What are Exogenous Ketones?

We’ve explored ketones extensively on this blog and shared our favorite recipes and experiences with ketosis. As the Keto diet becomes more popular and millions of people have experienced the benefits of ketosis, still many folks report difficulty achieving/maintain ketosis or negative side effects from the diet itself. As discussed in Keto 101, most people achieve ketosis with diet or fasting, but there is a 3rd way: supplementation with exogenous ketones. These synthetically-derived ketone bodies come from the lab–they are not produced in the body like endogenous ketones. With the advent of exogenous ketones, there is now a way to raise ketone levels significantly and safely without the need to fast or diet.

Exogenous ketones provide the body with another fuel to employ. Think about it like an electric car that runs on both gas and electricity: by consuming ketones along with carbohydrates, the body will preferentially burn the ketones first, saving the carbohydrates for later. Exogenous ketones allow us to enter a metabolic state that wouldn’t occur naturally: the state of having full carbohydrate stores, as well as elevated ketones in the blood. This could be advantageous to athletes looking to boost their physical performance. On the other hand, this is a novel physiologic condition that couldn’t be experienced without artificial manipulation, so a certain amount of trepidation is warranted.

Consuming exogenous ketones isn’t the same as following a ketogenic diet–the ketones in the blood haven’t been naturally produced by the breakdown of fat stores. However, scientists believe many of the health benefits of the keto diet and fasting (aside from weight loss) are triggered by ketones. Therefore, raising ketone levels through either endogenous or exogenous ketosis could help to improve health and performance by:

• Reducing inflammation: ketones reduce activation of inflammatory processes
  
• Reducing oxidative stress: ketones scavenge harmful reactive oxygen species
  
• Metabolic flexibility: Affecting gene expression and cellular processes associated with brain health and longevity
  

Our bodies are produce three types of ketone bodies for fuel: beta-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone. Each is used by the body differently. Acetone is the least abundant, produced in much smaller amounts, and is usually exhaled through the lungs rather than being used as fuel. Acetoacetate is part of the metabolic pathway whereby humans make and use ketones, but it tends to be found in the blood at lower levels than BHB. BHB is the predominant ketone body in the blood (and the one we measure with the Precision Xtra fingerstick), which is why it’s most often used in exogenous ketones.

So how does one take exogenous ketones supplements? Thankfully, they can simply be taken orally and are readily available from a number of manufacturers. There are 2 primary preparations: Salts and Esters. Since this isn’t an organic chemistry blog, and chances are you aren’t a pharmacologist, lets just stick with the basics…

Ketone Salts

Ketone salts are powdered supplements consisting of a ketone molecule bound to one of several mineral salts: sodium, calcium, magnesium, or potassium. Most of the available products on the market have sweeteners or flavorings added, and trust me you need them–it would taste foul without them. These supplements typically raise serum BHB mildly, up to ~0.8 mM. This is the range I’ll typically see with 24 hour fasting. The main advantages of ketone salts are cheaper cost and easier availability compared to esters. There is also longer, more robust clinically and lab data supporting their use. I’ve personally used the supplement pictured above and while it raised my serum BHB as advertised and I did not notice any negative side effects, it also didn’t seem to provide much benefit to me in a non-experimental setting.

So what are the disadvantages? Apart from the rather foul taste, most people report that they feel good while taking them and serious side effects are rare. The most common symptom is GI upset, especially at higher doses. Another concern is the total salt load, which could theoretically worsen things like blood pressure. Its also important to recognize that many of the ketone salts currently available are not considered FDA GRAS (generally regarded as safe)

Despite the recent growth of the ketone salt market, there is very little published work analyzing the effects of these products on any biomarkers or performance measurements in humans. Several studies have been carried out in rats, with blood BHB levels being relatively low (<0.5 mM) post-consumption of salt drinks. In humans, ketone salts provided peak D-BHB levels of 1 mM, whereas the same amount of BHB in a ketone ester (BD-BHB) raised blood BHB to 2.8 mM.

The clinical data, where available, aren’t too impressive either. In a recent study examining cycling performance after ingestion of ketone salt vs carbohydrate, the ketone group saw a reduction in performance despite a meaningful rise in serum ketone levels.

Ketone Esters

Ketone esters are salt-free liquids comprised of a chemical compound called an “ester” (not to be confused with your great aunt Esther). The product can be a “mono” or “di” ester, meaning one or two ester bonds, and the ketone body bound via this bond could be either BHB or acetoacetate. Lets take a closer look at a few of these products:

D-BHB Ketone Monoester

• Acutely raises D-Betahydroxybutyrate to high levels (up to 3-6 mmol/L) within 30 minutes
• Delivers D-BHB without salt or acid load
• Considered FDA Generally Recognized as Safe (GRAS) for use as a food
• Approved for use in sport by the World Anti-Doping Agency (WADA)
• With single doses of the D-BHB ester as a sports drink, gastrointestinal (GI) side effects are rare but can occur at high doses.
• Has been shown to improve sport performance

Acetoacetate Diester

• Mildly raises D-BHB to moderate levels (~1 mmol/L)
• In current formulation, some report GI symptoms
• No improvement in performance (may be related to GI symptoms)

Side effects?

Like any substance these supplements can have side effects. Again the largest are the GI upset that can occur with any ketone supplement. But probably the biggest “side effect” is the foul taste that many of these supplements. Take it from Peter Attia, who was one of the first to try these supplements outside of clinical studies:

” The ketone esters are, hands-down, the worst tasting compounds I have ever put in my body. The world’s worst scotch tastes like spring water compared to these things. The first time I tried 50 mL of BHB monoester, I failed to mix it with anything. Strategic error. It tasted as I imagine jet fuel would taste. I thought I was going to go blind. I didn’t stop gagging for 10 minutes.

Peter Attia, MD

So do ketone supplements actually work?
The first ketone ester was developed in the late 1970s and more were developed in the mid-1990s. A research group at the University of Oxford and National Institute of Health received funding from the US Military to develop one of these ketone ester compounds: R-1,3-butanediol-R-3-hydroxybutyrate (BD-BHB). This is the ketone ester that has been widely used and studied, and is currently available to consumers through HVMN.

The HVMN ketone product has excellent reviews and the science to back it up; it also costs nearly $100 and some report mixed or unimpressive results. I haven’t tried it yet, but looking forward to sharing my own experience with you once I have.

The second ketone ester compound was developed at the University of South Florida by ketone aficionado Dom D’agostino. This ketone diester of AcAc and BDO has shown the ability to raise blood D-BHB to 1-4 mM and blood AcAc to up to 5 mM in rodents. There is one published study of this ketone ester in humans with unimpressive results: it actually decreased cycling performance in a 31 km time trial performance.

At the end of the day, the jury is still out on exogenous ketones. The safety profile is certainly acceptable, and some people find them more palatable than others. If you’re keen to experiment with ketosis, but cant tolerate a ketogenic diet or fasting, these may be just the product for you. However, it is important to realize that ketosis with relatively hyperglycemia is not a naturally occurring physiologic state. Athletic and mental performance may be slightly improved, but by using this “hack” or physiologic shortcut you may be missing out on some of the potential benefits that come along with the process of getting into ketosis, which are as yet still poorly understood.

A version of this article was originally published at HVMN, but has been edited for content by OurHealthHabit.com. The original content can be accessed here.