Exogenous Ketones
(The 4^th Macronutrient?)

Edition: 2017-08-31

Exogenous Ketones (ExKs, henceforth) are (synthetic) ketone bodies formed outside the human body (vs. endogenous ketones, EnKs, synthesized internally). For UIC members, Dr. Davis covers ExKs on this page: Advanced Topics: Physiologic Ketosis, MCTs, and Exogenous Ketones This present page is an overview of the ExK topic for all readers.

This is not about ketone precursor products like capryllic acid, coconut oil, ghee or MCT. These are just dietary fats, although useful and effective on a ketogenic diet, particularly MCT. This is also not about “raspberry ketones” or 7-Keto DHEA, neither of which are products that inherently contain ketone bodies.

Why now?
Since 2013, ExK products have become available that are being marketed directly to consumers. These have a striking portfolio of possible benefits, but they are so novel that any hazards from excessive and/or chronic use may not yet be understood. No adverse events have come to my attention so far, but as Dr. Davis warns, some have dangerous levels of calcium and/or potassium.

TL;DR

Although the currently available products may not be optimal, Exks are currently being contemplated, if not formally investigated, for:

I expect to populate the above table with local or external links as I create or discover germane discussions on each possible application.

There are people using ExKs daily for mood and energy enhancement. That might be a premature move. Some of the products are being pitched for weight loss. That’s probably misleading per se, but ExKs suppress appetite, so might well aid in implementing the low-carb diets coincidentally suggested for those products.

Ketone Bodies Are

There are three ketone bodies. These occur naturally in human metabolism, during extended fasting and nutritional ketosis, and in the pathological states of starvation ketosis and diabetic ketoacidosis (DKA). They are:

• Beta-hydroxybutyrate (BHB, βHB or β-BHA)
  Formulations are available at retail and as research compounds, and so far are all salts, containing calcium, potassium and/or sodium in non-trivial amounts.
   
• Acetoacetate (AcAc)
  formulations appear to be only available as research compounds in ester form, such as 1,3 butanediol acetoacetate diester. There are groups working to bring some of these to market.
   
• Acetone (Ac)
  is the same chemical used in nail polish remover, and although it’s considered a GRAS food ingredient, and available in food-grade at retail, I have found no indication that acetone is used as an ExK (Searching on this is confounded by the fact that when in ketosis, by any method, acetone is commonly spilled in exhaled breath, so “acetone” dilutes web hits in addition to nail polish.)
  
  Don’t experiment with Ac. Undiluted acetone is volatile and explosively flammable. It’s considered a skin and eye irritant, and harmful to the respiratory and central nervous system. LD50 (rat) is 5.8 grams per kilogram of body weight.

Many body cells can use ketone bodies as an alternative to glucose and free fatty acids (FFA) to make Adenosine triphosphate (ATP). The brain in particular cannot run on FFAs, requires some glucose, but can operate on glucose plus ketones. Many investigators presently think that the brain can run (and run well) on up to 60% ketone bodies.

Ketone bodies can cross the blood-brain barrier (BBB), whereas FFAs cannot. This has profound implications for, among other things, neurological disorders in which glucose is a suspect antagonist.

Although there is ample evidence for at least part-time ketosis in all human populations, there is, as far as I can tell, no ancestral case for consumption of ExKs. Ketone bodies occur naturally in foods, but at low levels, with acetone perhaps being the most common.

Technically, ketone bodies are arguably considered fats, but they are never included under Fats on Nutrition Facts panels. This, plus the obscuration committed by many suppliers, can make it difficult to know just how much ExK a product provides.

Dietary Context

Ketogenic diets (KDs) have been used therapeutically for a century or more. Conditions in which they have been found useful include: type 1 diabetes (T1D), epilepsy and seizure disorders generally. The diet is also being investigated for Alzheimer’s, ASD, cancer, depression, GLUT1DS, Parkinson’s, PCOS and to accelerate reversal of T2D.

KDs are also popular with athletes (as carb-loading can be avoided), people desiring to lose weight, and with bio-hackers with various motivations.

The diet advocated by Undoctored and Wheat Belly is not inherently ketogenic. At 50 grams of net carbohydrate per day, the Ud/WB diet is at what is generally considered to be the borderline between glycemic and ketogenic diets. People following a net50, low/moderate protein, high specific fats diet are in glycemic metabolism part of the time, and ketotic metabolism part of the time (quite likely during the fasting time that sleeping represents). CR/WB can easily be made KD, by driving carbs lower and keeping protein moderate.

