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Peer-reviewed | Manuscript received: March 23, 2018 | Revision accepted: July 23, 2018

Dietary supplements based on the body β-hydroxybutyrate Market analysis and evaluation of ingredients of supplements used in the USA

Tobias Fischer, Thorsten Marquardt

In more recent years, there has Abstract been a continuous growth in low- The use of β-hydroxybutyrate (βHB) as a supplement to the everyday diet is a carb diets. The health merits of new development in the lifestyle supplement market. In the USA, the market is various versions of the diet with growing and the composition of the products varies greatly. The supplements different fat, protein, and carbo- are mainly postulated to be useful for providing energy, for weight loss, for in- hydrate contents are the subject of creasing athletic performance, improving mental performance, and increasing much discussion. Some versions the level of in the blood. Using βHB supplements in the form of are diets that closely correspond a salt has the unfavorable effect of increasing intake of sodium, potassium, cal- to a and contain less cium, and magnesium. Depending on the salt composition used, it is possible than 50 g of per day for these supplements to cause the reference values to be exceeded by up to five (very low-carb, high-fat – VLCHF) times. Based on the currently available research, side effects cannot be ruled out. [4, 5]. In the U.S. News Diet Rank- The available research currently supports the appetite-reducing effect of ketone ings, the Atkins, Eco-Atkins and bodies. Further research is required to confirm their effectiveness with regard to Keto diets were shortlisted by 24 the other publicized areas of application, such as targeted fat loss, weight loss, experts for the categories of best and increased performance (cognitive and physiological). However, exogenous overall diet, best for weight loss, intake of ketone bodies could be advantageous in the clinical field, for example and best for rapid weight loss. The in supporting a medically necessary ketogenic diet and making it easier to follow. rating was generally better for the Atkins-based diets. In the category Keywords: β-hydroxybutyrate, ketone bodies, supplements, market analysis, ketogenic diet for rapid weight loss, the ketogenic diet (kD) even came 13th. On the other hand, the kD only achieved 39th place in the overall assess- ment [6–8].

Introduction In stark contrast to this trend, the kD is highly relevant in the field of The original founder of the low- nutritional therapy. The positive carb diet is William Banting, who effects of the traditional kD were published his “Letter on Corpu- described in epilepsy patients as lence, Addressed to the Public” in early as 1921, and it is still prac- 1865. In this letter, he criticized ticed in a similar form today [9, Citation: the increasing obesity of the pop- 10]. In addition to drug-resistant Fischer T, Marquardt T (2018) ulation. In his view, the cause was epilepsy, the classic indications for Dietary supplements based on certain foods such as bread, butter, the kD also include some rare met- the ketone body β-hydroxy- milk, potatoes, sugar, and beer. abolic diseases such as pyruvate butyrate. Market analysis and The resulting meat-, fish-, and al- dehydrogenase (PDH) deficiency evaluation of ingredients of cohol-heavy diet bears little resem- and GLUT1 deficiency. Its use in supplements used in the USA. blance to modern habits [1]. In the other metabolic diseases such as Ernahrungs Umschau 65(12): 1970s, Dr. Atkins’ book launched glycogenosis (Type III, V, and VII) 204–212 a new trend in low-carb, high-fat and complex 1 mitochondrial res- This article is available online: diets (LCHF or HFLC) [2]. The first piratory chain deficiency is also a DOI: 10.4455/eu.2018.048 two books sold 12 million copies current subject of discussion [11, and achieved cult status [3]. 12].

