SUMMARY - Ketones are a class of natural molecules produced under certain physiologic conditions. These molecules are energetic substrates (often called the "4th macronutrient") and possess signalling properties, regulating genes and cellular functions.
Let’s talk “exogenous ketones”, including MCT oil, ketone salts, ketone esters, and poly-BOHB. We'll start with the basics and I will conclude with my product recommendations for each category, which I will update regularly with the newest and best products. Here we go!
What are Ketones?
Ketones are a class of natural molecules produced in the liver as metabolites of fat oxidation. This is called “ketogenesis” which will only occur when three conditions are met simultaneously; 1) low insulin, 2) depleted glycogen, and 3) elevated fat oxidation. Ketones are generated in the liver – but not used by the liver – and are exported into the blood stream to provide energy to peripheral tissues, like the brain, heart, and skeletal muscle in the (relative) absence of dietary carbohydrates. You can think of this process as the liver (a central metabolic organ) creating and distributing a highly-energetic fuel source to the peripheral organs during times of low energy intake.
The three ketones produced in the body are 1) acetoacetate, 2) beta-hydroxybutyrate, and 3) acetone. For the duration of this discussion we will refer to acetoacetate as “AcAc” and beta-hydroxybutyrate as “BOHB.” Small amounts of acetone are generated from spontaneous (non-enzymatic) degradation of AcAc. While acetone may have physiologic function, it is not applicable in the discussion of exogenous ketones so we won't discuss it further.
Here are some useful ketone facts:
Ketones are produced naturally by the body during times of severe carbohydrate restriction which satisfies the aforementioned conditions of ketogenesis and can be achieved by specifically limiting carbohydrate intake (i.e. the ketogenic diet) or through total food restriction (i.e. fasting or starvation). As a general rule, ketogenesis can be induced by eating fewer than 30g net carbs per day, although numerous factors are involved. Under these conditions, fat metabolism (from adipose stores and from dietary intake) increases to a critical point that results in the accumulation of acetyl CoA. Simultaneously low levels of oxaloacetate (OAA) - a substrate now diverted towards gluconeogenesis - results in the pool of acetyl CoA that is converted into ketones in the liver. This is called "endogenous" ketone production. “Endo” is significant as it means “from within.” These ketones are created within the body as metabolites of rapid fat metabolism in conjunction with carbohydrate restriction.
What are "EXO"GENOUS Ketones?
In addition to endogenous ketone production, scientific advancements have provided alternative means to artificially induce ketosis (the state of ketones in the blood) through exogenous ketone supplementation.
"Exo” means “from the outside.” In contrast to endogenous production of ketones in the liver, exogenous ketones are simply consumed (as dietary supplements) and absorbed into the blood stream. This poses a unique opportunity to increases ketosis (in individuals following a ketogenic diet or fasting) or induce ketosis without restricting carbohydrate intake.
To reiterate, the ability to induce ketosis without carbohydrate restriction OR to further elevate natural levels of ketosis occurring from a ketogenic diet or fasting has far-reaching applications, including longevity, disease management, and performance.
Unfortunately, this tool is rarely utilized correctly - especially by the general public - and has posed many questions while providing few concrete answers. Can exogenous ketones compliment (or impair) a ketogenic diet? Can exogenous ketones induce (or prevent) weight loss? Can exogenous ketones be used without carbohydrate restrictions? Are there superior (and inferior) forms of exogenous ketones? Is it difficult for the average consumer to understand exogenous ketone supplements? Are there specific (and often demanding) protocols required for proper exogenous ketone supplementation? The answer to all of these questions is emphatically “YES!” The nearly infinite number of uses and person-to-person metabolic variations and differences creates an incredibly complex scenario. In short, exogenous ketone supplementation is not a “one-size-fits-all” solution and needs to be understood and used correctly.
The following is a didactic overview of the current exogenous ketone options. I hope to provide insights into this exciting and complex topic so that you can properly utilize this tool.
