Ketone Supplements: The Pros and Cons

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Ketone supplements rapidly and transiently increase blood concentrations of beta-hydroxybutyrate (BOHB). There is a flurry of new studies being reported, some positive, some neutral and some negative.

The different forms (salts vs. esters), what they are co-ingested with (carbohydrates vs no carbs, minerals), the background diet (ketogenic vs. high-carb), and dosing, timing, and adaptation periods are just a few of the important factors that may determine the metabolic responses to ketone supplements.

In preparation for this Post it is helpful to first understand: Keto-Adaptation. Here is the link.

Ketones refer to the primary circulating fatty acid metabolites beta-hydroxybutyrate (βOHB) and acetoacetate (AcAc). More on ketone basics here

Shedding light on new methods of achieving ketosis:

  • Exogenous ketones (ketone supplements) and well-formulated ketogenic diets should not be assumed to have equivalent effects simply because they achieve similar BOHB blood levels.
  • For the past few million years, the only way for humans to make use of ketones for fuel was to restrict carbohydrates low enough and long enough to induce the liver to make them. An emerging alternative is to consume ketones as a dietary supplement.

Sources and Formulations of Exogenous Ketones

  • The source of most exogenous ketone supplements is chemical synthesis, which focuses on BOHB.
  • An important difference between endogenous (produced by your liver) and exogenous BOHB is that most synthetic BOHB used in dietary supplements is a mixture of the two ‘D’ and ‘L’ isomers, whereas endogenously produced BOHB consists of just the D-isomer. Metabolically, the two isomers are very different, and current published information indicates that most of the energy and signaling benefits of BOHB derive from the D-form. This is potentially problematic because the L-isomers are not metabolized via the same chemical pathways as the D-forms and it remains unclear whether humans can convert the L-form to the D-form.
  • Thus, while the L-isomers do not appear to be toxic, they are not likely to impart the same benefits as the D-forms.

Ketone Salts and Esters are two general formulations for dietary BOHB supplements – salts derived from the keto-acid or an ester formed between the keto-acid and an alcohol.

Ketone Salts: Salts typically utilize sodium, potassium, calcium, or magnesium. Given that recommended daily intakes of these various minerals range from a few hundred milligrams up to 5 grams, whereas the daily ketone intake goal to mimic nutritional ketosis blood levels would need to be on the order of 50 grams, achieving this goal with ketone salts would severely challenge human dietary mineral tolerance.

Most of the currently marketed ketone salt formulations are made with a mix of the D- and L-isomers of BOHB, so the actual delivered dose of the more desirable D-isomer is considerably less. The other concern with the salt formulations is that, as the salts of weak acids, they have an alkalinizing metabolic effect that might have a modest but cumulative effect on blood pH and renal function.

Ketone Esters are more appropriate for delivering higher doses of BOHB, but with repeated dosing can push the limits of taste and GI tolerance (loose bowels). This product has been shown to significantly reduce appetite after a single dose but its effect on body weight in humans over a longer period of time has not been studied, nor has its effect on blood glucose control been reported in humans with type 2 diabetes.

Comparison of ketone supplements (chemical ketosis) to nutritional ketosis

 The stimulus for the increase in ketones in response to a well-formulated ketogenic diet is the restriction of dietary carbohydrate, which triggers many favorable adaptations. Although both induce a form of ketosis, the lack of carbohydrate restriction in the context of using ketone supplements induces a different metabolic profile.

The blood levels of BOHB that can be achieved with the salts or ester formulations are in the 1-3 mM range, similar to what can be achieved with a well-formulated ketogenic diet in insulin sensitive humans. In more insulin resistant humans, the ester formulation may deliver higher blood levels than a sustainable diet.

In terms of epigenetic signaling, at levels of BOHB as low as 1 mM have potent effects. Furthermore, the association between very mild ketonemia (concentration of ketone bodies in the blood) and reduced coronary mortality with SGLT2 inhibitor use in patients with type 2 diabetes suggests that there might be clinical benefits with chronic BOHB levels as low as 0.3 mM.

That said, there also remains the question of the relative benefits of AcAc versus BOHB. AcAc generated in the liver acts as a NAD+ electron donor for the peripheral (aka non-liver), whereas pure BOHB taken orally potentially deprives the periphery of NAD+.

Another factor to consider is that in nutritional ketosis the liver makes a steady supply of ketones and continuously releases them into the circulation. In contrast, most ketone supplement protocols involve bolus intakes that don’t mimic the endogenous release pattern. The extent to which this impacts metabolic and signaling responses across different tissues remains unclear.

Some of the benefits of nutritional ketosis can be attributed to circulating levels of BOHB, and some of these benefits can accrue at blood levels at or even below 0.5 mM.

Practical Considerations in Prevention and Management of Chronic Disease

  • Until there is more definitive information, it will be difficult to specify the dosing and duration of supplemental ketones. However for fuel use, and very likely for exercise performance as well, sustained blood levels of BOHB in the range of 0.5 mM to 1.0 mM are likely to be required. This is achieved physiologically by an estimated ketone production of 50-100 grams per day in a keto-adapted human.
  • With the current ketone salt formulations, even 50 grams per day is likely above taste and physiologic mineral tolerances. So for these products, their potential benefits are likely limited to adding to existing blood ketone levels for someone already following a low carbohydrate diet.
  • For the ketone esters, on the other hand, repeated doses of 20-30 grams in any one day may be possible. Thus these products may be able to maintain a modest level of ketonemia without dietary carbohydrate restriction. Thus some of the cardiac and brain fueling benefits may follow, not to mention the epigenetic effects limiting oxidative stress and inflammation. But given the recent observation that administered ketone esters markedly reduce circulating free fatty acids – their sustained use in people with underlying insulin resistance may compromise their long-term benefits by promoting weight gain unless combined with carbohydrate restriction.
  • A drawback to the long-term use of ketone supplements is their poor palatability for the esters and their cost of about $1 per gram of delivered ketones for daily dosages from 25 to 100 grams.

Sports Performance:  There are enticing anecdotes of supplemental ketones being used to boost human physical performance in competitive events, notably among elite cyclists. Given that BOHB can deliver more energy per unit of oxygen consumed than either glucose or fatty acids, this makes sense. But what we do not know is if there is any required period of adaptation to the use of exogenous ketones, and thus how to employ them in training. It is clear that exogenous ketones decrease adipose tissue lipolysis and availability of fatty acids, the exact opposite to what happens on a well-formulated ketogenic diet. This distinction between exogenous ketones and ketogenic diets on adipose tissue physiology and human energy balance underscores an important reason why these two ketone-boosting strategies should not be conflated.

This Post has been condensed from the Virta Post, Ketone Supplements: The Pros and Cons – Shedding light on new methods of achieving ketosis by Stephen Phinney, MD, PhD and Jeff Volek, PhD, RD on March 12, 2018

More scientific information and Citations of the supporting studies are included in the Virta post.

Personally, I took ketone supplements for years. I finally lost the unwanted weight off and kept a healthy body fat percentage with the Ketogenic diet.

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Lydia Polstra




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Author: 2healthyhabits

My goal in life is to experience the exuberance of true good health by returning my body to the healthy state it was meant to have.

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