What are Exogenous Ketones?

Originally published on HVMN by Brady Holmer

This is a series of blog post which I publish in collaboration with HVMN about keto. Me wife and I had good success on the keto diet. We used it to lose weight before our wedding. Now we batch cook on weekends to be ready for the entire week.

The ketogenic diet is more lifestyle than diet. It’s gaining popularity among those who wish to improve their metabolic health, lose weight, or boost their productivity. The many purported benefits of the diet are due, in part, to the properties of ketones, which are produced by the liver in someone on the low-carb diet, or someone in a fasted state.

Table of Contents

Endogenous vs. Exogenous Ketosis

General Health Benefits of Ketosis

Exogenous Ketones: Another Avenue to Ketosis

Benefits of Exogenous Ketones

Ketone Salts

The Science on Ketone Salts for Health

The Science on Ketone Salts for Performance

Advantages and Disadvantages of Ketone Salts

Ketone Esters: Acetoacetate Diester

The Science on AcAc Diester for Health

The Science on AcAc Diester for Performance

Advantages and Disadvantages of AcAc Diester

Ketone Esters: BHB Monoester (HVMN Ketone)

The Science on BHB Monoester

Advantages and Disadvantages of BHB Monoester

Ketone Oils and Powders 

The Science on MCTs

Advantages and Disadvantages of MCTs

How do MCTs Differ from Exogenous Ketones?

When and How to Use Exogenous Ketones

Final Thoughts on Exogenous Ketones

But, keto isn’t for everyone. Some may find it restrictive, and others, like athletes, may find that this way of eating does not lend itself to optimal performance (depending on their specific needs). Fortunately, there is another way to benefit from ketones without going on a keto diet or fasting. 

Exogenous ketone supplements are another way to get into ketosis.

Endogenous vs. Exogenous Ketosis

Being in a state of ketosis means that you have elevated levels of ketones in your blood, usually measured at > 0.5mM. That’s simply the line you must cross to enter ketosis; but there are two distinct ways of arriving there. 

Traditionally, this happens as a result of eating a very low carbohydrate-ketogenic diet (called nutritional ketosis) or practicing caloric restriction or intermittent, prolonged fasting. In these situations, carbohydrate depletion and a reduction in insulin causes free fatty acids (FFAs) to be released from fat stores in the body through a process called lipolysis. Then, these FFAs are transported to the liver, where they’re used to produce ketone bodies. This is known as endogenous ketosis—meaning ketones are being produced by the body. 

Someone who is producing their own ketones is in a ketogenic state.

There are three ketones: beta-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone. 

However, we don’t produce an equal amount of each.  

Normally, the ratio of circulating BHB to Acetoacetate is about 1:1. However, in ketosis (whether due to fasting or a ketogenic diet), this ratio can rise up to 6:1. In ketosis, you’ll have higher levels of circulating BHB compared to AcAc.1 Acetoacetate is the first ketone produced and from this. BHB and then acetone are also produced. While BHB is highly active and stable, acetone can essentially be thought of as a waste product of metabolism—most of it gets excreted in the breath, although a small amount may be metabolized.

The other avenue by which we can enter ketosis is known as exogenous ketosis. Exogenous means that ketones are coming from an outside source—either directly through exogenous ketone supplementation or indirectly through another supplement that can serve as a ketogenic precursor (like an MCT oil). We will discuss these later on.

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General Health Benefits of Ketosis

What’s the big deal about being in ketosis? In order to enter ketosis, the BHB ketone body must be present in your blood at >0.5mM—this is true regardless of whether ketosis is achieved endogenously or exogenously (through supplements). 

Ketosis achieved through dietary or fasting-related routes has a variety of health benefits. Some of these are distinct to endogenous ketosis, and some benefits are provided by ketones regardless of the source.