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The kD is based on the formation fits described were the supporting The following article will provide of ketone bodies from acetyl-CoA, and compliance-increasing effects an overview of the ketone body which is formed by the breakdown of concomitant treatment with supplements based on βHB salts of fatty acids. In this context, ke- exogenous ketone body products available on the US market, and tone bodies means acetoacetate while on a ketogenic diet [26]. In will then weigh up the risks and (AcAc), β-hydroxybutyrate (βHB), recent years, several publications benefits. At present, no such eval- and , although acetone does on ketone body salts have been uation is available – none that can not play a significant role in terms published in the wellness and life- provide an overview of the market of providing energy [13, 14]. style sector. In these publications, situation, its development, and the There are three ways to trigger the main focus is on sports ap- extent of the current “keto trend”. – meaning an increase in plications and the health benefits the level of ketone bodies in the of opting for a ketogenic diet or blood. These are fasting (hunger), choosing to supplement with ke- Methodology exercise, or a very high-fat diet tone bodies themselves [28–30]. with simultaneous reduction of It should be noted here that a ke- To compile the dataset, the largest carbohydrate intake [15–17]. In totic metabolic state was a normal online mail order company, Ama- all three cases, the deficit condition for the vast majority of zon.com, was searched for prod- and the stimulation of lipolysis human history (“movement guar- ucts falling under the keywords trigger the production of an al- anteed, food intake uncertain”), “hydroxybutyrate” and “beta hy- ternative source of energy, which and it only began to disappear over droxybutyrate”. All of the products is particularly important for the the last 200 years due to increas- displayed that belonged to the cat- brain. This alternative source of ing sugar consumption, higher en- egory of foodstuffs in the broadest energy is the ketone bodies, and ergy intake and changes in lifestyle sense were viewed and listed. The especially βHB , which is the most (“movement uncertain, food intake data collection period was four abundant among them [18]. In guaranteed”) [31, 32]. The use of weeks and ended on 20 February order to significantly increase the ketone bodies as nutritional sup- 2018. In order to ensure that the level of ketone bodies in the blood plements is a new and interesting data was entered correctly, data (> 2 mmol/L), 60–90% of daily development on the global market. entry was done by two people. In energy intake (E%; Low Glycemic the case of several pack sizes, the Index Treatment [LGIT] vs. clas- Increasing general and scientific medium-sized pack was listed. Dif- sic kD 4:1) need to come from fat interest in the kD has led to new ferent flavors or formulations with [19]. Generally, it is assumed that areas of application being opened different ingredients (e.g. with or in adults, a carbohydrate intake of up. In addition to the classic appli- without caffeine) were entered into over 50 g per day will not produce cations of weight loss and perfor- the dataset as separate products. ketosis, or will only do so to a very mance enhancement, there is also The following information was limited extent [20]. The fact that much discussion about positive ef- gathered and used for the evalu- this diet is so different from a nor- fects when used in cancer or neu- ation: the product name, manu- mal balanced diet leads to problems rodegenerative diseases (dementia, facturer, quantity, price, serving with compliance, which in turn Alzheimer’s, etc.) [33]. In terms of size, ingredients (macro and mi- leads to treatment discontinuation trend diets using ketone bodies or cronutrients, βHB), additives, other [21, 22]. the kD, the appetite-reducing effect ingredients (sweeteners, plant ex- is one of the most commonly cited tracts, etc.), consumer ratings and Back in the 1980s, exogenous in- advantages [34]. the main advertising statements. take of ketone bodies had already For the statistical calculation, de- caught the attention of the field The kD appears to have great mar- scriptive statistical methods (mean of sports medicine [23, 24]. Later ket potential. At present, there is value, median, standard deviation) on, possible medical applications no data on the size of the market were carried out using the pro- started to be discussed and com- for the kD and related products. grams Microsoft Excel 2016 and passionate use treatments were Alongside the supplements men- IBM SPSS Statistics 24. For nomi- carried out using sodium βHB in tioned above, during the kD, it is nal data, such as advertising state- various rare metabolic diseases, also possible to self-track by meas- ments, the number of them was such as Multiple Acyl-CoA-De- uring general vital parameters, determined and compared with the hydrogenase Deficiency (MADD), blood values (βHB, glucose), and total quantity of products. PDH deficiency, and hyperinsu- the concentration of acetone in the linism [25–27]. Among the bene- exhaled air [35, 36].

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N = 86 Price ($) Price per portion ($) Pack size (g) Portion size (g) Portions per day Mean 50.24 2.99 316.7 17.3 2.8 Median 49.95 2.80 240.0 15.0 3.0 SD 23.12 1.52 154.8 7.2 0.4 Min.–Max. 12.95–154.97 0.40–9.96 57.3–825.0 1.0–59.0 2.0–3.0

Tab. 1: Price, pack size, and recommended daily portion amount of the recorded βHB salt products Mean, median, standard deviation [SD], minimum [min.], maximum [max.]

