Interestingly, the effects of exogenous ketones on blood substrate concentrations were preserved with the metabolic stimulus of a mixed meal. Following KE drinks, FFA and glucose fell and remained low in both fed and fasted subjects, despite higher insulin throughout the fed arm, suggesting that there was no synergistic effect of insulin and βHB to further lower blood glucose or FFA. In agreement with previous work, the threshold for the effects of βHB on glucose and lipids appears to be low (<1 mM), as there was no significant dose-response relationship between increasing blood βHB and the small changes in plasma FFA, TG or glucose across all of the study drinks (Mikkelsen et al., 2015).
Other ingredients: Many of the supplements contain large amounts of caffeine – the supplement we tested from Prüvit contains the same amount as a 16 oz cup of coffee! Some supplements also contain malic acid, which is “known for its ability to increase energy and tolerance to exercise”. This leaves the nagging doubt: if the experiment shows an increase in energy and physical performance, for example, how do we know it is the (expensive) BHB causing the effect and not the (inexpensive) other ingredients?

In terms of epigenetic signaling, initial studies of the effects of BOHB on class-1 histone deacetylase activity against oxidative stress (Schimazu 2013), NLRP3 inflammasome suppression (Youm 2015), mouse longevity (Roberts 2017), and other epigenetic regulatory effects suggest that levels as low as 1 mM have potent effects. Furthermore, the association between very mild ketonemia and reduced coronary mortality with SGLT2 inhibitor use in patients with type 2 diabetes (Ferranini 2016) suggests that there might be clinical benefits with chronic BOHB levels as low as 0.3 mM (Gormsen 2017. Vetter 2017).


The table below shows the same measurements and calculations as the above table, but under the test conditions. You’ll note that BHB is higher at the start and falls more rapidly, as does glucose (for reasons I’ll explain below). HR data are almost identical to the control test, but VO2 and VCO2 are both lower. RQ, however, is slightly higher, implying that the reduction in oxygen consumption was greater than the reduction in carbon dioxide production.
Exogenous ketones drinks are growing in popularity as a method to elevate blood ketone concentrations and mimic a ketogenic diet without the need for dietary changes (Ari et al., 2016; Cox et al., 2016; Kesl et al., 2016; Caminhotto et al., 2017; Evans et al., 2017). The present study describes the pharmacokinetic and pharmacodynamics properties of ketone ester and salt drinks in humans at rest, and characterizes the effects of a prior meal, which is pertinent to use as a dietary supplement. The main findings were that KE drinks elevated blood d-βHB > 50% higher than KS drinks, the latter significantly increasing blood l-βHB, which was metabolized more slowly by the body. Both drinks had similar effects on FFA, TG, glucose and electrolyte concentrations, although with disparate effects on pH. A prior meal decreased total blood d-βHB appearance after a KE drink. Finally, either three KE drinks or nasogastric feeding effectively maintained nutritional ketosis over 1 mM for 9 h.
Ketosis is a metabolic state where most of the body’s energy supply comes from ketone bodies in the blood, in contrast to a state of glycolysis where blood glucose provides most of the energy. Ketosis is characterised by serum blood concentrations of ketone bodies over 0.5 millimolar with low and stable levels of insulin and blood glucose. However, with ketone supplementation (as you’ll learn about later in this article) ketosis can actually be induced even when there are high levels of blood glucose
Participants refrained from alcohol and caffeine for 24 h prior to each visit AND were asked to consume a similar meal the night before each visit. All studies were carried out at the University of Oxford Human Physiology Laboratories and started at 0800 h following an overnight (>8 h) fast, with a minimum of 72 h between visits. Visit order was randomized prior to commencement by an administrative investigator using a pseudo-random number generator to produce a list of combinations of visit order, which were then allocated based on order of enrolment by a different investigator.
Intermittent fasting is using the same reasoning – instead of using the fats we are eating to gain energy, we are using our stored fat. That being said, you might think it’s great – you can just fast and lose more weight. You have to take into account that later on, you will need to eat extra fat in order to hit your daily macros (the most important thing). If you’re overeating on fats here, you will store the excess.