For anyone who desires to increase their levels of ketone bodies, the approach over the last century or so is a fully ketogenic diet (KD). Reducing net carbs to 20 grams or less per day, with some attention to protein intake, usually suffices. Any calorie deficit is usually addressed by increasing fat (not protein) intake, particularly fats that are feedstock for ketone synthesis, such as MCTs.
Caution: be sure to maintain intake of prebiotic fiber on a full-time KD.

Excess protein needs to be avoided for KD, due to gluconeogenesis - synthesis of glucose from protein. The body can also synthesize glucose from fat. This how the brain gets its required glucose when on a strict KD that provides no exogenous glucose.

Exogenous Ketones Arise

Elevating blood levels of ketones to therapeutic levels can be challenging, particularly in our current milieu of high-carb, adverse-fat, food-like substances. The situation that apparently sparked the development of ExKs was oxygen toxicity seizures in deep sea divers. It was known that ketosis was protective, but it was not thought practical to keep operators on a full-time ketogenic diet.

Nutritional ketosis usually results in a ketone blood titer in the range 0.5 to 3.0 mmol/L. This is as measured by a blood test. Meters that test breath or urine use completely different units of measure, and are less reliable, primarily because they are measuring spilled (excess) ketones, and secondarily because they provide no insight into how much ketone is being consumed for energy production.

It can take 2 to 4 weeks to get the blood ketone level above 1.0, and some people have difficulty getting above that. Using ExKs, it’s apparently possible to get into the 3.0-5.0 range without much difficulty - ketone levels can be brought into the KD range this way even on a glycemic diet (but I’m dubious that this latter is a wise idea absent a specific problem being addressed).

Here’s a rodent trial of ExK effect on various diets:
N&M: Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats

According to Patrick Arnold (who appears to be the chemist who formulated the first of the currently-available products) says:
“Your body can burn ketones while on a normal diet
its just that your body won’t make ketones on a normal diet“
and even on a glycemic diet, does so
“…for about 3 hours”
(emphasis added by me). Apparently, on ExKs, you won’t be burning any fat either.

A key question is: can an exogenous ketone body provide the sought benefit even if the person is not on a ketogenic diet?

For at least some seizures, the answer is: apparently yes.
This question then also arises for all the other conditions for which KD is being explored. Will an ExK provide benefit even if not on KD, and/or will it provide additional benefit on a KD. We can’t presume the answer is always yes.

Considerations for Use

Safety

With the current BHB salts, some product formulations present potentially serious hazards due to excess potassium, and/or undesired levels of calcium and/or sodium. But let’s start with the active ingredient in all, BHB.

ExKs have now been in use since 2012, and available at retail since 2013. They were able to come to market quickly because BHB is considered GRAS. The AcAc products in development apparently don’t have that luxury, and are having to invest in safety studies. If there have been adverse events with the BHB ExKs, they have not been widely published (or were mistaken for something else). This, however, is no basis for complacency.

It’s easy enough to find articles skeptical of ExKs, such as:
Hyperlipid Blog: Are ketone esters dangerous?
and
T Nation: Avoid This Ketogenic Rip-Off

Absent a specific problem needing resolution or long-term therapy, I’m personally reluctant to assume that chronic consumption of ExKs is necessarily harmless. Unlike most of what those of us following enlightened ancestral diets consume, there is obviously no ancestral case for something that never existed ancestrally.

I will not be the least bit surprised if using ExKs on a full-time glycemic diet in particular is a big mistake.

On the upside, I would conjecture that for an endurance athlete presently carb-loading, and perhaps for a keto-adapted athlete feeding carbs into glycogen depletion during an event, that it is net safer to be keto-adapted, and feed ExKs for bonk-avoidance. The KGZ Boost product might actually be suitable for this if you can figure out how much BHB it provides.

Know what amounts of calcium, magnesium, potassium and/or sodium are in any product under consideration, per dose. Not all salts are present in all formulations.

Determine both grams for mineral (not total salt), and percent DV (Daily Value) per mineral. Note that some products violate labelling rules by failing to specify both of these numbers (a reason to reject a product per se).

Potassium:
We have already observed one ExK product with 80%DV (3.8 grams). On a diet with typical amounts of food-sourced potassium, particularly if routinely consumed at the upper end of the brand’s “1-3 times a day” range, there is risk of hyperkalemia, with possibly fatal cardiac consequences.

