-cake. You can use coconut oil in virtually anything, from cooking veggies and meats, to adding in smoothies and protein shakes. The options are endless (and delicious).

Ketone Salts

They’re not something you sprinkle on top of your roasted vegetables or use to season your stew. 

Rather, ketone salts are a supplement that comes in powder form, to be mixed (traditionally) in some type of liquid for consumption. Ketone salts contain a ketone (usually BHB) bound to a mineral salt; usually sodium, potassium, calcium, or magnesium or an amino acid like lysine or arginine. 

Ketone salts are one way to raise blood ketone levels. Studies have shown that ketone salt ingestion can elevate blood BHB levels to around 0.6 - 0.8mM (i.e. ketosis).9,10

Benefits of Ketone Salts: What Does the Research Say?

Ketone salts aren’t a new “invention.” They’ve been around for quite some time, and early studies of these ketone supplements were conducted in children with metabolic disorders, where they showed efficacy in inducing ketosis and an improvement of symptoms like better cardiac performance and cognitive function due to better ability to oxidize fatty acids.11,12 

Similar levels of ketosis around 0.5mM have been observed in rats given BHB ketone salts. Health benefits such as improved blood glucose, beneficial changes in lipid biomarkers and fat mass, and reduced anxiety-like behavior were noted in multiple different studies.13,14,15

Disadvantages of Ketone Salts: What Does the Research Show?

Compared to other ketone supplements, ketone salts might not deliver as much “ketogenic power”—meaning they don’t elevate blood BHB to levels as high as other products. 

For example, one study showed that blood BHB was raised to around 1mM following ketone salt ingestion, while the same amount of BHB provided from a ketone ester raised blood ketone levels to 2.8mM.16 The salt also provided a greater amount of the L-isomer of BHB as opposed to the D-isomer. While not going into the deep end of structural chemistry, L-BHB is like a mirror image of D-BHB (like your left and right hand). They are what is known as optical isomers. While structurally similar, L-BHB may not have the same pattern of metabolism nor the benefits that D-BHB has. 

The concept of optical isomerism.

Another disadvantage with ketone salts has less to do with the ketone element, and more to do with the salt. 

Typically, you’ll need about 50g of BHB in a ketone salt to mimic nutritional ketosis. Given the formulation of many salts, this would require an intake of about 5,800mg magnesium, 9,600mg of calcium, 11,000mg of sodium, and 18,800mg of potassium. Needless to say, these values are above and beyond any recommended daily allowance for humans.

Excessive salt intake may come with health concerns such as high blood pressure and cardiovascular disease in some individuals.17 Regardless, the high dosage of minerals that would accompany the ketone dose consumed with a salt make this form of supplementation less than practical.

And finally, ketone salts may have no benefit for athletic performance and, in the worst cases, actually impair it.18 

In one study, oral BHB salt ingestion prior to exercise actually led to a 7% decrease in high-intensity cycling performance.10 Even though the participants were in ketosis and oxidizing fat for fuel, they reported massive GI side effects which inhibited optimal performance. This isn’t uncommon; two more studies (one in athletes) reported gastrointestinal side effects in 68% and 50% of participants.18 

So, should anyone use ketone salts? And, if so, who?

These supplements might be best for those already on a ketogenic or very-low carbohydrate diet and looking to further increase ketone levels—since this would require a lower dose of ketone salts and prevent many of the side effects seen with higher doses.

One final point. Many ketone salts on the market aren’t FDA approved as a “generally recognized as safe” (GRAS) food ingredient. Make sure to do your research before buying any supplement. 

Ketone Esters

While ketone salts are solids, ketone esters come in liquid form and usually contain one of two ketones; BHB or AcAc bound to a ketone precursor such as butanediol or glycerol. 

The word “ester” refers to the specific chemical bond (an ester bond) which attaches the two molecules. The two most popular formulations of ketone esters are the D-BHB monoester and the AcAc ketone diester. Each of these has its own effects. 

D-BHB Monoester (HVMN Ketone Ester)

The BHB ketone monoester (R-1,3-butanediol-R-3-hydroxybutyrate; BD-BHB) was first invented through a DARPA program called “Metabolic Dominance, with the intent of being used primarily to enhance the endurance and performance of US Soldiers. Through years of research with Oxford University, and the NIH, this ketone supplement can now be purchased and consumed by anyone as a ketone ester drink.

