Originally published on HVMN by Dr. Brianna Stubbs and Nate Martins
Though nuanced, there’s a big difference between a “ketogenic” body and a body “in a state of ketosis.”
A body in a ketogenic state is one actively producing ketones. Ketosis simply marks the presence of ketones in the blood.
Ketones can be produced naturally even though ketones aren’t found in high concentrations in our food. Fasting and dieting aim to achieve a ketogenic state and encourage the body to produce its own ketones, the all-important fuel and signal of a body in ketosis.1
Ketones can be introduced to the body from an external supplement–like HVMN Ketone. Through ketone supplements, the body can receive some of the benefits of ketosis without being in a ketogenic state.
To understand the different ways ketones enter the blood, it’s important to look at the basic biology of ketones themselves.
Endogenous vs Exogenous Ketones
There are two ways to achieve ketosis, which is usually defined as having blood ketone levels elevated >0.5mM.
Endogenous ketones are produced by the liver during a ketogenic state, this usually occurs when fasting or following a ketogenic diet. One must strictly follow the low-carb, high-fat diet, which can be difficult in today’s society that has a long-standing love affair with carbohydrates.
- Endogenous = ‘Endo’ = within. ‘Genous’ = origin. Originates from a source internal to the body.
Exogenous ketones are ketones consumed through a nutritional supplement. They can deliver a state of ketosis without changing the diet.
- Exogenous = ‘Exo’ = external. ‘Genous’ = origin. Originates from a source external from the body.
It’s important to note that exogenous ketones don’t trigger natural ketone production, meaning they don’t put you in a ketogenic state. A ketogenic state can only be achieved by the body naturally producing ketones. Exogenous ketones do, however, promote a state of ketosis, which means that blood ketones levels are elevated.
Different Types of Ketones: Beta Hydroxybutyrate and Acetoacetate
Most forms of exogenous ketones deliver beta hydroxybutyrate (BHB) rather than acetoacetate (AcAc). This is due to a combination of factors:
- BHB is the ketone present in the blood at the highest level when produced naturally.2
- BHB is more ‘reduced’ than AcAc. This means when BHB is used inside the mitochondria, it generates a co-enzyme called NADH. NADH is needed for ATP production in the mitochondria. By contrast, when consuming an AcAc-based supplement, some of the AcAc will be reverse-converted to BHB, using up NADH, which is not helpful for mitochondrial ATP production.
- BHB is a more stable molecule than AcAc: AcAc can spontaneously breakdown in the blood to produce acetone, which cannot be used for energy production. BHB is therefore easier to formulate into a consumable product.
In short, the body usually chooses to transport more of the ketones in the blood as BHB instead of AcAc. This is likely because BHB not only is better for cell energy production, but also an inherently more stable ketone molecule.
BHB and Optical Isomerism
Optical isomerism describes the occurrence of compounds made from the same number and order of atoms, but different in the 3D arrangement of the atoms’ bonds. This happened via evolution, allowing compounds to be used (and created) differently.
There are two optical isoforms of BHB, called D-BHB and L-BHB. Think of it like this: our left and right hands have identical components (put together in the same order) but can’t overlay perfectly.
Figure 1: Optical isomerism is similar to the left and right hand, both composed of the same material but are mirror images of each other
Because of the subtle differences between D- and L-BHB, the body can’t use the two forms in the same way.
The body releases D-BHB into the blood and uses it for energy. While there is L-BHB inside our cells, the body does not release significant amounts of L-BHB into the blood3 and really, it’s unclear how the human body uses L-BHB. Studies in rats suggest it’s not readily used as fuel, and is mainly used to synthesize fats.4,5
L-BHB appears to be a “weaker” form of D-BHB, both regarding its ability to provide energy, but also in its ability to act as an antioxidant.6
BHB is delivered through two main classes of exogenous ketone supplements: ketone esters and ketone salts. Medium Chain Triglycerides (MCTs) are also used to artificially raise blood ketone levels by providing a source of fat that is easily converted into BHB–but there is no BHB in MCT itself.
Overall, ketone salts and MCTs don’t increase ketone levels like ketone esters. Let’s analyze why.