1) MCT Oil
MCTs (medium chain triglycerides) are saturated fats of “medium length” that are quickly absorbed in upper intestine (without the need for chylomicron transport), brought to the liver through the portal vein (not the lymphatic system like other fats), and are quickly metabolized to produce ketones. It is unlikely for MCTs to be stored as body fat and contain significantly fewer calories per gram than LCTs (~7 cal/g compared to 9 cal/g). In addition, MCTs do not require carnitine for transport into the mitochondria (source). MCTs range from 6 to 12* carbons in length and are found in high concentrations in coconut oil (60% of total fats) and palm kernel oil (50%), and some dairy sources (up to 12%). The shorter the carbon chain, the more ketogenic the MCT. In the below description, the “C:#” refers to the length of the carbon chain.
How it works...
MCTs are absorbed In Upper Intestine --> Transported through Portal Vein to Liver --> Converted into Ketones --> Ketones and residual MCTs are exported from Liver and sent to the periphery.
While technically not true “exogenous ketones” (MCTs are technically fats that must be converted into ketones), MCT oil - specifically the “capra” family (C:6-10) – is worth discussing as these fats are relatively inexpensive, capable of quickly inducing ketosis (although only marginally), and are overall metabolically healthy oils.
A quality, high C:8 MCT oil may increase ketosis by +0.5 to 1 mmol/L from baseline. MCTs quickly reach a maximum tolerable amount due to significant gastrointestinal distress at 1.5+ tbsp (20g+). Tolerance to MCT increases over time and it is recommended to start with as little as 1 tsp and gradually build up to servings of 1 tbsp, depending on use.
Interesting Bullet-Proof Coffee Fact: It is worth noting that both MCTs and LCTs can drive the immune system towards a pro-inflammatory state by increasing Tcell differentiation towards Th1 and Th17 cells (pro-inflammatory) in a dose and chain-length-dependent manner. This means that as the length of the carbon chains of the MCTs increases (C:8 to C:10 to C:12 and on) so does the tendency for Tcells to differentiate towards a pro-inflammatory lineage. This is another reason that coconut oil and cheap MCT oils high in C:12 lauric acid should not be used as a panacea, especially in individuals predisposed to auto-immunity or with inflammatory conditions. Interestingly, SCFAs (short chain fatty acids) exert the opposite effect and increase Treg cell differentiation (considered anti-inflammatory). For those interested in putting fats in their morning coffee (aka “bullet-proof coffee”), I recommend choosing a high C:8 MCT oil and pairing it with an equal part of grass-fed butter (high in the SCFA “butyric acid”) or a butyric acid supplement to balance Tcell differentiation.
Overall, MCT oil is a metabolically healthy oil that can be substituted for inferior vegetable oils in food preparation (but don't use it to fry or sautee, it will "boil" due to its molecular structure). MCT oils are mildly capable of inducing ketosis and may suppress hunger, potentially leading to weight loss in certain conditions. MCT oil functions best in the presence of a high-fat, low-carb ketogenic diet but can be used by anyone looking for the metabolic benefit.
➡️ MY RECOMMENDATION: MCT OIL C8 BRAIN FUEL by Kiss My Keto ⬅️
Why It Wins: Compared to other pure C:8 MCT oils, this product is the best value, serving-for-serving. I'm also impressed with the glass packaging and included pump, which is a really convenient feature. The oil is 100% sourced from coconuts (not palm oil). Contains 63 servings of 15g MCT per bottle.
2) Ketone Salts
Ketone salts are aptly named, as they are a ketone molecule (specifically BOHB) with an ionic bond to a "salt" - a term for a mineral cation (positively charged). In currently available products, the BOHB molecule is bound to 1) sodium, 2) potassium, 3) magnesium, and/or 4) calcium. Most products simply choose one or two salt varieties; however, a recent trend to achieve a more balanced mineral profile by including all four salts has been noted. This trend is likely due to outside criticism of the excessive mineral loads required to provide a “sufficient” dose (discussed shortly) of BOHB, often reaching 1+ grams of sodium and more than 100% of the %DV for the other minerals.