In contrast to the BHB salts, the BHB in the ketone monoester is all of the D-isoform. When the ester bond is metabolized, D-BHB is released into the blood along with the ketone precursor butanediol, which is eventually metabolized into D-BHB in the liver. 

The ketone monoester provides the highest levels of blood BHB (around 3 - 6mM) which is achieved rapidly (usually within 30 minutes of ingestion).

And levels stay elevated. Blood BHB following BHB monoester ingestion is ~1.1mM after 4 hours and ~.7mM after 8 hours.16 

 It’s also salt-free, permitted by the world anti-doping agency (WADA), and to date has been shown to be relatively side-effect free at normal doses (meaning no stomach aches!).19,20

Research on Ketone Esters

To date, many studies have been done (with more in the works) on the BHB monoester. Several of these studies have looked at the effect of ketone ingestion on athletic and physical performance. 

Consumption of a ketone ester has been shown to improve endurance exercise performance by 2% - 3% when taken before exercise with carbohydrates.19 In addition to boosting performance directly, ketone esters enhance recovery by boosting post-exercise muscle glycogen replenishment20 and raising post-exercise activation of genes involved in muscle protein synthesis.21 In each case, ketone ester was consumed with either a source of carbohydrates or carbs and protein.

In the most recent study on ketone esters, chronic intake during a period of endurance training overload blunted many symptoms of overtraining, revealing a heretofore unseen potential for this supplement in athletes.22 Athletes were able to go harder in training because they recovered more effectively. 

BHB monoester might also have some metabolic benefits. 

Exogenous BHB lowers blood glucose levels23 and has also been shown to have an appetite-suppressant effect, lowering the desire to eat—this may be related to the reduction in ghrelin (the hunger hormone) after BHB ingestion.24 Many people claim that a ketogenic diet also has many similar effects on satiety. 

Acetoacetate Diester 

The second type of ketone ester is the acetoacetate (AcAc) diester (1,3-butanediol acetoacetate diester)—a sodium-free precursor to the ketone acetoacetate. Compared to the BHB monoester, AcAc diester results in lower blood BHB levels (about 1mM) and may result in a few more side effects. Most common among these are gastrointestinal related issues.25 

Research on Acetoacetate Diester

The AcAc diester has much less data to support or refute its use when compared to other ketone supplements. 

In terms of athletic performance, results are inconclusive or non-existent. One study showed that ingestion of a 1,3 butanediol AcAc diester before a 31 kilometer cycling time trial actually impaired performance around 2%. However, this wasn’t likely due to the athletes being in ketosis, but rather the side effects. Several of the study’s participants complained of gut discomfort that likely put a hamper on their ability to perform.25 

More research has been done in the area of neurological health. Studies have shown that ketosis achieved with an AcAc diester is able to delay the onset of seizures from central nervous system toxicity in rats26 and lead to lower seizure activity and improved brain plasticity in a mouse model of neurological disease.27 

The research is pretty convincing in favor of the use of AcAc diester to treat neurological conditions and benefit cognition, while less supportive of its use for exercise performance.

Blood ketone levels of HVMN Ketone, MCT and ketone salts

General Benefits of Exogenous Ketones: How do They Compare to Nutritional Ketosis?

The blood levels of BHB that can be achieved through nutritional ketosis (ketogenic diet or fasting) are likely similar to those you can achieve using certain exogenous ketone supplements: about 1 - 3mM. In this regard, your “level” of ketosis might be the same. 

However, achieving endogenous ketosis has unique benefits that aren’t achieved with exogenous ketone supplements. One of these is in regards to “fat burning.” 

When you achieve endogenous ketosis, you’re using your own body fat as a fuel, and this has several metabolic and health-related benefits. 

But, with exogenous ketones, you actually decrease adipose tissue lipolysis (breakdown) and FFA availability—essentially the opposite of what happens when you’re in a ketogenic state.

Thus, exogenous ketones likely have little to no benefit in terms of fat burning and weight loss.

Most exogenous ketone supplement protocols involve taking one “large” bolus of ketones. While this raises blood ketone levels rapidly, it’s not really what happens “naturally” when the body is in a ketogenic state, where blood ketone levels rise more gradually. 