Most of the information regarding the effects of ketosis come from studies on the ketogenic diet, wherein ketones are made by the liver and become a major fuel source for the body. The ketogenic diet is currently under investigation for its potential therapeutic effects in a number of healthy and disease states. More recently, studies are beginning to reveal that many of the effects observed with the ketogenic diet are mechanistically attributable to ketones, which is a primary reason that exogenous ketones are being developed and studied. However, because they are such a new technology, there’s not a lot of data on exogenous ketones themselves. In a few pre-clinical studies, exogenous ketones have mimicked the therapeutic effects of the ketogenic diet”
If the claims about the benefits of exogenous ketones are accurate and true, then it’s fantastic news for people who are looking to enhance their keto lifestyle and who have the money to spend. But two of our core values are trustworthiness and goodness, and it is important to us to test assumptions made by marketing claims and help make sure that people are getting what they are told they are getting when they spend money on a product.
Fortunately, you don’t need to be a dietary math savant to cash in on these rewards because the supplement eggheads took the liberty of creating exogenous ketones, which act as direct substitutes to the ones your body creates. Unlike other fat burners that give you the skits jitters, these are actually helping exercisers reach new personal bests while getting leaner, and are totally legal. Here’s what you need to know to get a slice of the action safely.
Compared to our other cellular gasoline (carbs), we can store an unlimited supply of energy from ketones in our body within our fat. When you’re reliant on carbohydrates, you’re forced to keep your tank partly full as we can only store just over 2,000 calories of glycogen from carbs. An empty carb tank results in carb-withdrawal symptoms from not being able to switch into a ketone or fat burning metabolism.
The liver is always producing ketones to some small degree and they are always present in the bloodstream. Under normal dietary conditions, ketone concentrations are simply too low to be of any significant benefit. A ketogenic diet and exogenous ketone supplements will increase the amount of ketone in your body. The idea that ketones are “toxic” is ridiculous. Ketones are a normal physiological substance that play many important roles in the human body.
Blood, urine, plasma, and breath ketone concentrations following mole-matched ketone ester or isocaloric dextrose drinks in fed and fasted subjects (n = 16) at rest. Data from both of the two study visits in each condition (fed and fasted) completed by an individual are included in the analysis. Values are means ± SEM. (A) Blood d-βHB. (B) AUC of blood d-βHB. (C) Urine d-βHB excretion. (D) Plasma acetoacetate (AcAc). (E) Measured breath acetone (ppm = parts per million). (F,G) Mean d-βHB Cmax and difference between βHB Cmax over two visits when subjects separately consumed two ketone ester drinks in both the fed (F) and fasted (G) state. X axis = mean d-βHB Cmax of the 2 visits (mM), Y axis = difference between d-βHB Cmax in each visit. 95% confidence limits are shown as dotted lines. Significance denoted by: *p < 0.05 fed vs. fasted.
How BHB turns into energy is a fairly simple process. As we’ve mentioned, beta hydroxybutryate eventually leads to energy production after you consume it or after your body breaks stored body fat down. It does this by going into the cell, entering the mitochondria (energy factories) at which stage it cleaves the carboxyl acid group and becomes acetoacetate (another “ketone body”). Acetoacetate turns into acetoacetyl-CoA, which then is cleaved to acetone (another “ketone body”) and acetyl-CoA. Acetyl-CoA is the whole reason we want BHB in the first place. This jumps into what is called the Kreb’s cycle (don’t you remember any of your biochemistry classes?) and is churned into ATP — the energy currency of your cells!
Keep these studies in mind as your body tries to play tricks on you during your first day of fasting.  Even after three days of fasting, health complications are highly unlikely. However, it is important to know about the possible issues that can be caused by fasting. If you choose to incorporate fasting into your daily diet, you typically want to eat every day as well. Occasionally going on a longer period of fasting.
Hi, I still a little confused about when or how to take this. I am trying to get adapted and minimize the flu. Is it most beneficial before eating, after eating, with food or in place of food? I have been keto in the past but this time I am not switching over to fat burning mode even though my macros are good. ( I am thinking it is just too many calories and carbs at this point but I get hungry!) Help please.

Full disclosure: after carrying out the background research, I was already, as you might imagine, feeling a little less neutral about these products. You may have noticed a hint of that in part 1 of the 2-part video series we made about the project (watch part 2 at the top of this page!). However, and although this was by no means a controlled scientific study under laboratory conditions, we designed the experiment in a very objective way. The aim was to give the supplements the best possible chance of showing the benefits they are claimed to have.