Calcium:
We have seen more than one ExK product with 140%DV (1400 mg) of calcium. On the Undoctored program, we want added Ca to be zero. Reject any product than has more than about 10 mg of calcium.

Sodium:
We have seen one product with 66%DV (1600 mg) of sodium. Although the Undoctored program does not support the consensus low-salt folly, this is a significant fraction of the program’s conjectured 3000-6000 mg/day range. If sodium is present, it needs to be factored into whatever daily Na target you have in mind. Anyone with a specific sodium/salt sensitivity also needs to remain alert.

Magnesium:
Whatever amount of Mg an ExK provides needs to be accounted for in routine supplementation. So far, no products have appeared with concerning levels (perhaps over 500 mg), but even 100 (which has been seen) would suggest cutting back on your daily magnesium water.

Purity

ConsumerLab has not yet tested any ExK products.

Here’s a question to ask your supplier of an ExK supplement:
Where is the BHB itself made?
The four most likely answers are (with their translations):

1. The BHB is made in the USA
   (this is true for KetoSports)
2. The “final product” is made in the USA, or similar weasel-wording not responsive to the exact question
   (trans: but the BHB is from China)
3. That’s “proprietary information” or similar intellectual property / trade secret babble
   (trans: the BHB is from China)
4. We’ll have to get back to you on that
   (and when they don’t, the BHB is from China)

Other Ingredients

As mentioned earlier, the presently available ExK products are all BHB salts: BHB with calcium, potassium, sodium, magnesium, or some combination thereof, discussed above under Safety.

The various products available may also contain: amino acids, ascorbic acid, butyrate, caffeine, citric acid, disodium phosphate, flavorants, gum acacia (an emulsifier), gum arabic (an emulsifier), malic acid, milk products, mono and diglyceride esters, prebiotic fiber (inulin), potassium citrate, silicon dioxide, soy lecithin (an emulsifier), sweeteners (erythritol, inulin, stevia), xantham gum (an emulsifier).

You’ll either have or need to develop a posture on these. Is much of this just filler? How much of it deliberately intended to prevent figuring out how much BHB you get? Does that “chocolate” product actually contain any cacao?

Strength

Insist on a plain declaration of BHB per serving (not “BHB salt” per serving, or total grams per serving).

For some brands, unless they start admitting it, you need to ask:
How much actual BHB (not BHB salt) is in a serving?
Expect the usual proprietary misdirection.
OK, then, how much BHB salt is in the product?
Expect more stonewalling. Yes, you are buying the product to get BHB. No, they will not tell how much you are buying.

If you are an advanced amateur food formulator, you can work out how much BHB is in some of the other products. Thanks to the Prüvit(Keto//OS^®) vs. ForeverGreen(Ketopia™ Ketonx) lawsuit (now settled), we learned how, from the declaration of Dennis Jones, Ph.D in that case. He didn’t work it out down to the final BHB number, but for the specific product examined at the time, it might be as little as 8.6 grams. I haven’t worked out the numbers for all the concealing products. Personally, I consider the withholding of this crucial information to be a prima facie product disqualifier.

Economy

If you just plan to consume the product’s standard serving size, economy is a simple matter of:
$daily = (net_price + shipping + tax) ÷ serving_count
In general you can expect to spend US$4.00/day and up for this class of product, and then only if one listed serving size per day meets your objectives.

If your intent is to reach a specific measured level of ketones, however, you may need to adjust the serving size. Then the question might become: how much does a gram of BHB cost you? Some of the available brands don’t want you to be able to run that calculation, so you’ll have to work it out by trial and testing.

Palatability

Ketone ester products haven’t even come to market yet, in large part due to this issue. Ketone salts have, but their formulations are still being dialed in to address taste. Here’s Dr. Peter Attia on his experience.

The original Prototype Nutrition KetoForce product is highly alkaline (pH 10 to 11). Follow the instructions on serving.

Current Products

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Now that Dr. Davis is minding the market, I’ve given up trying to keep track of all the products.

In closing, this page was prepared to support comments I might make on the ExK topic in various forums. I have not used any of these products, and have no plans to. I have no relationship with any of the brands mentioned. I have no product recommendations to suggest at this time, which in any case would be a hazard ranking list.

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Bob Niland [disclosures] [topics] [abbreviations]