Results popularity with an average of 4.0 ± was present in the form of a race- 0.7 stars (median: 4.0; min./max.: mate, i.e. a mixture of the D and L Products, flavors and presentation 1–5) and 199 ± 390 overall ratings forms of βHB. The information on A total of 86 products based on the (median: 38; min./max.: 1–1.543). the packaging referred to the total ketone body βHB made by 49 differ- salt content, which means this in- ent manufacturers were identified. formation included the cations that Pack size and price The majority of these (94.2%) came were present. The average quantity in powder form, to be used for mak- The average pack size of the prod- of βHB salt present in the products ing a drink. The remaining products ucts was 316.7 ± 154.8 g. The wide was 11.4 ± 2.7 g. In 50% of cases, were a liquid, a capsule formulation, variation in the size of the pack- a combination of Na-, Ca- and Mg- two bars, and a spray for spraying aging units is due to the fact that βHB was used. The next most com- directly into the mouth. some products came in the form of mon combination was a mixture of The manufacturers varied widely in large packs, and some came as for- four HB salts (Na, Ca, Mg, K), which terms of the selection of flavors they mulations in sachet portions. One accounted for 18.6% of cases, and offered. There were 40 different fla- pack had a price of $50.24 ± 23.12 then a mixture of Na- and Ca-βHB, vorings in total, from classic flavor- (median: $49.95), corresponding to which accounted for 9.3% of the ings such as orange to variations such $2.99 ± 1.52 (median: $2.80) per total number of products. All other as cucumber and melon, blue rasp- serving or $0.22 ± 0.27 per gram possible combinations and formula- berry or tropical frost. Some products of final product. The most expen- tions using individual salts were less used no flavorings or additives what- sive supplement found had a price well represented (1.16–5.8%). soever, and offered pure βHB salt. of $154.97 for a pack size of 663 g. Including the use of individual salts, One aspect that stood out in terms One portion as recommended by the there were 10 different combinations of product design was the gender- manufacturer corresponds to 17.3 of βHB salts. The most commonly ing of the products. Some of them ± 7.2 g of the ready-to-eat mixture, used salt, sodium salt (91.9%) was clearly targeted a particular gender distributed over 2.8 ± 0.4 portions used with 860.3 ± 358.5 mg sodium (male/female), using a correspond- per day ( Table 1). per portion on average, and the sec- ing selection of flavorings (e.g. pink ond most common element, calcium, lemonade). The Amazon ranking was used with an average quantity of Composition of the products system of 1 to 5 stars (5 stars = 824.1 ± 348.6 mg per portion. The highest possible rating), showed The most abundant ingredient in high standard deviations and corre- good customer satisfaction and high terms of volume was βHB, which sponding minimum–maximum val-

N = 86 Sodium Potassium Calcium Magnesium βHB Energy (mg/portion) (mg/portion) (mg/portion) (mg/portion) (g/portion) (kcal/portion) Number of 79 31 73 61 79 66 products (n) Percentage 91.9 36.1 84.9 70.9 91.9 76.7 Mean 860.3 501.7 824.1 198.6 11.4 40.2 Median 908.0 99.0 850.0 170.0 11.7 37.5 SD 358.5 871.0 348.6 137.2 2.7 27.2 Min.–Max. 0–1 611.0 0–3 800.0 0–1 635.0 0–722.0 0.1–15.0 0–140.0

Tab. 2: Overview of the composition of ketone body supplements per portion (serving size) using the number of products Percentage, mean, median, standard deviation [SD], minimum [min.], maximum [max.]

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ues demonstrated the flexibility of the In terms of the other ingredients, ers showed a clear trend. Advertising formulations (βTable 2). most of the mixtures had a simple focused mainly on the provision of In almost all products, the energy per composition, made up of flavorings, energy through βHB intake (70.9%), portion came mainly from βHB itself stevia, citric acid, or other additive and this was closely followed by state- and was 40.2 ± 27.2 kcal/portion. acids. These were therefore also the ments about weight loss and fat loss In a few exceptional cases, there was additives most commonly found (67.4%). An increase in mental and a higher total energy content (max. in the products. The sweeteners cognitive performance was also fre- 140 kcal), which was mainly due used showed a clear trend towards quently mentioned as a benefit of in- to the addition of fats such as medi- natural alternatives such as stevia take (50.0%). um-chain triglycerides (MCT). (70.9%) and monk fruit (9.3%). Even Advantages in terms of the imple- the thaumatin that was used (3.5%) mentation of a ketogenic diet, such The extrapolation to a three times came mostly from natural sources. as rapid ketosis and an increase in daily intake of the products yielded Acesulfame potassium salt was used levels of ketone bodies in the blood, a daily intake of 2,580.9 mg Na, in only one product. In addition to indicated the direct advantage of the 1,505.1 mg K, 2,472.3 mg Ca and the use of sugar alcohols as an addi- products. These statements were usu- 595.8 mg Mg for the mean value. tive (5.8%) (erythritol for instance), ally supported by a label such as “keto Using the maximum determined sucralose (2.3%) was also used as a friendly” to illustrate the benefit of in- values in the calculation yielded an sweetener. take while on a kD. Approximately even higher cation load ( Table 3). Dyes or anti-caking agents were 35% of the products evaluated referred Comparing these values with the not present in > 70% of the salt to an increase in performance and en- D-A-CH reference values and the mixtures and thickeners were only durance while doing sports or work- Tolerable Upper Intake Level (UL) used in isolated cases (10.5%). Sup- outs ( Figure 2). For all of the sup- of the Institute of Medicine (IOM) plementary amino acids, vitamins, plements, there was a notice (usually showed that, except in the case MCTs, or caffeine were contained in in small print), stating that the state- of the mean value of K, the rec- 15–20% of the products. The use of ments had not been reviewed by the ommended values were markedly these substances was mostly based Food and Drug Administration (FDA). exceeded. This deviation from the on customer demand, i.e. aimed at recommendations was particularly targeted use by athletes or use in noticeable when considering the the wellness/fitness sector. All other Discussion possible maximum values of min- ingredients, such as dietary fiber or erals. In the case of alkali metals L-carnitine, were present in a maxi- Current research, uptake, (Na, K) the intake would be three mum of 10.5% of products ( Figure and sport times higher, and in the case of 1). Within the current trend, there are alkaline earth metals (Mg, Ca) as many products and product innova- much as five times higher β( Table tions based on βHB salts. The rapidly Manufacturers’ advertising 3). Regular intake is therefore asso- developing market is focused primarily statements ciated with a risk of electrolyte dis- around lucrative areas of application, orders and of developing metabolic The evaluation of the main advertis- such as obesity, sport, or mental per- alkalosis. ing statements from the manufactur- formance. However, the selection of