For one, using ketones as an energy source, as opposed to carbohydrates, actually produces more ATP molecules per unit of oxygen consumed.2 The ketogenic diet is one way to create a body that burns a “cleaner” fuel that results in less oxidative stress. When looking specifically at the benefits of the ketogenic diet, appetite suppression and satiety,3 enhanced memory,4 lower levels of inflammation,5 weight loss, increased fat burning, and protection from cardiovascular diseases and diabetes6 are all cited. 

Similar metabolic benefits have been shown to occur with intermittent/prolonged fasting—which is another way to achieve ketosis.

Exogenous Ketones: Another Avenue to Ketosis

As you already know, instead of becoming ketogenic (producing our own ketones from body fat stores), we can consume ketones and ketogenic precursors exogenously. If your blood ketones are above 0.5mM, you’re in ketosis—regardless of how you got there. 

For the most part, exogenous ketones come in the form of BHB or acetoacetate. The ketogenic precursors include types of fats known as medium-chain triglycerides (MCTs) which are also present in food sources like coconut oil, another exogenous “ketone supplement.” We have “ketone supplement” in quotes because these products don’t actually contain ketones—they’re simply the fats that are readily converted into ketones in someone following a low-carb high-fat diet.

Exogenous ketones provide a way to achieve ketosis even in the absence of a ketogenic diet, carbohydrate restriction, or fasting. While the route to ketosis differs, the signaling effects of exogenous vs. endogenous ketones are virtually the same—BHB and AcAc from the liver are no different structurally than BHB or AcAc taken as a supplement. It’s just simple biochemistry!

Since exogenous ketones don’t require modified dietary practices, they can be used by anyone who wants to get the benefits of ketosis without the time it takes to get there through diet alone (sometimes it can take weeks). Athletes and mathletes alike can use ketone supplements to get themselves into a ketotic state. These supplements rapidly elevate blood ketones and with consistent supplementation, can keep blood ketone levels elevated for a prolonged period of time. For example, H.V.M.N. Ketone Ester drink keeps blood ketones elevated between 4 - 6 hours. 

It is important to differentiate ketosis from ketogenesis here. Those who elevate blood ketones through supplements aren’t ketogenic, but they are in ketosis.

For those who are eating a ketogenic diet or practicing fasting, exogenous ketones can be used to deepen ketosis, helping to achieve higher levels of blood ketones than might be possible through dietary restriction. Essentially, you’d be superimposing exogenous ketones onto the endogenous ketones you’re already producing.

Benefits of Exogenous Ketones

Using supplements vs. a ketogenic diet or fasting does have some benefits. While the metabolic health boost might not be the same (for instance, exogenous ketones aren’t ideal for weight loss), exogenous ketones have several other assets, depending on your personal needs. 

Quicker ketosis is one of them. 

Many ketone supplements, like H.V.M.N. Ketone Ester, can elevate blood ketone levels within 30 minutes of ingestion.7,8 For this reason, they can be used like many other performance aids (i.e. caffeine) in a short period of time. They don’t require a change in diet or prolonged fasting. This could be ideal for those who might not find either of these lifestyle practices ideal or enticing. Intermittent fasting is a hot topic, sure, but it’s not for everyone.

Exogenous ketones are also a great way to aid the transition into a ketogenic diet. 

For example, if you’re practicing a carbohydrate periodization or carb cycling routine, exogenous ketones can quickly get you back into ketosis. New to the keto diet? Exogenous ketones could help prevent the keto flu—the period when the brain has no glucose for energy, but the liver hasn’t yet fully started to produce a steady supply of ketones.9

For already-keto folks, exogenous ketones can be one way to deepen ketosis. Using these supplements while on a fast can also raise ketone levels above what your body is naturally producing. 

Finally, while they don’t directly aid in weight or fat loss, exogenous ketones have an appetite suppressant effect.

This property just might help you adhere to a dietary regimen or prevent the munchies that could derail your strict eating habits. H.V.M.N. Ketone Ester reduces ghrelin (the hunger hormone).10

With the benefits explained, it’s time to delve into the various types of exogenous ketone supplements. The most common—ketone salts and ketone esters—directly elevate blood ketones. In addition, MCTs and other sources of fat (coconut oil) can be consumed as supplements to provide a source of fat through which ketone production can be stimulated or maintained.