It’s unclear what this might mean in terms of metabolic signaling, but there exists a difference in the two ways to achieve ketosis. 

Choosing the Best Ketone Supplement

While several different ketone supplements are on the market, what you choose may depend on your individual goals. Let’s take a look at which types of supplements might benefit specific groups of people.

Considerations for Athletes

If you’re not ready to commit to a ketogenic diet for your training regimen, but are curious about how ketosis might impact your performance, exogenous ketones might be your go-to experiment. Several athletes and sports teams are now using exogenous ketones as a way to fuel performance. 

The main thing to consider is the proper time, situation, and adaptations required for exogenous ketone use. How you strategically employ exogenous ketones might make all the difference. 

Since BHB monoester is cleared by WADA (meaning it’s not a “performance enhancing drug”), athletes can rest easy in this regard. 

A majority of the positive research for exogenous ketones lends support to ketone monesters, where benefits have been shown for endurance performance, enhanced adaptations to training, and in the prevention of overreaching syndrome. Another aspect is cognitive performance; we’ve heard many anecdotal responses that athletes who use ketone esters for training experience a feeling of being “locked in” mentally, too.

Some smaller studies on MCTs suggest they might benefit endurance exercise performance28 and enhance gene expression and mitochondrial biogenesis.29 

Data on other supplements such as ketone salts and AcAc diesters is less compelling and in most cases, negative.

Consideration for General Health

The support for exogenous ketones in non-disease states is more in the anecdotal stage right now. 

Anecdotal reports include claims of enhanced mental clarity, alertness, energy, and productivity.

None of these claims has been scientifically tested yet. While the theoretical basis might be sound, you’ll have to wait for some trials—until then, experiment for yourself.

A huge role for exogenous ketones might be in dietary adherence, whether that means eating less, eating better, or sticking to a low-carb or ketogenic diet. 

Exogenous ketones suppress appetite,24 and might help reduce certain food craving or obliterate those “hangry” feelings. If you’re into fasting and not opposed to consuming ketones on a fast, ketone supplements might help you get through an extended no-food period. Even better, they might deepen your fasting-induced state of ketosis. 

Are Exogenous Ketones for You? 

Whether you are an athlete looking to boost performance through exogenous ketones, or simply out to harness to power of ketones for better mental or physical performance, there are several questions you should ask before buying and using a ketone supplement.

First, what is your goal? And what level of ketosis do you need to achieve to accomplish those goals? Consider if you want constant low levels of ketones in your blood, or a larger level for a shorter amount of time (for a competition, for example). 

Are you looking for something inexpensive? Something palatable? Maybe something that can be integrated into meals and/or other supplements? Or perhaps, even a post-workout smoothie? What about the side effects? If you have had stomach issues with other kinds of supplements in the past, this should be taken into consideration. 

Maybe you want to achieve the benefits of ketosis without making a change in your lifestyle, like adopting a low-carb ketogenic diet or becoming a regular intermittent-faster. That’s fine, too—these practices aren’t for everyone, but ketosis can be. 

All it takes is a well-formulated exogenous ketone supplement and obviously, a bit of attention paid to maintaining a generally healthy diet and exercise regimen. Your nutrition strategy is an investment in your life. 

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H.V.M.N. Co-founders Michael Brandt and Geoffrey Woo

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© 2019 HVMN Inc. All Rights Reserved. H.V.M.N.®, Health Via Modern Nutrition™, Nootrobox®, Rise™, Sprint®, Yawn®, Kado™, and GO Cubes® are registered trademarks of HVMN Inc. ΔG® is a trademark of TΔS® and used under exclusive license by HVMN Inc.

H.V.M.N.
38 Mason St, 3rd Floor, San Francisco, CA 94102
Email us: care@hvmn.com

These statements have not been evaluated by the FDA. Our products are not intended to diagnose, treat, cure, or prevent any disease.

© 2019 HVMN Inc. All Rights Reserved. H.V.M.N.®, Health Via Modern Nutrition™, Nootrobox®, Rise™, Sprint®, Yawn®, Kado™, and GO Cubes® are registered trademarks of HVMN Inc. ΔG® is a trademark of TΔS® and used under exclusive license by HVMN Inc.