The “BHB salt” is simply a compound that consists of sodium (Na+), potassium (K+), and the ketone body β-hydroxybutyrate. In supplements like Pruvit’s Keto OS these individual components are being held together by ionic bonds; however, when you consume the product, it is absorbed into the blood where it dissociates into free Na+, K+, and BHB since it is a water-based solution. Thus, consuming the product directly and immediately puts more ketones into your blood.

As KE drinks achieved a significantly higher d-βHB concentrations than KS, we investigated factors that may be important in the use of ketone drinks to achieve nutritional ketosis. Initially we determined the repeatability of blood ketosis following KE drinks and found little variation in kinetic parameters between individuals. Variability between participants was less than within the population, and accurate individual prediction of the d-βHB Cmax following a body-weight adjusted KE drink was achieved. Variability within individuals was likely due to normal daily changes in GI function, including gastric emptying, portal blood flow or intestinal transit time, which may alter KE hydrolysis and absorption.
It might sound absolutely crazy to go that long without food. Especially when you consider traditional diets that recommend eating 3-5 small meals each day, starting with breakfast – the “most important” meal of the day. But if you think back to hunter gatherer times, human beings didn’t always have food accessible to us. Farming and agriculture hadn’t existed so our first meal each day would vary quite vastly. If you think about the word itself, ‘breakfast’ means to break-fast. We didn’t have a set time where we would consume our first meal – it was dependent on accessibility. So if you’re wondering how you’re going to survive without going for food for 16 hours, the answer is straight forward – you can! Let’s simplify this and break down what this may potentially look like.
Meanwhile Brinkworth, et al., in their 2009 paper "Long-term Effects of a Very Low-Carbohydrate Diet and a Low-Fat Diet on Mood and Cognitive Function" looked at the effects on ketogenic diet on cognitive function and mood. The study participants ate a ketogenic diet for a year and the researchers found that mood levels decreased when compared to a group eating a high carb/low fat diet. They go on to remark “there was no evidence that the dietary macronutrient composition of LC and LF diets affected cognitive functioning over the long term, as changes in cognitive function were similar for both diets”.

That’s not to say that the supplements don’t work. They very well might. But they could also be useless—or even dangerous, says Christine Palumbo, RDN, Nominating Committee member for the Academy of Nutrition and Dietetics. As of right now, there’s no way to know. “Currently, there’s just not enough evidence from research studies to answer those questions,” Barnes adds.


Hi Mark, sorry this is off topic but not sure where to send a question for a future Ask Mark. I’m about to go into my yearly physical and I am wondering if there is any specific bloodwork that you like to do for your annual check up. I’m 47 year’s old and the than the basic blood work like lipid panel, etc..I’m going to ask my doctor to test my testosterone, HbA1C, fasting insulin, and Vitamin D levels. I’m also going to ask my doctor to do a stool test to check for parasites or other infections I may have picked up from open water swimming for triathlons. Can you recommend any other blood work that might be useful? Thanks!
There are several ways to approach the “intermittent” part of food restriction. One of the most common is limiting the window in which food is consumed to about eight hours a day. Another is fasting for a full 24 hours once a week, or once a month. Fasting beyond three days can be stressful on the body and should be done with medical advice and supervision.
Ketosis supplements made in poor quality have proven to lead to side-effects such as constipation and increased levels of cholesterol and triglycerides in men. Women may also experience amenorrhea or other disruptions to the menstrual cycle. This is why it is essential to know what combination of compounds you are consuming while you are on this very strict diet. The wrong balance can mess with you in the long term and won't give you the results that you are looking for.
Not everything is perfect with Ketōnd, so there are a few things you should know. One is that it is extremely powerful. The company is pretty adamant about taking the correct dosage - and they are right. This isn't your typical ketone supplement. I'd recommend starting off at half a scoop, even if you are used to taking a different ketone supplement. Odds are if you have your product was underdosed. So, it’s kind of a pain to remember all the time, but once you feel good with the half serving then you can work your way up to a full scoop. If you think it is too strong for you – just take one serving a day, not two, and you will be okay.
If you do the same calculations as I did above for estimating fat oxidation, you’ll see that EE in this case was approximately 13.92 kcal/min, while fat oxidation was only 67% of this, or 9.28 kcal/min, or 1.03 g/min. So, for this second effort (the test set) my body did about 5% less mechanical work, while oxidizing about 25% less of my own fat. The majority of this difference, I assume, is from the utilization of the exogenous BHB, and not glucose (again, I will address below what I think is happening with glucose levels).

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