Blood ketone levels of HVMN Ketone, MCT and ketone salts
Ketone Salts
Ketone salts are a powder containing BHB bound to a mineral salt (most commonly sodium or calcium) or sometimes an amino acid (such as lysine or arginine). The powdered salts are dissolved into a liquid to make it easier to consume. Published human clinical trials report blood BHB levels of 0.6 – 0.8 mM after ketone salt drinks.7,8
Benefits of Ketone Salts
- Sub-Optimal BHB: Mildly raise BHB up to 0.8 mM.7,8,9
- Inexpensive: Currently cheaper to produce than ketone esters.
- Co-Deliver Other Nutrients: It is possible to add amino acids as an organic salt to BHB, delivering other useful nutrients along with BHB.
Disadvantages of Ketone Salts
- Health Concerns: Excess salt consumption may have long-term health implications. Use of ketone salts results in an intake of sodium (or other electrolytes) far higher than the recommended daily allowance. High salt intake is linked to conditions such as hypertension, cardiovascular disease and stomach cancer.10 In the first 1-2 weeks of following a ketogenic diet, there is a higher requirement for electrolytes due to increased excretion in urine. This has led to suggestions that regular ketone salt consumption might compensate for these losses. However, electrolyte imbalances do not persist after the adaptation period of ~28 days,11 excessive salt consumption may still be harmful.
- Side Effects: Drinking ketone salts has a high risk of causing gastrointestinal symptoms, especially at high doses.12,13
- Metabolic Redundancy: Most ketone salts are a mixture of the two optical isoforms of BHB (D- and L-). Human metabolism of L-BHB has not been studied in detail, although it does not appear to be metabolized as rapidly as D-BHB.9
- Not Recognized by FDA: Many of the ketone salts currently available on the market are classified as supplements not approved as a “Generally Recognized as Safe” (GRAS)food ingredient by the FDA.
Overview of Clinical Research
Despite the recent growth of the ketone salt market, there is very little published work looking at the effects of these drinks on any biomarkers or performance measures in humans. Several studies of ketone salts have been carried out in rats,14,15,16 with blood BHB levels after salt drinks being relatively low (> 0.5 mM). The earliest human studies of ketone salts were a small number of clinical studies in sick children,17,18 who were being treated with ketone salts to help with inborn metabolic defects. The maximal BHB levels seen were 0.4 – 2.5 mM and doctors noticed improvements in their clinical symptoms.
In a recent study of healthy young adults, ketone salts gave a peak D-BHB of 1 mM, whereas the same amount of BHB as a ketone ester (BD-BHB) raised blood BHB to 2.8 mM.9 Also noted was a high amount of L-BHB in the blood after salt drinks (> 2 mM). L-BHB took far longer to be removed from the blood compared with D-BHB, indicating that L-BHB likely has a different metabolic fate to D-BHB.
Recently, four published studies investigated the effects of ketone salts in athletes (total n = 22).7,8,19,12 None of these studies found an improvement in performance; in one study, performance actually decreased by 7%. Blood BHB levels peaked between 0.5 and 0.8 mM in these studies. GI distress (nausea, diarrhoea, vomiting, and lightheadedness) was reported in high percentages of athletes taking ketone salts alongside exercise (78% and 60%).12,13
Some commercial ketone salt supplements contain other ingredients such as MCT, caffeine, and carbohydrate. It is unknown if adding these extra ingredients will help or hinder the effects of the ketone salt consumed.
Medium Chain Triglycerides (MCTs)
Medium chain triglycerides don’t contain ketones themselves–they’re actually fat molecules (made up of glycerol joined to 3 medium-length fatty acids). In this case, “medium” chain length means that there are 6-12 carbons in the fatty acid chain.
Ketones form as a result of the breakdown of MCT fat molecules by the body. Coconut oil is a natural source of medium chain triglycerides, but MCTs can also be taken as synthetically purified oils.
Medium chain triglycerides are processed by the body differently compared to long-chain fats. Long-chain fats are absorbed and released into the blood via the lymphatic system, bypassing the liver. However, medium-chain triglycerides are transported straight to the liver in the blood. There, they are either used directly as a source of energy or turned into ketones.