How it works...
BOHB + salt (Na+, K+, Mg++ and/or Ca++) --> Enter the blood stream and circulate freely.
Ketone salts are moderately effective at increasing ketosis and the typical serving of 12g of ketone salts typically results in an increase of 0.5 – 1.5 mmol/L, beginning at ~30 minutes and lasting up to a few hours. Ingesting multiple servings of ketone salts to further increase ketosis quickly results in gastrointestinal complications, likely due to mineral overload. Worth noting, many brands are beginning to include MCTs in their ketone salt formulations which has been shown to increase (marginally) peak ketosis and prolong the duration.
VERY IMPORTANT KETONE SALT INFORMATION – In addition to the excessive mineral load, there is a glaring issue with ketone salts that is rarely considered or understood. I will keep this chemicstry bit as brief as possible but if you are considering ketone salts, this is a "must read." Almost all ketone salts – save one product that I am aware of – are “racemic” which means that they contain 50% of the “D-form” and 50% of the “L-form” of the BOHB molecule (or R and S, depending on your naming system). Hold your hands, this is the easiest way to conceptualize this. Notice that the left and right hands are mirror images of each other. In composition, they are identical. In orientation, they are opposite and cannot be superimposed upon each other. The same thing occurs with molecules and industrial production typically results in two “forms” of the same chemical structure being produced. These mirror images often function extremely differently in the body. In most cases, one form is the active form and the other is entirely inactive, serving no function in the body. In some cases, the “wrong” form is actually dangerous (Google the “thalidomide tragedy”). Concerning ketones, specifically BOHB, only the D isomer is active and is the only form produced endogenously. While more research is needed, the L isomer is largely inactive but fairly unlikely to be “dangerous" (although we really don't know for sure).
This is important because almost all ketone salts are racemic. In these salts 50% of their advertised BOHB content is the L form and essentially useless, explaining why ketone salts are disappointingly ketotic and tend to produce poor results in research experiments.
To illustrate the dosing issue with racemic ketone salt formulations, let us consider a real ketone salt product label. First, find the dose of ketone salts. For this example, a popular product lists their ketone salts at 11.38 grams per serving across magnesium (340mg), sodium (650mg), and calcium (570mg) salts. First, we subtract the total weight of the salts (1560mg or 1.56g) from the weight of the ketone salts (11.38g), which equals 9.82g of delivered D/L-BOHB. Finally, divide this number by 2 as only 50% of these ketones are the active enantiomer (D-form), equaling a mere 4.91g of effective D-BOHB per serving.
➡️ MY RECOMMENDATION: Coming Soon ⬅️
3) Ketone Esters
While MCT oil and ketone salts dominate the market, almost all of the research focused on exogenous ketones uses ketone esters. For many of you, this is the first time you’ve heard of these compounds. Like ketone salts, ketone esters directly deliver BOHB to the blood stream. Importantly, esters do not suffer from the racemic or mineral issues hindering ketone salts.
Discovered more than 30 years ago, ketone esters have been inaccessible to general public until the past few years, due to staggering costs from the immense research, development, and manufacturing required to produce these compounds. Over the past decade, the “per gram” cost has been lowered from tens of thousands of dollars to mere dollars per gram. However, even with these strides in manufacturing efficiency, efficacious doses of ketone esters remain in the realm of $15 to $30 per serving.
IMPORTANT – A quick glance considering esters vs. salts would lead the consumer to believe that esters are far more expensive than salts; however, after deeper consideration, these two products are highly price comparable in terms of delivered D-BOHB. Gram for effective gram of D-BOHB, the price is virtually the same.
