Again, there are very interesting animal studies plus some single case reports and small uncontrolled trials of humans with neurodegenerative disease and cancer given ketogenic diets and/or exogenous ketones (Murray 2016, Poff 2015, Roberts 2017, Newport 2015, Cunnane 2016). In some cases where the patient does not have the cognitive resources to comply with a well-formulated ketogenic diet, or where target blood levels of BOHB that work in animals are hard to achieve in humans by diet alone, supplemental ketones may have an important role to play in the prevention, management, or reversal of these disease categories.
There are three types of ketones produced when you’re on ketogenic diet: acetoacetate, beta-hydroxybutyrate (BHB), and acetone. The kinds that you’ll find in your supplements are BHB because your body can readily use and absorb them. This means that not all ketones are created equal and there are several different types, each with unique properties that are worth considering when shopping.
I had the chance to interview Dr. Ryan Lowery, Ph.D. about this in person. He performs some (not peer-reviewed) research on different brands of ketone salts and is listed as one of the “specialists” on Prüvit’s website. He suggested that we had perhaps ran the tests too long after the supplements were taken, stating that blood ketones tend to peak at 30 minutes. This is, however, not what Prüvit themselves state in their article on the 59-minute test, or the promise to reach ketosis in 60 minutes on the Kegenix Prime packaging. Plus, do you really want to spend up to $390/month on a product that gives you the benefits of ketosis for half an hour?
But there have also been studies done showing that the Inuit Eskimo’s do not actually reach a state of ketosis. This is due to numerous factors. One being that the diet the eskimo’s eat ‘would not be expected to cause ketosis, because the calculated anti-ketogenic effect of the large protein ingestion was somewhat more than enough to offset the ketogenic effect of fat plus protein.”
Keto-adaption is a complex set of metabolic processes in which the body shifts from using primarily glucose for energy to using largely ketones and fat for energy. Achieving ketosis doesn’t mean the body is maximizing the use of these ketones; it takes longer than a few days for the body to get used to burning fat and ketones as its predominant fuels.
It was like getting the benefits of a five-day fast in just 15 minutes! As my body and brain began sucking up the ketones, I felt a rush of energy and my mind became very sharp and focused in ways beyond what I attain doing an extended fast. But in this case it was the 40g of ketones I had just consumed. Even at the two-hour mark, when I took my last reading, I was still in deep ketosis.
Yes — you read that correctly — 24 hours of intermittent fasting without any resistance training and these subjects were able to preserve more muscle mass than the subjects that ate fewer calories every day without fasting at all. This finding contradicts our common sense, but when we dig deeper into autophagy we can find the mechanism behind this result.
While ketone salts are widely available, unfortunately in the near-term ketone esters are in short supply and the only people who will be able to afford taking them several times per day will be elite athletes, the military, corporate CEO-types, and professional poker players. Even with economies of scale and ramping up production, the cost of raw materials to produce pure ketone esters will keep their price tag prohibitively high for most people, but could realistically get down to a few dollars per gram.
The effects of ketone drinks on endogenous insulin secretion are unclear. Whilst the small increase in plasma insulin after KE and KS drinks may have been due to the small quantity of dextrose in the diluent, it has been proposed that ketones could potentiate or even stimulate insulin secretion. Isolated pancreatic islets secreted insulin when stimulated by ketones at glucose concentrations of >5 mM (Biden and Taylor, 1983), and small amounts of insulin are secreted in vivo following exposure to exogenous ketones in animals (Madison et al., 1964; Miles et al., 1981). In response to an intra-venous 10 mM glucose clamp, ketone ester drinks increased glucose uptake and plasma insulin (Holdsworth et al., 2017). The increases in insulin with ketone drinks taken whilst fasted were small compared to the increases seen when the ketone ester drink was consumed with a meal and with consumption of a dextrose drink. Furthermore, the lack of difference in peak plasma insulin between the two latter conditions indicates that nutritional ketosis did not inhibit or increase normal carbohydrate induced insulin production.