Ketone Salts

Ketone salts won’t be found in your table-side salt grinder. 

These supplements usually are found in a powder form which can be mixed with a liquid and consumed. Ketone salts are composed of a ketone body (usually BHB) bound to one of several minerals that might include sodium, potassium, calcium, or magnesium. 

Some salts also include an amino acid like lysine or arginine. The fact that ketones come bound to another mineral or amino acid makes ketone salts one way to consume ketones plus some necessary nutrients. But they aren’t without certain considerations of side effects.

The Science on Ketone Salts for Health

The use of ketone salts for health conditions isn’t exactly a new concept. Two of the earliest studies on these supplements investigated their potential therapeutic use for children with metabolic disorders (fatty acid oxidation defects). In these studies, ketone salts were found to improve heart function and cognitive performance, which resulted in a better walking ability and disappearance of many neurological symptoms.11 

In rats, exogenous supplementation with BHB salts has been shown to improve blood lipid profiles (higher HDL, lower LDL/HDL ratio), reduce blood glucose, and reduce the amount of visceral fat and the size of fat cells.12,13

More studies (again, in rats) show that ketone salts can reduce anxiety-like behavior. This suggests that ketosis achieved through supplementation may be one strategy to reduce anxiety in people, but more studies need to be done in this area, especially in humans.14

The Science on Ketone Salts for Performance

If you’re an evidence-based athlete, the published literature suggests you might want to steer away from ketone salts, or at least be aware of the potential performance-negating side effects that have been reported. But hey, you are your own experiment.

To date, there have been three studies on ketone salts and athletes. 

One study was done on cyclists. They were put through a maximal exercise protocol (essentially, a VO2 max test) after ingesting a BHB ketone salt. While ketosis was achieved, the BHB salt showed no advantage compared to a placebo beverage when comparing lactate appearance, perceived effort, or muscular efficiency. In fact, 13 out of the 19 participants complained that the ketone salt led to severe gastrointestinal issues that limited their athletic performance.15

In a second study, ketone salt ingestion prior to exercise (again, cycling) led to a 7% decrease in average power output throughout a time trial simulation (though the participants' fat oxidation was increased during exercise). Again, it’s important to note that the performance impairment likely occurred due to GI issues reported by many participants—and not to direct effects of ketosis itself.16 

A third study investigated how ingestion of a BHB salt would influence high-intensity cycling performance and cognitive measures during and after exercise. While the ketone salt induced ketosis (0.53mM), no improvement was seen in cycling or cognitive performance. In fact, a “fatigue index” measured in the study was higher in the participants consuming BHB compared to the control group not receiving a ketone supplement.17 

While the efficacy for ketone salts inducing ketosis is strong, the impact on performance is inconclusive, if not mostly negative.

Advantages and Disadvantages of Ketone Salts

Compared to other ketone supplements, ketone salts only mildly raise blood BHB (up to around 1mM). This is still well above the ketotic threshold (0.5mM) but below levels achieved with ketone esters.

Ketone salts are also cheaper to produce (and purchase) than currently available BHB ketone esters (discussed later).

Salts are also one way to deliver other nutrients (minerals, amino acids) along with BHB, which could have certain health benefits.

On the other hand, pairing BHB with a mineral comes with a cost. To get 50g of BHB in a formulation with a ketone salt would require consuming about 5,800mg of magnesium, 9,600mg of calcium, 11,0000mg of sodium, or 18,800mg of potassium—amounts way above any FDA recommended intake for these minerals.

Another obvious disadvantage is the possible side effects, often taking the form of gastrointestinal issues. This may be a result of the acid load and/or mineral load that is obtained when consuming BHB salts at high doses.