N = 86 Sodium Potassium Calcium Magnesium Mean (mg/day)a 2 580.9 1 505.1 2 472.3 595.8 Maximum (mg/day)b 4 833.0 11 400.0 4 905.0 2 166.0 D-A-CH-reference valuesb (mg/Tag) 1 500.0 4 000.0 1 000.0 400.0 Tolerable Upper Intake Level (UL), 2 300.0 4 700.0 2 500.0 350.0 IOMc (mg/day)

Tab. 3: Table showing the intake of minerals (Na, K, Ca, Mg) in the case of three times daily intake of the correspon- ding βHB salt, compared to the D-A-CH reference values and the UL of the Institute of Medicine (IOM) in mg/ day a Calculation based on three times daily intake of the product b Adults > 19 years Mg = use of the maximum available level (male, 19–25 years) Na, K = adequate intake Ca, Mg = recommended intake c Adults (19–50 years); no UL available for K, here the Adequate Intake (AI) was used

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energy supply 61 70.9

fat loss, fat burning, weight loss 58 67.4

mental performance, increased alertness 43 50.0

sports & workout 30 34.9

increasing blood ketone levels, ketosis 29 33.7

ketogenic diet, keto “friendly” 21 24.4

jumpstart, rapid ketosis 17 19.8

return to ketosis after intake of 4 4.7

appetite control 3 3.5

suitable for a low-carb diet 2 2.3 stress reduction 1 1.2

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 number (n) percentage (%)

Fig. 1: Overview of the main advertising statements of the manufacturers of βHB salt supplements Graph showing the number of times each was mentioned (multiple mentions possible) and percentage out of all products

studies available is rather disappoint- Rare metabolic diseases umented here either [27]. However, ing. Human studies often concentrate The only field in which there has been in the authors’ own experience, on the area of sport or metabolic uti- long-term experience with the intake disturbances in the electrolyte and lization after a single dose or one-day of ketone body salt (Na-βHB) is the acid-base balance can be expected intake of a βHB salt dissolved in water. field of rare metabolic diseases. The starting from a daily dose of 1 g In all cases, an increase in blood levels use of exogenous ketone bodies is an of ketone body salt per kg body of D-βHB was found in healthy, nor- important form of treatment, espe- weight. mal-weight study subjects or athletes cially in the case of MADD, in which Ketone body salts are also of medi- [28–30]. For an intake of 282 mg/kg the breakdown of fatty acids is com- cal interest for diseases that require of a ketone body salt based on Na-K- pletely defective. a ketogenic diet. The fact that they βHB, a maximum increase to 1.0 ± A clear improvement in health and/ can be used as a supplement or as a 0.1 mmol/L βHB in the blood within or improvement of disease-related supporting aid for a diet, or to in- approx. 1.5 hours was determined accompanying symptoms, such as crease ketosis through exogenous [30]. In further studies with 300 mg/ leukodystrophy (= progressive de- intake of ketone bodies is of interest. kg and 11.7 g as the total portion, generation of the white matter of In the case of PDH deficiency, it has maximum values from 0.6 to approx. the nervous system), has been re- already been demonstrated that the 0.8 mmol/L βHB were determined ported in various case reports. In use of ketone body salts can achieve [28, 29]. According to the data, ex- this field, up to 2.6 g of the sodium a clinical improvement of the initial ogenous intake of ketone bodies can salt per kg of body weight was used. situation, while at the same time increase the D-βHB level in the blood, The longest published period of ad- simplifying the kD [26]. thus allowing a supply of energy. ministration is three years and no An increase in performance in sport individual case description refers to Mental and cognitive could not be demonstrated for βHB possible side effects [25, 37, 38]. performance salts. On the contrary, a decrease in The same applies for an individual performance was observed, although medical treatment in two patients The mental and cognitive perfor- there was increased fat oxidation [29, with hyperinsulinism, in which up mance enhancement aspect mainly 28]. There are no long-term studies in to 4 g/kg body weight per day was originates in research on neuro- healthy volunteers available. used. No adverse effects were doc- degenerative diseases. It has been