To answer that question, we're going to break down the methods that can get you the results you want in the least possible time. We're going to let you in on a couple of tips and tricks that you will need to know before trying out the diet yourself. We guarantee you that these tips will help you achieve success in your chosen diet quickly and easily.
Ketostix are very unreliable. There are many factors which can alter results such as hydration level, if you’ve worked out recently and the amount of unused ketones in your body to name just a few. Never rely of Ketostix to determine whether you are in ketosis or not. The Precision Xtra blood ketone monitor is the gold standard for testing for ketones in your body. After following a ketogenic diet for a while, you should be able to tell if you are in ketosis or not by the way you feel.
Taking exogenous ketones not only eliminates the need to follow a strict ketogenic diet to achieve ketosis (so you can have your high carb cake and eat it too), it can also help users get there faster. “They can expedite the process of getting into ketosis and becoming fat adapted,” Davis explains. “They can also help people push past the keto flu and potentially experience more mental energy and clarity than from diet alone.”
Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3–4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3–1.4 moles.min.
As seen in this exercise, glucose tends to fall quite precipitously following exogenous ketone ingestions. Without exception, every time I ingested these compounds (which I’ve probably done a total of 25 to 30 times), my glucose would fall, sometimes as low as 3 mM (just below 60 mg/dL). Despite this, I never felt symptomatic from hypoglycemia. Richard Veech (NIH) one of the pioneers of exogenous ketones, has suggested this phenomenon is the result of the ketones activating pyruvate dehydogenase (PDH), which enhances insulin-mediated glucose uptake. (At some point I will also write a post on Alzheimer’s disease, which almost always involves sluggish PDH activity —in animal models acute bolus of insulin transiently improves symptoms and administration of exogenous ketones does the same, even without glucose.)
Next, BHB salts are the only supplement that elevates BHB levels while muscle glycogen remains at capacity (low muscle glycogen can drastically impede long-duration athletic performance). In short, athletes who consume carb-based diets, and those on low-carb diets, stand to benefit from exogenous ketone supplements taken prior to training/exercise.
Intellectual property covering uses of dietary ketone and ketone ester supplementation is owned by BTG Ltd., the University of Oxford, the National Institute of Health and TΔS Ltd. Should royalties ever accrue from these patents, KC and PC, as inventors, will receive a share of the royalties under the terms prescribed by the University of Oxford. KC is a director of TΔS Ltd., a company spun out of the University of Oxford to develop and commercialize products based on the science of ketone bodies in human nutrition. At the time of data collection and manuscript preparation, BS was an employee of TΔS Ltd., funded by the Royal Commission for the Exhibition of 1851. SH is an employee of NTT DOCOMO, Inc. (Japan). The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
For whatever reason, many patients won’t attempt a ketogenic diet—even if the evidence is clear that it could help. Doctors are often hesitant to recommend dramatic dietary shifts—even if they believe in their efficacy—to patients who are already dealing with difficult health issues. If you’ve got a picky kid with epilepsy, a pickier adult with Alzheimer’s, or a cancer patient who refuses to give up the familiar-yet-non-ketogenic foods that give him some small manner of comfort in this trying ordeal, exogenous ketones could make a big difference.
At the same time, research suggests that getting as much of your calcium from your diet, rather than supplements is a good idea. For instance, there is some evidence that the calcium intake from food is better for bone mineral density than the same calcium intake from supplements. Foods that are high in calcium include dairy, leafy green vegetables, fish with edible bones, tofu made with calcium sulfate, and calcium-fortified foods and beverages.
More tolerable than MCT oil: MCT oil has been known to cause gastrointestinal distress in users, especially when taken in higher amounts. Exogenous ketones in the form of ketone salts, in comparison, are well-tolerated. Thus they enable one to avoid adverse GI events while providing the body with similar types of benefits. Figure 2 shows Ketone esters can be effective at reducing appetite. A combination of MCT oil and exogenous ketones may aid weight loss and allow a lower loading of ketone supplements, without the GI distress seen with MCT oil.