Finally, most BHB salts contain a mixture of BHB isoforms—essentially a different structural configuration of BHB. The D-form of BHB is the one we produce. The L-form, which is basically a “mirror image” of the D-form, is only obtained exogenously, and might not be as rapidly metabolized as the D-form, and thus may not have the same benefits; although studies are needed to confirm this. 

Ketone Esters: Acetoacetate Diester

The acetoacetate diester (1,3-butanediol acetoacetate diester) is one of two common supplements collectively known as ketone esters. It’s comprised of the ketone body acetoacetate and butanediol (BDO), connected by an ester bond (hence the name “ketone ester”). 

While fewer studies on this ester have been done compared to the more popular BHB ester (discussed later), there is still some science to support using this ketone supplement.

The Science on AcAc Diester for Health

Most studies to date on this ketone ester have been done in mice; application to humans should come with the necessary caveats. Nevertheless, the AcAc diester has shown promising results in regards to neurological health. 

Ketosis achieved through AcAc diester ingestion effectively delayed the onset of seizures due to central nervous system oxygen toxicity18—a danger encountered by undersea divers and patients on oxygen therapy. This same protective mechanism has also been shown to occur as a result of fasting, perhaps by altering brain energy metabolism.18 

In a mouse model of neurological disease, AcAc diester ingestion improved several aspects of brain health including motor coordination, learning, memory, and synaptic plasticity.19 This could have relevance for several human diseases of the brain, like cognitive decline, epilepsy, and other learning disorders. More research needs to be done here, however. 

The Science on AcAc Diester for Performance

There has been only one performance-related study to date conducted on AcAc; results were generally negative. When ingested prior to a 31-kilometer cycling time trial, AcAc ingestion led to a greater reduction in performance compared to consuming just carbohydrates and caffeine.20 These results should be interpreted with caution, however. A probable cause of the performance decline, similar to the ketone salts, was the severe and frequent GI symptoms experienced by the study participants who ingested the ketone.20 

Instead of ketosis, it seems like tummy trouble was a big reason for the bonk in performance.

Advantages and Disadvantages of AcAc Diester

The AcAc diester produces a milder elevation in blood BHB (~1mM) compared to other ketone supplements. 

As with some of the ketone salts, AcAc diester has been described as “unpalatable” and routinely produces GI symptoms in research study participants who consume it. This, or potentially some other reason, leads to performance declines. 

As such, this ketone supplement might not be recommended for athletes prior to competition or training, especially if it’s your first time experimenting with it.

Ketone Esters: BHB Monoester (HVMN Ketone)

The BHB Monoester (R-1,3-butanediol-R-3-hydroxybutyrate) is the ketone ester found in H.V.M.N. Ketone. 

In contrast to the BHB salts, this ketone ester, when broken down, releases D-BHB into the blood along with a molecule of butanediol (BDO), which is eventually metabolized to D-BHB in the liver. This results in two molecules of D-BHB in the blood, one reason why this particular ketone supplement is the most efficacious for elevating blood ketones.

The Science on BHB Monoester

There have been few studies regarding the BHB monoester in regards to general human health, but one study suggests that this ketone ester may have the ability to treat human conditions associated with metabolic abnormalities. 

When rats were given a diet containing the BHB monoester, they experienced an improvement in heart function, increase in endurance capacity, cognitive performance enhancement, and were more efficient at using energy from ATP breakdown.21

The data on human performance is much more promising for the BHB monoester than for the other exogenous ketone supplements.

Ketosis achieved through BHB ester ingestion has been shown to improve physical endurance in cyclists by switching the body’s fuel preference to favor ketone metabolism vs. glucose/glycogen oxidation even in the presence of high muscle glycogen.22 

The BHB ester has also been investigated as a recovery aid. When consumed along with a post-exercise carbohydrate or protein source, the BHB monoester increases activation of mTORC123 (which plays a role in protein synthesis) and also enhances the resynthesis of muscle glycogen.24 

A recent study provides compelling evidence that chronic BHB monoester (which is the key ingredient in H.V.M.N. Ketone Ester) ingestion during periods of strenuous endurance training can prevent symptoms of overreaching and improve endurance performance in fit individuals.25 

“The real magic isn’t what ketones do for you during exercise; it’s what they do afterwards.” - Alex Hutchinson, Outside Magazine

While the precise metabolic signals responsible for the benefits are not completely known, the evidence for using BHB ketone ester in the setting of athletic performance is strong.