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69 flavorings 80.2 61 stevia 70.9 56 citric acid 65.1 38 other acid(s) 44.2 24 anticaking agents 27.9 22 dyes 25.6 17 added vitamins 19.8 15 amino acids 17.4 14 MCTs 16.3 13 caffeine 15.1 9 dietary fiber 10.5 9 thickeners 10.5 8 monk fruit 9.3 7 L-carnitine 8.1 7 salt/sea salt 8.1 5 sugar alcohols 5.8 4 plant extracts 4.7 3 thaumatin 3.5 3 cocoa 3.5 2 sucralose 2.3 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 80.0 100.0

number (n) percentage (%)

Fig. 2: Table showing the number and percentage of products with other ingredients in addition to the main ingredient βHB salt MCT = medium chain trigycerides shown that an increase in ketone Critical mineral content also lead to gastrointestinal side ef- body levels in the blood caused by When using βHB salts, a particu- fects such as diarrhea, and it is also MCTs or a ketone supplement can larly critical consideration is the suspected that it may be associated contribute to an improvement in high cation load, i.e. the absorption with increased cardiovascular risks cognition [39, 40]. Further con- of minerals (Na, K, Mg, Ca), which [45, 46]. trolled studies with the respective in some cases markedly exceeds the Discussion is ongoing as to whether substances must be carried out in established reference values (see the two divalent alkaline earth met- order to confirm efficacy in this area comparison with reference values als Ca and Mg work against each of application.  Table 3). As the supplements are other as antagonists. The mutual used in addition to the diet, it can inhibition of absorption that is the be assumed that the daily intake of subject of the discussion has the Obesity minerals is significantly higher. potential to cause mineral deficien- The use of a kD and the effect of ke- A markedly increased Na intake is cies and should not be ignored [47]. tone bodies in the case of overweight associated with a variety of prob- Mg alone can cause diarrhea in high and obesity is highly controversial. lems, such as increased blood pres- doses. A toxic effect with hypoten- Depending on the evaluation in sure, cardiovascular diseases, and sion and muscle weakness is only question, the kD was either found effects on the calcium balance in possible if the specified limits are ex- to have a clear advantage for weight the body. The negative effects of ceeded to an extreme extent (e.g. by loss, or no difference was found excessive salt consumption are well 10 times) [48]. compared to other diets [4, 5]. How- known today and extremely high The effect of higher (or in this case, ever, the current consensus is that intake is not recommended [41–43]. very high) doses of potassium is kD reduces appetite and that users In the case of increased calcium in- not clear. However, positive aspects feel less hungry compared to carbo- take in particular, one of the long- such as blood pressure reduction hydrate-based normal diets. Ketosis term consequences can be an in- and improved control of the glucose is considered to be a possible expla- creased risk of kidney stones [41, balance, i.e. reduction of the risk nation for this [34]. 44]. An increased calcium intake can of type 2 diabetes mellitus, are fre-