As with ketone salts, the available esters deliver BOHB; however, an AcAc containing ester has been developed but is not yet commercially available. AcAc is not used in commercial products as the molecule is unstable and spontaneously degrades to acetone over time. BOHB is a much more stable molecule. The compound in the available ester products is R-1,3-butanediol-R-3-hydroxybutyrate. In simple terms, this is a D-BOHB molecule bound to a similar compound called butanediol. The “ester” bond between these two molecules is broken by gut esterase enzymes, releasing butanediol and D-BOHB into the blood. Butanediol (approved by the FDA as a food) is structurally similar to D-BOHB and is rapidly metabolized by the liver to form a second molecule of D-BOHB. Both molecules of D-BOHB are exported into circulation, as the liver is unable to use ketones for fuel.
How it works...
R-1,3-butanediol-R-3-hydroxybutyrate à Hydrolyzed into D-BOHB + Butanediol in the gut à D-BOHB enters the blood stream and circulates freely, whereas Butanediol is rapidly converted to D-BOHB in the liver and exported to the blood stream.
For athletic performance benefits, doses of ketone esters range of 20-30g of ketones per serving. This dose is capable of raising blood ketone levels to ~5 mmol/L in under 1 hour, similar to levels experienced after 5 days of fasting. These ketones can be (and often are) co-administered with carbohydrates to induce a unique metabolic state where carbohydrate-based and fat-based energy is available, allowing the body to be “fuel flexible” which can provide clear advantages in endurance (possibly other forms as well) athletics (source). Lesser doses, in the range of 5 to 15g of ketone ester, are being investigated for cognitive, longevity, and disease management benefits. These lesser doses range between $5-15 per serving, an attractive cost for most consumers in this space. It is worth noting that most ketone esters are diluted to a 1:1 ratio (or similar) of ketones to water. A 30g ketone dose would require 60 mL of ketone ester. Dilution and dosing instructions are noted on the packaging for the various products.
➡️ MY RECOMMENDATION: Coming Soon ⬅️
Finally, there is another source of D-BOHB (remember “D” is the bioactive isomer of BOHB comprising 100% of BOHB in esters and 50% of BOHB in most ketone salts) called Poly-BOHB. This is a large chain-like molecule carrying many attached molecules of BOHB, similar to how glucose is stored in chains called glycogen. This is an important energy source for many microorganisms and initial research shows potential function in mammalian mitochondrial membranes, calcium channels, and protein folding; however, the extent to which humans can digest and utilize poly-BOHB is unknown (source).
More to come as the research advances…
How to Use Exogenous Ketones
Ketones are not miracle molecules. This has to be said. Ketones are natural products of human metabolism.
Ketones are molecules - recently popularized as "the 4th macronutrient" - containing energy just like carbohydrates, fats, and proteins. They are also signaling molecules capable of modulating genetic expression and metabolic activities.
The point: Ketones are incredibly interesting and powerful health tool.
That said, as a natural component of human metabolism, the body tightly regulates ketosis and will prevent excessively high levels of ketones in the blood. This regulation is accomplished primarily through suppression of fat metabolism via insulin release. Some of you are already connecting the dots between excessive or incorrect ketone supplementation and insulin production. Well done! As an interesting fact, improper ketone supplementation may be contraindicated in persons with insulin resistance or other metabolic dysfunctions without concurrent carbohydrate restriction and/or other dietary and lifestyle improvements. Incorrect usage of ketone supplementation may actually impair fat loss.
The point: Exogenous ketones are a powerful tool that must be understood and used correctly.
My goal with this article is to emphasize that exogenous ketones CAN BE an incredible powerful and exciting tool to achieve numerous health outcomes; HOWEVER, benefiting from ketone supplementation is not as simple as arbitrarily loading ketones into your system. Exogenous ketones are tools that must be fully understood and used correctly or they can actually work against you.
I will end the discussion here and link to a “How to Use Exogenous Ketones” article that I will write shortly.
Any questions? Just ask!