Advantages and Disadvantages of BHB Monoester

The BHB monoester results in the most rapid and highest elevation of blood BHB of all the ketone ester supplements (3 - 6 mM within 30 minutes).8 One study demonstrated that blood BHB can be elevated to about 2.8mM following BHB ketone ester ingestion, while the same amount of BHB provided from a ketone salt will elevate blood ketones to around 1mM.7

Furthermore, this ketone ester delivers only the D-isoform of BHB (this is the isoform we naturally produce when ketogenic). Ketone salts also provide a greater amount (but usually a mix) of the L-isoform of BHB along with some of the D-isoform.

H.V.M.N. Ketone Ester is FDA generally recognized as safe (GRAS) for use as a food, and is approved by the world anti-doping association (WADA). No doping violations here, if you’re a serious athlete who has these types of considerations for your supplements. 

The side effects of BHB monoester appear to be generally mild, if not non-existent, at low doses. 

Most studies report no side effects of ketone ester ingestion.8,7 BHB ketone esters do have a distinct, bitter taste, which some may find unenjoyable. The tolerability of this aspect is highly individual, however. We like to say “it tastes like it works.”

Ketone Oils and Powders 

What are ketone oils and powders? This name may be a bit misleading, since technically these supplements are actually types of fats known as medium-chain triglycerides (MCTs) and not actually ketones. 

However, they can be considered as part of the family of exogenous ketone supplements because once they’re ingested, they can serve as substrates for ketogenesis. 

Popular among the keto crowd is a supplement known as MCT oil or powder. MCTs are fat molecules made up of a glycerol bound to medium-length fatty acids that are 6 - 12 carbons in length. Coconut oil is a rich source of MCTs. 

These fats are the most efficient type for producing ketone bodies. 

The medium-chain fats go right into the liver once ingested, where they are then broken down faster in comparison to short- and long-chain fatty acids. There are several MCTs: caproic acid (C6), caprylic acid (C8), capric acid (C10), and lauric acid (C12). Caprylic acid (C8) is the most “ketogenic” of the MCTs;26 if you’re looking for an MCT supplement, this should be the one you look for. Coconut oil is high in lauric acid (C12), which makes up about 50% of the stuff. 

Due to it’s ketogenic nature, we selected pure C8 a part of the base (along with prebiotic acacia fiber) of H.V.M.N.’s MCT Oil Powder. It’s 100% natural, real food, harvested sustainably and carefully purified into pure C8. No additives, no artificial ingredients, zero net-carbs. It’s a great source of MCT without all the other junk you might find in other MCT products.

The Science on MCTs

The benefits of MCTs for a ketogenic or low-carbohydrate diet might come in the form of appetite-suppression. 

This might be great for those having a hard time adhering to a dietary regimen and may indirectly aid in weight loss. Intake of MCT oil has been shown to lead to a reduction in food consumption, while also reducing the rise in blood glucose and triglycerides after eating.27 This satiating effect was observed with MCT, but not coconut oil.28 Interestingly, the subjects also reported that the MCT oil was more palatable than the coconut oil. 

There is also interesting research on the ability of MCTs to assist in weight loss directly. Supplementation with MCTs led to weight loss in overweight men. 29 This might have been due to the effects that MCTs had on increasing energy expenditure, fat oxidation, metabolism, and body heat production (thermogenesis). 

MCTs have also been shown to lower cardiovascular risk factors like LDL cholesterol and increase lipoprotein particle size.30 

Advantages and Disadvantages of MCTs

Like any supplement out there, consuming a large amount of MCTs has been reported to induce GI issues as a side-effect.31,32 

Unfortunately, consuming enough MCTs or coconut oil to get blood ketones as high as you could with a ketone supplement (like H.V.M.N. Ketone Ester) might require a dose likely to upset your stomach. Expect an elevation of blood ketones to around 0.5 - 1mM following a reasonable dose of MCTs. This will depend highly on diet and other lifestyle factors, however. 