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quently reported for an adequate or Investigations into the safety and spray make little sense in practice in slightly increased supplementation tolerability of the ester showed gas- light of the rather high intake level of potassium [49, 50]. Continuous trointestinal side effects such as diar- of βHB required. In future mixtures supplementation of 2–3 g potas- rhea, nausea and vomiting only at a in particular, an increase in addi- sium per day showed no effect on very high dose of 2.1 g/kg [56]. The tives is to be expected, as this will the heart rate [51]. The occurrence ester tastes bitter and the taste needs be needed to ensure differentiation of hyperkalemia (> 5 mmol/L) is to be masked in order for the prod- from the competition. unusual in healthy adults due to uct to be accepted by consumers. The market volume of the prod- good renal excretion, even at higher When directly compared with a ucts is unclear at present. Overall, intakes. In individuals with kidney ketone body salt, the combination the price of the products appears to problems, increased intake is a crit- of βHB and 1,3-butanediol leads to be stable and high, leading to high ical factor and should therefore be a significantly higher increase in costs of approx. $80–160/month avoided [52]. D-βHB in the blood (1.0 ± 0.1 vs. in the case of a once daily intake, 2.8 ± 0.2 mmol/L). This is mainly depending on the supplement cho- due to the enantiomerically pure sen. In the case of recommended Racemate formulation of the ester, i.e. the use three times daily use, costs of above An additional limiting factor of the of the pure D-form. $200 per month (range ~ $80–500/ salt mixtures is the use of the race- Despite the absence of accompany- month) are quickly reached. mate. Only the D-form can be suf- ing salts, there were no clear dif- ficiently metabolized by the human ferences in electrolyte levels after a Limitations body. The L-βHB is the non-phys- single dose. The only difference was iological form and is therefore not in the acid-base balance. The salts The market analysis is subject to cer- produced by the body itself. Some led to an increase in the pH value, tain limitations. Due to the fact that animal tests have indicated that the esters to a reduction. It was also this is a constantly growing market L-βHB can be converted into active possible to achieve ketosis by using a and due to the many online avenues ketone bodies (D-βHB) and fatty ketone ester alongside normal food. through which dietary supplements acids, but only to a very limited Overall, the ester led to a higher and can be procured, it is not possible to extent [53, 54]. In humans, a sig- more stable increase in D-βHB levels provide a complete overview. In par- nificantly lower rate of metaboliza- in the blood [30]. ticular, products that are only sold tion and significantly higher renal This emerging alternative offers via the manufacturer’s own online excretion of L-βHB was observed some advantages over the βHB salts store are not included in this over- after taking a racemic βHB salt [30]. and could compete well on the mar- view. It should be assumed that the Based on the available research, it ket. Based on the information above actual range of βHB supplements must be assumed that the conver- as a whole, gastrointestinal side ef- available on the market is much sion of L-βHB is minimal. fects, in particular diarrhea, are to larger. Furthermore, the information According to current knowledge, be expected in the case of excessive provided by the manufacturers re- increased intake does not represent intake of ketone body salts. garding the ingredients has not been any particular advantage, but rather checked extensively (e.g. through a disadvantage, because 50% of the laboratory analyses), and therefore Dosage form and price ingested product cannot be effec- errors cannot be ruled out. tively used by the organism. How- The dosage form, in particular the In some cases, the declarations were ever, the actual normal value for dosage form of a drink, is compre- illegible or poorly displayed, and human is still unclear and requires hensible and is in part attributable therefore it is possible that there further investigations into the utili- to the fact that it is easy to optimize may have been some under-report- zation of the L-enantiomer. the taste of a drink, and due to the ing in the ingredient data. Entry of fact that the product is diluted by incorrect data was reduced through dissolving it in water. Some ketone the use of the four-eyes principle. Second generation: body salts themselves have an un- Ester compounds pleasant salty or bitter taste, which As early as spring 2018, the “second needs to be masked by flavorings, Conclusion generation” of ketone body supple- sweeteners and acids. The reason ments appeared on the US market. behind the often very simple com- In summary, dietary supplements The trend is moving towards salt-free position of the products at present based on the ketone body β-hydrox- ester compounds, which still refer to could be due to the rapid entry to ybutyrate represent an interesting the main ketone body βHB [55]. market. Formulations such as the development. A new development