Before the Nobel Prize was awarded to Yoshinori Ohsumi, other researchers were making groundbreaking discoveries about autophagy. In 2009, an article was published in Cell Metabolism entitled Autophagy Is Required to Maintain Muscle Mass. In this article, researchers described how deactivating an important autophagy gene resulted in a profound loss in muscle mass and strength.
After a minimal amount of internet "research," I decided to try my first exogenous ketones. I have used the ketogenic diet off and on for at 15 years and my body is pretty efficient at fat adapting. (Usually by the end of 2 strict days, I am in ketosis, but not without symptoms and intense cravings.) I can consistently fast from carbs for 20 - 24 hours and do this consistently. However, around hour 20, my mind begins to negotiate that intermittent fasting is advantageous too and that I can afford to have some carbs once a day. Hence the yo-yo effect.
If you are trying to lose weight, following a ketogenic diet can help you burn fat fast. However, trying to get into ketosis can be a frustrating experience. Am I eating too many carbs, not enough fat, too much protein? Getting into ketosis usually takes 3 to 5 days at least, and can take people up to two weeks. Recently I have discovered a simple and easy way to get into ketosis very quickly. I went from eating lots of carbs one night, to in ketosis 24 hours later.
KE was synthesized as previously described . BMS is a novel agent (sodium/potassium- βHB mineral salt) supplied as a 50 % solution containing approximately 375 mg/g of pure βHB and 125 mg/g of sodium/potassium. Both KE and BMS were developed and synthesized in collaboration with Savind Inc. Pharmaceutical grade MCT oil (~65 % caprylic triglyceride; 45 % capric triglyceride) was purchased from Now Foods (Bloomingdale, IL). BMS was formulated in a 1:1 ratio with MCT at the University of South Florida (USF), yielding a final mixture of 25 % water, 25 % pure βHB mineral salt and 50 % MCT. BD was purchased from Sigma-Aldrich (Prod # B84785, Milwaukee, WI).
I came across a new company called KetoneAid that has begun producing small batches of ketone monoesters (KMEs). The main molecule in their product (D-β-hydroxybutyrate / D 1,3-butanediol) is based on a five-year, $10M study commissioned by the Defense Advanced Research Projects Agency (DARPA), looking to create the most powerful source of energy for special operations soldiers such as Navy SEALs, when undertaking very physically and cognitively challenging missions. In fact, the main researcher of the DARPA study is Dr. Richard Veech, the same person that authored the longevity study I just mentioned. Very cool.
Let me introduce myself. My name is Mark Sisson. I’m 63 years young. I live and work in Malibu, California. In a past life I was a professional marathoner and triathlete. Now my life goal is to help 100 million people get healthy. I started this blog in 2006 to empower people to take full responsibility for their own health and enjoyment of life by investigating, discussing, and critically rethinking everything we’ve assumed to be true about health and wellness...
Exogenous ketones (also known as ketone supplements) and well-formulated ketogenic diets share at least one thing in common. They both result in increased circulating concentrations of beta-hydroxybutyrate (BOHB), but ultimately are associated with very different patterns of ketosis, as well as differing metabolic and physiologic outcomes. In short, they should not be assumed to have equivalent effects simply because they achieve similar BOHB blood levels. Having said that, there are many reasons we should continue to study the various forms and potential applications of ketone supplements.
Plenty of supplements make you a fractionally better sportsman and these are no different. The synthetic exogenous ketones helped Olympic-caliber cyclists cover an average of 411 additional meters during a 30-minute time-trial, which resulted in a two percent increase in overall speed, found a paper in Cell Metabolism. That can be the difference between feeling the glorious tug of the winner’s ribbon across your chest or rolling in with the stragglers.
If the goal is to deplete glucose levels so that we can start producing ketone bodies, then forcibly exerting physical energy through exercise is a great way to go about it. Keeping it relatively low intensity to begin with and working out in the morning is recommended as this helps to keep down your cortisol (stress hormone) levels. This only applies at the beginning of your keto adaptation process, as intense workouts such as HIIT once already keto-adapted will be completely fine.
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”.