Benefits of MCTs
- All Natural: Sources of MCT exist naturally in our food, such as coconut oil.
Disadvantages of MCTs
- Side Effects: Many people get gastrointestinal symptoms following high levels of medium chain triglyceride consumption.20,21
- Highly Caloric: High amount of calories in relation to the elevation of blood ketones.
- Sub-Optimal BHB: Comparatively low blood ketone levels (0.5-1mM) compared to other ketone supplements.
Overview of Clinical Research
There are a large number of research papers demonstrating that MCTs are safe to consume. However, gastrointestinal side effects (such as diarrhea) are common, especially when consuming high amounts.20,21
This presents a problem, as high amounts of MCT are required to raise blood BHB. In general, studies of MCT supplements report that blood ketone levels achieved while using MCTs are low (0.5-1 mM).20
There is not a clear answer as to which chain length of fatty acids comprising MCT (6-12 carbon chain length) is best at raising blood BHB levels. The available research suggests that C6 (caproic) and C8 (capric) fatty acids have the greatest effects on blood BHB.22,23
Ketone Esters
Ketone esters are liquids that contain BHB or AcAc bound to another ketone precursor (such as butanediol or glycerol) by an ester bond. There are several types of ketone ester in existence and they affect the body differently: the D-BHB Ketone Monoester (HVMN Ketone) and the AcAc Diester.
It’s important to distinguish which ketone ester is being used because there are differences in their physical characteristics and metabolic effects.
HVMN Ketone (D-BHB Ketone Monoester)
- Optimal BHB: Acutely raises D-BHB to high levels (up to 3-6 mM) within 30 minutes.9,24,25,26
- Salt-Free: Delivers D-BHB without salt or acid load.
- Food, Not Supplement: HVMN Ketone is considered FDA Generally Recognized as Safe (GRAS) for use as a food.
- Permitted for Athletes: HVMN Ketone is compliant for use in sport by the World Anti-Doping Agency (WADA).
- Side Effect Free: With single doses of the D-BHB ester mixed with a sports water, gastrointestinal (GI) side effects are very rare. Most studies of athletes using HVMN Ketone reported no side effects that hindered the ability to perform.26,27 Some studies have reported mild GI side effects of HVMN Ketone drinks at extremely high doses (4x usual serving size) or when given in a thick, meal replacement formulation.24,28
- Evidence-Based Performance Improvement: Published clinical evidence demonstrates efficacy for performance and/or recovery.
- Taste: Distinct and bitter but palatable, even before extreme exercise.
Acetoacetate Diester
- Sub-Optimal BHB: Mildly raises D-BHB (~1 mM).29
- Side Effects: In current formulation, many report GI symptoms.29
- Performance Effect Unclear: No improvement in performance seen in a clinical trial, but this is likely related to GI symptoms, or sub-optimal BHB levels, not to ketosis itself.29
Overview of Clinical Research
Contrary to what you might think, ketone esters aren’t a recent discovery. The first ketone ester was developed in the late 1970’s (a glycerol and acetoacetate ester)30 and other types of ester were developed in the mid-1990’s (RS-1,3-butanediol-acetoacetate mono- and di-esters).4
Currently, two different ketone esters are under active investigation in rodents and humans.
One ketone ester compound was developed at the University of South Florida. This is an acetoacetate diester, made up of two molecules of acetoacetate bound to one molecule of D/L-butanediol (See Figure 2B).
In rodents, the acetoacetate diester raises blood D-BHB to 1 – 4 mM and blood AcAc to up to 5 mM.31 There is one published study of this ketone ester in humans, with results showing a 2% decrease in 31km cycling time trial performance.29 This is likely due to the high rate of side effects of this ester studied. Other factors may have included low levels of BHB (<2 mM), the short high-intensity time trial used, or the use of AcAc vs. BHB.32
Figure 2: Structural formula of BHB monoester and AcAc diester compounds.
The other ketone ester, the BHB-monoester, was invented by a DARPA program to enhance US soldier endurance and performance. A research group at the University of Oxford and NIH received funding from the US Military to develop R-1,3-butanediol-R-3-hydroxybutyrate (BD-BHB, See Figure 2A).