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of the market and the associated 2. Atkins RC. Dr. Atkins diet revolution. old of ketogenesis. J Biol Chem 52: 393–401 research is providing much new The high calorie way to stay thin forever. 18. Cahill GF (2006) Fuel metabolism in star- information about ketone bodies. Bantam Books, New York (1972) vation. Annu Rev Nutr 26: 1–22 However, βHB should be used with 3.Lenzer J (2003) Robert Coleman Atkins. BMJ 19. Schoeler NE, Cross JH (2016) Ketogenic caution because the side effects, 326: 1090 dietary therapies in adults with epilepsy: a such as gastrointestinal symptoms, 4. Bravata DM, Sanders L, Huang J et al. practical guide. Pract Neurol 16: 208–214 can only be assessed to a limited (2003). Efficacy and safety of low-carbohy- 20. Bier DM, Brosnan JT, Flatt JP et al. (1999) extent at present. In particular, no drate diets. A systematic review. JAMA 289: Report of the IDECG working group on lower statements can be made regarding 1837–1850 and upper limits of carbohydrate and fat the potential long-term effects. An 5. Bueno NB, Melo ISV de, Oliveira SL de et al. intake. International Dietary Energy Con- overall evaluation of the individ- (2013). Very-low-carbohydrate ketogenic sultative Group. Eur J Clin Nutr 53(Suppl ual advertising statements (such as diet v. low-fat diet for long-term weight 1): S177–S178 those regarding use in neurodegen- loss. A meta-analysis of randomised con- 21. Ye F, Li X, Jiang W et al. (2015) Efficacy erative diseases and weight reduc- trolled trials. Br J Nutr 110: 1178–1187 of and patient compliance with a ketogenic tion), shows that further research 6. U.S. News. U.S. News‘ 40 best diets overall. diet in adults with intractable epilepsy. A is needed in many areas before the 03. Januar 2018. URL: https://health.us- meta-analysis. J Clin Neurol 11: 26–31 possible effects of βHB can be said to news.com/wellness/food/slideshows/best- 22. Payne NE, Cross JH, Sander JW et al. (2011) be proven. diets-overall Zugriff 21.02.18 The ketogenic and related diets in adoles- The appetite-reducing effects have 7. U.S. News. Best weight-loss diets. URL: cents and adults--a review. Epilepsia 52: been confirmed in the last few years. https://health.usnews.com/best-diet/best- 1941–1948 In terms of use in the medical sector, weight-loss-diets Zugriff 21.02.18 23. Langhans W, Wiesenreiter F, Scharrer E the development of this areas as a 8. U.S. News. Best fast weight-loss diets. URL: (1983) Different effects of subcutaneous whole may open up new options for https://health.usnews.com/best-diet/best- D,L-3-hydroxybutyrate and acetoacetate nutritional therapy, and it therefore fast-weight-loss-diets Zugriff 21.02.18 injections on food intake in rats. Physiol merits further investigation. Use as 9. Wilder RM (1921) The effects of ketonuria on Behav 31: 483–486 an addition to the kD is an interest- the course of epilepsy. Bull Mayo Clin 2: 307 24. Féry F, Balasse EO (1988) Effect of exer- ing aspect that could significantly 10. Och U, Fischer T, Marquardt T (2017). Ke- cise on the disposal of infused ketone bodies simplify and improve the everyday togene Diät – eine Herausforderung für Pa- in humans. J Clin Endocrinol Metab 67: nutritional composition of the diet, tienten und Fachkräfte. Einsatz, Wirkungs­ 245–250 e.g. by using smaller amounts of fat weise und Durchführung bei Epilepsien im 25. van Hove JLK, Grünewald S, Jaeken J et al. in the kD. Kindesalter und seltenen angeborenen Stoff- (2003) D,L-3-hydroxybutyrate treatment of wechselerkrankungen. Ernährungs Umschau multiple acyl-CoA dehydrogenase deficiency 64: M444–M457 (MADD). Lancet 361: 1433–1435 Conflict of interest 11. Scholl-Burgi S, Holler A, Pichler K et al. 26. Habarou F, Bahi-Buisson N, Lebigot E et al. The authors declare no conflict of interest. (2015). Ketogenic diets in patients with in- (2017) Ketone bodies as a possible adjuvant herited metabolic disorders. J Inherit Metab to ketogenic diet in PDHc deficiency but not in Dis 38: 765–773 GLUT1 deficiency. JIMD reports 38: 53–59 Fischer Tobias, M.Sc.1 12. Arbeitsgemeinschaft der Wissenschaft- 27. Plecko B, Stoeckler-Ipsiroglu S, Schober E et 2 Univ.Prof. Dr. med. Thorsten Marquardt lichen Medizinischen Fachgesellschaften al. (2002) Oral beta-hydroxybutyrate sup- 1 Fachhochschule Münster Fachbereich Oecotrophologie • Facility (AWMF) (2014) Ketogene Diäten. S1-Leit­ plementation in two patients with hyper- Management linie 022/021. Leitlinien der Gesellschaft insulinemic hypoglycemia: monitoring of Corrensstr. 25, 48149 Münster für Neuropädiatrie: 1–21 beta-hydroxybutyrate levels in blood and [email protected] 13. Zammit VA (1984) Mechanisms of regula- cerebrospinal fluid, and in the brain by in 2 Universitätsklinik Münster tion of the partition of fatty acids between vivo magnetic resonance spectroscopy. Pedi- Albert-Schweitzer-Campus 1, 48149 Münster [email protected] oxidation and esterification in the liver. Prof atr Res 52: 301–306 Lipid Res 23: 39–67 28. Rodger S, Plews D, Laursen P et al. (2017). 14. Mitchell GA, Kassovska-Bratinova S, Oral β-hydroxybutyrate salt fails to im- Boukaftane Y et al. (1995) Medical aspects prove 4-minute cycling performance fol- References of ketone body metabolism. Clin Invest Med lowing submaximal exercise. J Sci Cycling 18: 193–216 6: 26–31 1. Banting W. Letter on corpulence, addressed 15. Cahill GF (1970) Starvation in man. N Engl 29. O‘Malley T, Myette-Cote E, Durrer C et al. to the public. With a review of the work J Med 282: 668–675 (2017) Nutritional ketone salts increase fat from blackwood‘s magazine, and an arti- 16. Koeslag JH, Noakes TD, Sloan AW (1980) oxidation but impair high-intensity exercise cle on corpulency leanness from Harper’s Post-exercise ketosis. J Physiol 301: 79–90 performance in healthy adult males. Appl Weekly. Forgotten Books, London (2017) 17. Wilder RM, Winter MD (1922) The thresh- Physiol Nutr Metabol 42: 1031–1035

