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.
However, it's important to NEVER overlook the power of exercise and of course sticking to a proper routine to get the most optimized results. The most common mistake people make is by treating any keto supplement like a "wonder drug" that will help them shred weight in their sleep. Seriously... how is that even scientifically possible. So if you are thinking about trying out a particular supplement, I would suggest two things:
There are many different variations of intermittent fasting as well. Dr. Dom D’Agostino, the well-known ketogenic diet researcher, suggests doing a longer intermittent fast for 3 days, 3 times a year. This means not eating for 3 days, and eating normally until the next fast. Daily intermittent fasts are recommended as well. He says that it is ideal to have one to two meals after fasting for most of the day to reap the benefits of intermittent fasting every day.
Satiety decreased in both cases, slightly less with the supplements than with the placebo: participants reported feeling less hungry after taking the supplements than after taking the placebo. However, we are doubtful whether this would be enough of a difference to impact food intake and therefore induce weight loss indirectly, compared to not taking a supplement at all. Especially since, as noted before, BHB switches off lipolysis.
Exogenously delivered ketone supplements significantly altered rat weight gain for the duration of the study (Fig. 6). However, rats did not lose weight and maintained a healthy range for their age. Rats have been shown to effectively balance their caloric intake to prevent weight loss/gain [97–99]. Due to the caloric density of the exogenous ketone supplements (Table 1) it is possible for the rats to eat less of the standard rodent chow and therefore less carbohydrates while maintaining their caloric intake. Food intake was not measured for this study. However, if there was a significant carbohydrate restriction there would be a signifcant change in basal blood ketone and blood glucose levels. As the hallmark to the KD, carbohydrate restriction increases blood ketone levels and reduces blood glucose levels. Neither an increase in basal blood ketone levels nor a decrease in basal blood glucose levels was observed in this study (Fig. 7). Additionally, if there were an overall blood glucose decrease due to a change in food intake, this would not explain the rapid reduction (within 30 min) in blood glucose correlated with an elevation of blood ketone levels after an intragastric bolus of ketone supplement (Figs. 2, ,33 and and44).
However, with the ketone esters, the effects are nearly immediate, and my entire body was humming throughout the entire day, but not in a jittery way. I was full of mental and physical energy that lasted without any sort of crash (it was a gradual taper). During my cognitive tests, things felt almost effortless as I played the various games. After my experiment was complete I continued writing code for several hours, then went to the gym to work out. I did forget to each lunch though, so there must be some suppressive effect on appetite.
Ketone Bodies are then used by tissues as a source of energy3 through a pathway that leads to formation from β-hydroxybutyrate of two molecules of acetyl CoA, which are used finally in the Krebs cycle. It is interesting to note that the KBs are able to produce more energy compared with glucose because of the metabolic effects of ketosis—the high chemical potential of 3-β-hydroxybutyrate leads to an increase in the ΔG0 of ATP hydrolysis.3
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.
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.
Another important difference between endogenous 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 (Lincoln 1987, Stubbs 2017), and it remains unclear whether humans can convert the L-form to the D-form.
“Consumption of KETO//OS before exercise can result in significant decreases in oxygen demand and increases in performance. We recommend 30 minutes before a workout. Note: Pre-workout use is recommended after building up to a full dose. The best way to maximize energy, appetite control and sustain energy is to take KETO//OS first thing in morning. To maximize benefits, build up to 1 serving 3 times daily – morning, afternoon and early evening. May be used with carbohydrate supplements if desired or by itself as a non-carb, highly efficient energy source.”
The fate of excess ketones: In the event someone has an excessive amount of ketones in the blood, the body (specifically the kidneys) will work as quickly as possible to filter out ketones via urine rather than converting them to adipose tissue.9 This is not to say that you can’t gain fat if you consume an exorbitant amount of exogenous ketones, but that they are less prone to be converted to fat than other nutrients.
If you stop eating carbs, your body first uses up glucose reserves stored in the liver and muscles. After it burns all that's left of glucose, it has no other options but to start burning fat. It can burn either your body's fat stores or the fat you eat. However, not all cells in your body can use fat to make energy and this is where ketones come into play.