Do I still follow a ketogenic diet? Not anymore. I was strict keto for 12 weeks – enough time to experiment and learn about it. I did enjoy parts (lots of fat!) but I don’t see it as a sustainable way of eating, nor did I benefit from it health or sports performance wise (more on this in an upcoming article). But, I was following a strict keto diet – sans carbs. I think if I were to follow a ketogenic diet AND incorporate a regular carb refeed then the results may be different.
Currently, we lack enough evidence to change the recommendations for calcium intake. The Tolerable Upper Intake Level (UL) for adults 19-50 years old is 2500 mg. This is well over the RDA of 1000 mg for the same age group. Calcium supplements commonly contain 600-1200 mg. When assessing your own calcium intake, keep in mind that calcium from food sources and calcium from supplements may have different outcomes.
If you’re somebody who isn’t already a keto-goer, then you might be wondering why? Why do I need to limit my carbohydrate intake to get my body into a state of ketosis? Simply put, and without getting to technical; you want your body to be in a constant state where fat is the is the primary source of fuel for the body rather than glucose. You see, once you eat carbs, the body will break this down into glucose which it will then use for fuel before tapping into your fat reserves for energy. If you limit the amount of glucose that is in your system by restricting your carbohydrate intake, the body has no choice but to tap into your fat stores for energy. Fats are metabolised in the liver where ketones are then produced for your physical and cognitive needs.
Look around your grocery store, and you’ll soon start to see “Fortified with Calcium” on a variety of different labels, along with calcium supplements everywhere you look. Calcium is essential for cardiovascular health, but several studies have found too much calcium to be associated with cardiovascular events and even death. One study found that consumption of 1000+ mg of supplemental calcium per day was associated with an increased risk of death from cardiovascular disease in men but not women. Dietary calcium intake (i.e., calcium from incorporated foods such as milk, etc.), on the other hand, was not associated with death from cardiovascular disease in men or women. Additionally, a different study found 1000 mg of supplemental calcium to be associated with an increase in rates of cardiovascular events in women.
One other thing I must point out is also that we are talking about being in ketosis and not being fully keto adapted. You enter ketosis when your body starts producing ketones above a specified level, being fully keto adapted means that your body is full adapted to use fat as your primary energy source and that the production of certain enzymes in your body is fully adapted. This doesn’t happen in one day and it takes about 1 month on average to be fully keto adapted. But we are not looking for this as we just want to end the most unpleasant period and to start losing weight.
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.
In general, too much caffeine on a regular basis can prevent you from going into ketosis. But since we are trying to get into ketosis in 24 hours I believe it will help you for one day by curbing your hunger and getting through the fast easier. In case, you do not like coffee, you can opt for caffeine drinks or you can opt for other beverages which consist of caffeine in smaller quantities.
The difference in peak blood d-βHB concentrations between matched amounts of βHB as ester or salts arose because the salt contained l-βHB, as the blood concentrations of d- plus l-βHB isoforms were similar for both compounds. It is unclear if kinetic parameters of KE and KS drinks would be similar if matched d-βHB were taken in the drinks. Unlike d-βHB, blood l-βHB remained elevated for at least 8 h following the drink, suggesting an overall lower rate of metabolism of l-βHB as urinary elimination of l-βHB was in proportion to plasma concentration. Despite similar concentrations of total βHB, breath acetone was ~50% lower following KS drinks compared to KE, suggesting fundamental differences in the metabolic fates of D- and L-βHB. These findings support both previous hypotheses (Veech and King, 2016) and experimental work in rats (Webber and Edmond, 1977), which suggested that the l-isoform was less readily oxidized than the d-isoform, and is processed via different pathways, perhaps in different cellular compartments. It seems that l-βHB is not a major oxidative fuel at rest, and may accumulate with repeated KS drinks. However, the putative signaling role of l-βHB in humans remains unclear. In rodent cardiomyocytes, l-βHB acts as a signal that modulates the metabolism of d-βHB and glucose, Tsai et al. (2006) although no differences in blood glucose were seen here. Furthermore, L-βHB can act as a cellular antioxidant, although to a lesser extent than D-βHB (Haces et al., 2008).
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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