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30. Stubbs BJ, Cox PJ, Evans RD et al. (2017) 39. Newport MT, VanItallie TB, Kashiwaya erals. EFSA, Parma (2006) On the metabolism of exogenous in Y et al. (2015) A new way to produce 49. Stone MS, Martyn L, Weaver CM (2016) humans. Front Physiol 8: 137 hyperketonemia: use of ketone ester in a case Potassium intake, bioavailability, hyperten- 31. Cordain L, Eaton SB, Sebastian A et al. of Alzheimer‘s disease. Alzheimers Dement sion, and glucose control. Nutrients 8: 444 (2005) Origins and evolution of the Western 11: 99–103 50. Binia A, Jaeger J, Hu Y et al. (2015) Daily diet: health implications for the 21st cen- 40. Reger MA, Henderson ST, Hale C et al. potassium intake and sodium-to-potassium tury. Am J Clin Nutr 81: 341–354 (2004). Effects of β-hydroxybutyrate on ratio in the reduction of blood pressure: a 32. Cleave TL. The saccharine disease. Condi- cognition in memory-impaired adults. meta-analysis of randomized controlled tions caused by the taking of refined carbo- Neurobiol Aging 25: 311–314 trials. J Hypertens 33: 1509–1520 hydrates, such as sugar and white flour. 41. Cappuccio FP (2013) Cardiovascular and 51. Gijsbers L, Molenberg FJM, Bakker SJL et Elsevier Science, Burlington (2013) other effects of salt consumption. Kidney Int al. (2016) Potassium supplementation and 33. Paoli A, Rubini A, Volek JS et al. (2013) Be- Suppl (2011) 3: 312–315 heart rate: a meta-analysis of randomized yond weight loss: a review of the therapeutic 42. Perrin G, Korb-Savoldelli V, Karras A et al. controlled trials. Nutr Metab Cardiovasc uses of very-low-carbohydrate (ketogenic) (2017) Cardiovascular risk associated with Dis 26: 674–682 diets. Eur J Clin Nutr 67: 789–796 high sodium-containing drugs. A systematic 52. Palmer BF, Clegg DJ (2017) Diagnosis and 34. Gibson AA, Seimon RV, Lee CMY et al. review. PloS ONE 12: e0180634 treatment of hyperkalemia. Cleve Clin J Med (2015). Do ketogenic diets really suppress 43. WHO. Guideline: sodium intake for adults 84: 934–942 appetite? A systematic review and meta-an- and children. World Health Organization 53. Lincoln BC, Des Rosiers C, Brunengraber H alysis. Obes Rev 16: 64–76 (WHO), Geneva (2012) (1987) Metabolism of S-3-hydroxybutyrate 35. Danaher J, Nyholm S, Earp BD (2018) The 44. Cirillo M, Laurenzi M, Panarelli W et al. in the perfused rat liver. Arch Biochem Bio- quantified relationship. Am J Bioeth 18: (1994) Urinary sodium to potassium ratio phys 259: 149–156 3–19 and urinary stone disease. Kidney Int 46: 54. Desrochers S, David F, Garneau M et al. 36. Paton C, Hansen M, Fernandez-Luque L et 1133–1139 (1992) Metabolism of R- and S-1,3-butane- al. (2012) Self-tracking, social media and 45. Lewis JR, Zhu K, Prince RL (2012) Adverse diol in perfused livers from meal-fed and personal health records for patient empow- events from calcium supplementation: rela- starved rats. Biochem J 285(Pt 2): 647–653 ered self-care. Contribution of the IMIA so- tionship to errors in myocardial infarction 55. HVMN Ketone - Ketone Ester Superfuel. cial media working group. Yearb Med Inform self-reporting in randomized controlled HVMN Ketone. URL: https://hvmn.com/ 7: 16–24 trials of calcium supplementation. J Bone ketone Zugriff 01.03.18 37. Gautschi M, Weisstanner C, Slotboom J Miner Res 27: 719–722 56. Clarke K, Tchabanenko K, Pawlosky R et et al. (2015) Highly efficient ketone body 46. Reid IR, Bristow SM, Bolland MJ (2015) al. (2012) Kinetics, safety and tolerability treatment in multiple acyl-CoA dehydro- Calcium supplements: benefits and risks. J of (R)-3-hydroxybutyl (R)-3-hydroxybuty­ genase deficiency-related leukodystrophy. Intern Med 278: 354–368 rate in healthy adult subjects. Regul Toxicol Pediatr Res 77: 91–98 47. Schuchardt JP, Hahn A (2017) Intestinal Pharmacol 63: 401–408 38. van Rijt WJ, Heiner-Fokkema MR, du absorption and factors influencing bioavail- Marchie Sarvaas et al. (2014) Favor- ability of magnesium. An update. Curr Nutr able outcome after physiologic dose of so- Food Sci 13: 260–278 dium-D,L-3-hydroxybutyrate in severe 48. European Food Safety Authority. Tolerable DOI: 10.4455/eu.2018.048 MADD. Pediatrics 134: e1224–e1228 upper intake levels for vitamins and min-

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