An alternative to the ketogenic diet is consumption of drinks containing exogenous dietary ketones, such as ketone esters (KE) and ketone salts (KS). The metabolic effects of KS ingestion have been reported in rats (Ari et al., 2016; Kesl et al., 2016; Caminhotto et al., 2017), in three extremely ill pediatric patients (Plecko et al., 2002; Van Hove et al., 2003; Valayannopoulos et al., 2011) and in cyclists (O'Malley et al., 2017; Rodger et al., 2017). However, the concentrations of blood βHB reached were low (<1 mM) and a high amount of salt, consumed as sodium, potassium and/or calcium βHB, was required to achieve ketosis. Furthermore, dietary KS are often racemic mixtures of the two optical isoforms of βHB, d-βHB, and l-βHB, despite the metabolism of l-βHB being poorly understood (Webber and Edmond, 1977; Scofield et al., 1982; Lincoln et al., 1987; Desrochers et al., 1992). The pharmacokinetics and pharmacodynamics of KS ingestion in healthy humans at rest have not been reported.
I feel like I should also mention that the GI discomfort is real, people. I would recommend starting this product on a weekend or a day where you’re able to just take it easy. After my first dose, which was only 1/2 scoop, I literally just felt like lying in bed all day due to feelings of nauseousness; however, by the next day I was fine and even bumped my dose to a full scoop.
The chart below shows my ketone and glucose response to consuming 40g of KetoneAid’s ketone esters, which had been calculated to be my optimal serving size based on my weight (170lbs) and type of activity (I am moderately active/athletic, but cognitive experiments are a “low” physical activity). Normally, for increased physical performance ketone esters are consumed along with some glucose, but since I was only focusing on cognitive performance I did not consume any glucose.
The effects of the two exogenous ketone drinks on acid-base balance and blood pH were disparate. In solution the ketone salt fully dissociates (giving a total of 3.2–6.4 g of inorganic cation per drink), allowing βHB− to act as a conjugate base, mildly raising blood and urine pH, as seen during salt IV infusions (Balasse and Ooms, 1968; Balasse, 1979). Urinary pH increased with the salts as the kidneys excreted the excess cations. In contrast, KE hydrolysis in the gut provides βHB− with butanediol, which subsequently underwent hepatic metabolism to form the complete keto-acid, thus briefly lowering blood pH to 7.31. Electrolyte shifts were similar for both KE and KS drinks and may have occurred due to βHB− metabolism, causing cellular potassium influx and sodium efflux (Palmer, 2015).
EK use can be compared to the nootropics that have been developed for optimizing focus, memory creation, and faster cognitive performance. While you may not notice this effect on a minute to minute basis if you keep a journal of “forgetful moments” you’ll find that you have fewer of them as time goes on. You’ll also find that you’re able to come up with better ideas, and your workflow is more efficient through the day (10, 11).
Although decreases in FFA, TG and glucose occurred, there were no significant differences between the KE and KS drinks or with intake amount. Ingestion of ketone drinks significantly decreased overall mean plasma FFA from 0.7 to 0.4 mM, TG from 1.1 to 0.9 mM and glucose from 5.7 to 4.8 mM after 1 h (all p < 0.05). Concentrations were the same as at baseline by 4 h, with FFA at 0.6 mM, TG at 0.9 mM and glucose 5.1 mM (Figures 2A–C). There was a rise in insulin concentrations 30 min following all drinks, probably due to the small amount of carbohydrate in the sweetener (Figure (Figure2D2D).
Fasting blood samples were collected prior to all interventions. Following consumption of study drinks (details below), blood, expired gas and urine samples were collected at regular intervals for 4 h. Water was freely permitted and participants remained sedentary at the test facility throughout the visit. A subset of participants returned for samples 8 and 24 h after the ketone drinks (Study 1).
Caveat emptor: the following post doesn’t come close to answering most of these questions. I only document my experience with BHB salts (and a non-commercial version at that), but say little to nothing about my experience with BHB esters or AcAc esters. But it will provide you will some context and understanding about what exogenous ketones are, and what they might do for athletic performance. We’ll likely podcast about the questions and topics above and cover other aspects of exogenous ketones in more detail.
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