This is the ketone ester in HVMN Ketone.
When taken as a drink, the ester bonds are broken by gut esterase enzymes, releasing butanediol and D-BHB into the blood. Butanediol (which is approved by the FDA as a food) is an alcohol that is structurally similar to BHB, which is metabolized by the liver to form D-BHB. Both molecules of D-BHB reach the circulation, as the liver is unable to use ketones. Consumption of this ketone ester reliably and safely elevates blood ketone levels in humans with few GI and systemic side effects.24
This ester has been approved by the FDA for use as food, and cleared for use in athletes by the World Anti Doping Agency. HVMN Ketone is batch tested as part of the NSF ‘safe for sport’ program. There are seven published human studies, in which 128 people have shown:
- Safe, Tolerable, Side Effect Free: The D-BHB ester has repeatedly been shown to be safe and well tolerated at several escalating doses. Even at high doses, there are minimal side effects.24
- Optimal BHB: D-BHB ester raises BHB levels higher than ketone salts and works even when taken with a carbohydrate-rich meal.9 The D-BHB ester can reliably raise blood ketones in a dose-dependent way.25 If you take more, you get higher blood BHB.
- Greater Endurance: D-BHB ester improved endurance performance in a 30-minute cycling test by 2-3% (400m) when taken before exercise with carbohydrate. 26
- Muscle Replenishing: When taken after exercise along with IV glucose, D-BHB ketone ester improved the resynthesis of the storage form of carbohydrate, glycogen.27
- Muscle Building: When taken after exercise with carbs and protein, the D-BHB ketone ester strongly activated cellular pathways controlling muscle protein synthesis.28
- Appetite Suppression: D-BHB ketone ester decreases appetite and also the levels of the hunger hormone, ghrelin.33
- Lowers Blood Glucose: D-BHB ketone ester lowers blood glucose response to an oral glucose tolerance test.34
- Additional Health Benefits: In a case study of one patient with Alzheimer’s Disease, daily D-BHB ketone ester consumption improved cognitive impairment.35
Choosing the Best Ketone Supplement
Advice for Athletes
It can be confusing to pick which ketone supplement suits your needs, especially if you’re an athlete. There are a few extra things to consider.
Elite athletes must take extra precautions with sports foods (e.g., energy bars and drinks) and supplements (e.g., caffeine, creatine) to ensure they don’t violate anti-doping rules.
First, the specific compound itself must not be prohibited by the World Anti Doping Agency (WADA). Then, an independent laboratory must test each batch of the food/supplement to confirm no contamination with a banned substance. This is important because 44% of failed drugs tests in the UK in 2012 were caused by contaminated supplements. In the US, the major independent testing laboratory is NSF Safe for Sport. (Informed Sport also offers testing, and is more popular outside the US).
Ketone supplements are not currently banned by WADA, although as far as we are aware, the only ketone product to have been explicitly cleared by WADA is the BHB monoester in HVMN Ketone. Some of the commercially available ketone salts are tested by Informed Sport, and HVMN Ketone is tested by NSF Safe for Sport. Current customers include elements within the US Special Operations Command, Grand Tour Cycling teams competing in the Tour de France, NFL teams, World Tour Tennis players, professional triathletes, USA Olympic hopefuls and more.
General Advice
If you’re not a competing athlete, questions should circle around performance, quality and experience. When considering ketone supplements, ask yourself:
- How high do you want blood ketones levels and thus, the resulting level of ketosis?
- Is this a high-quality supplement that’s free of impurities? What other ingredients are added (e.g., sugar, MCT powder or caffeine)?
- What is the overall experience you desire (price, taste, tolerability or side effects, etc.)?
Exogenous ketones, like HVMN Ketone, are a new and exciting dietary tool.
They may give you some of the benefits of ketosis without needing to make big lifestyle changes, such as following a restrictive ketogenic diet or fasting to trigger ketone production.
Of course, for optimal health and performance, you should always aim to eat a healthy and balanced diet. Contrary to some press, even diligent dieting and use of ketone supplements can quickly be undone by a weekend of pizza and doughnuts.