Another downside to MCT/coconut oil consumption might be the caloric load. When using these supplements in large quantities, it’s easy to overdo it. 

Even though MCTs result in a lower level of ketosis compared to ketone salts and esters, MCT oils are a cost-effective and approachable option for people new to the keto diet.

MCTs might be advantageous especially for people looking to lose weight. Through their thermogenic and appetite suppressing effects, MCTs might help you feel fuller longer and more satisfied when added to a meal, shake, or coffee.28,29 And, similar to ketones, MCTs have been shown to have a variety of protective effects for the cardiovascular system and other health markers.30 

How do MCTs Differ from Exogenous Ketones?

MCTs have their benefits, which include being a bit more tasty (especially if you’re mixing them in coffee or baked goods), less expensive, and versatile—you can use MCTs in everything from cooking veggies and meats to preparing smoothies and shakes. 

But MCTs aren’t direct ketone supplements, and therefore aren’t as effective at raising blood ketones when compared to salts or esters. The shorter length MCTs must first be broken down in the liver and then used to produce ketones, it’s not a “direct path” to ketosis. 

Nevertheless, feeding MCT oil has been shown to elevate blood ketones 18-fold (in rats) after just one hour, suggesting this fuel source is readily and rapidly oxidized.33 Furthermore, it was shown that MCT administration led to lower blood sugar and depressed lipogenesis, which appeared to potentiate ketosis, but not initiate it. Although these findings are interesting and may apply to humans, more studies are needed to confirm this. 

This suggests that MCTs might be more beneficial in terms of sustaining or maintaining ketosis rather than directly plunging you into it.

When and How to Use Exogenous Ketones

There are many different scenarios where exogenous ketones could make a big difference in your performance or help you reach your goals, whatever they may be. 

One situation to use ketone supplement is on top of your ketogenic diet. In this sense, exogenous ketones would be used to deepen your level of ketosis by raising blood ketones even further. They might also come in handy if you’re trying to re-enter ketosis after a cheat day or a carb-cycling routine.

You might give ketone supplements a try while you’re on a prolonged fast—say something like a 24 - 48-hour water-only fast. While ketones do contain calories, they’re negligible, and might help you last a bit longer in your fast, or help with mental clarity and focus, if those are your fasting goals. 

If you’re someone who likes to workout while fasting, exogenous ketones might be the perfect supplement to fuel your workout instead of some quick-burning carbohydrates.

But you don’t have to be on a keto diet or regularly fast to use exogenous ketones. 

Anyone wishing to raise blood ketones can use these supplements. Athletes might try them out before a workout or big race, or perhaps even consume exogenous ketone supplements regularly throughout a tough training stint to prevent overtraining.

Exogenous ketones are also great for recovery—take them after a workout with a meal high in protein and some carbohydrates to refuel.

What does dosing look like? This depends on how high you want your blood ketones to be. For acute benefits, supplements like the BHB ketone ester should be taken about 30 minutes before activity and perhaps another serving during. For workout recovery, take one serving of a ketone supplement like H.V.M.N. Ketone Ester with your normal post-workout nutrition. 

For more information on dosing H.V.M.N. Ketone Ester, visit this page for instructions.

If you’re transitioning to ketosis, using ketone supplements for about 3 - 5 days is recommended to “jump start” ketosis and prevent some of the symptoms (from keto flu) that might occur before your body is naturally producing ketones. 

Final Thoughts on Exogenous Ketones

Whatever your goal, exogenous ketones and other ketone supplements have the potential to help you meet them. 

The advancing science is allowing new and more practical formulations of ketone supplements to be produced and consumed. The benefits of ketosis are now available to almost everyone.

Scientific Citations