BHB Science

βHB is Beta-Hydroxybutyrate, one of three molecules classically defined by physiologists as ketone bodies. Ketone bodies, such as β-hydroxybutyrate (βHB or β-OHB), acetone and acetoacetate (AcAc), are produced in the liver and serve as alternative energy sources for the brain, heart, and skeletal muscle cells. They are produced during glucose deprivation (i.e. starvation), fasting or when consuming low-carbohydrate diets (Yudkoff et al., 2007; Branco et al., 2016). During prolonged fasting, glycogen stores (a source of glucose) are used as the primary energy source. When those stores are exhausted, the level of total blood ketone bodies can increase up to 5-8 mM (Owen et al., 1969). At ketone levels of 0.5 mM or above, it is clinically defined as a state of nutritional ketosis, which spares muscle loss (Veech, 2004; Paoli et al., 2015b), and may boost mitochondrial and neuronal metabolism for a myriad of physical and cognitive benefits (Achanta et al., 2017). In other words, βHB is a water-soluble fat-derived energy metabolite produced in the liver.


βHB crosses the blood brain barrier, accumulates in brain tissue and provides a source of energy for the central nervous system (CNS) (Plecko et al., 2002; Yudkoff et al., 2007; Newman and Verdin, 2014; Achanta and Rae, 2017). Preserving brain energy metabolism serves a very important evolutionary function with particular regard to the enormous energy demand of the human brain. Ketones help sustain that demand during glucose energy restriction, as well (Veech et al., 2001; Veech, 2004; Cahill, 2006). Cells of the CNS are not able to use Long Chain Fatty Acids/ Triglycerides (LCTs) as an energy source under normal physiological circumstances: these cells utilize glucose as fuel, and under certain conditions (hypoxia), lactate. During dietary glucose energy restriction from carbohydrate and protein restriction (ketogenic diet; KD), or prolonged fasting, the human metabolism shifts from burning glucose to burning fatty acids and ketones. In the brain exclusively, ketones can become the predominate fuel for the massive energy requirements of the CNS (Cahill, 2006).


The ketone bodies—βHB and AcAc—are synthetized by liver cells’ mitochondria from fatty acids, which lead to ketosis when blood ketone levels rise above 0.5 mmol/L (Figure 1.; fatty acid metabolism in liver). These ketone bodies then reach the brain via blood vessels by transporter molecules. Similar to heart and skeletal muscle cells, ketone bodies can metabolize directly to acetyl CoA and provide energy for brain cells, as well as through the Krebs (ATP) cycle (Yudkoff et al., 2007; Newman and Verdin, 2014; Branco et al., 2016; Egan and D’Agostino, 2016; Achanta and Rae, 2017). While ketone metabolism may appear new, it is interesting to note that βHB is an ancient molecule - from an evolutionary perspective – designed to provide energy when glucose was restricted. For example, many bacteria are able to synthetize βHB polymers to store energy (Cahill, 2006). Moreover, blood levels of βHB, and how βHB is metabolized and used, are all dependent on age, brain area and species. This suggests a different and diversified physiological role of βHB in the body of several species (Hawkins and Biebuyck, 1979; Achanta and Rae, 2017).



• Alternative and preferred energy source: Despite the fact that the human brain (weighing approximately 1.5 kg) represents 2-3% of body weight, it consumes 20% of the body’s total energy output. βHB represents an alternative form of energy that most of body’s cells, including the brain, can use in many ways (Yudkoff et al., 2007; Pinckaers et al., 2017) (Figure 2.). In fact, the brain is shown to burn ketones preferentially over glucose in two ways: (1) In the developing brain, ketones preserve glucose for the pentose phosphate pathway, which results in ribose for DNA synthesis and NADPH for lipid biosynthesis and (2) under conditions of long-term starvation and KD, metabolism shifts from burning glucose to fatty acids and ketones as fuel. Under different conditions from above, glucose is the predominate fuel for the brain (Nehlig, 2004; Cahill, 2006). The brain is like a hybrid engine, able to switch from ketones to glucose and vice versa. Interestingly, it can even burn a third fuel—lactate—for energy (Nehlig and Pereira de Vasconcelos, 1993). For example, one study showed that in 15 day-old rats, glucose was the major fuel (57%); but both βHB (20%) and lactate (23%) also supported the brain’s energy supply (Dombrowski et al., 1989). These observations show that the brain has a remarkable ability for adaptation and metabolic flexibility.


Fourth macronutrient: βHB enhances mitochondrial energy production (as a “high-octane” fuel), or as a molecule that can provide unique health benefits that are completely independent of its role as an energy metabolite (Hashim and VanItallie, 2014; Newman and Verdin, 2014; Cox et al., 2016; Dyer, 2016; Egan and D’Agostino, 2016).


• Suppression of oxidative stress and inflammatory processes: Partly by suppression of oxidative stress and inflammatory processes, ketosis/βHB may improve the symptoms of different diseases such as Parkinson’s disease, Alzheimer’s disease, schizophrenia, amyotrophic lateral sclerosis (ALS), glucose transporter 1 (GLUT1)-deficiency syndrome, anxiety, autism, depression, cancer, and epilepsy not only in model animals of different human diseases but also in patients (Masino et al., 2009; Stafstrom and Rho, 2012; D’Agostino et al., 2013; Shimazu et al., 2013; Hashim and VanItallie, 2014; Poff et al., 2015; Youm et al., 2015; Ari et al., 2016; Branco et al., 2016; Chavan et al., 2016; Rogawski et al., 2016; Achanta and Rae, 2017; Bostock et al., 2017; Cheng et al., 2017; Rho, 2017; Simeone et al., 2017; Tefera et al., 2017).


• Improvement of cognitive functions: βHB improved cognitive functioning (e.g., working memory and executive function) in both memory-impaired patients and in healthy non-demented subjects (Reger et al., 2004; Krikorian et al., 2012; Ota et al., 2016).


• Reduction in seizure activity: Approximately 50% reduction in seizure activity was demonstrated in 50-60% of children with drug-resistant childhood epilepsy after KD, which effect may be in relation, among others, to progressive elevation of serum ketone bodies/βHB (Ross et al., 1985; Groomes et al., 2011; Thammongkol et al., 2012; Kim et al., 2016). 


Homeostatic role: βHB is one of the main components of homeostatic mechanisms, which allow us to survive prolonged starvation. For example, βHB negatively regulates its own synthesis preventing life-threatening high-level ketoacidosis (ketoacidosis is explained later in this white paper) and promotes effective use of fat tissue (as an energy store) under this circumstance (Taggart et al., 2005).


• Longevity-enhancing effects: βHB could also have longevityenhancing effects (Newman and Verdin, 2014; Veech et al 2017). In C. elegans (roundworms), βHB was shown to increase lifespan through inhibiting histone deacytelase (HDAC) and reducing metabolic stress (Edwards et al, 2014). 


Reduction of hunger (cravings) and effect on weight management: Nutritional ketosis/βHB plays a role in regulating food intake and body weight (Atkins, 2002; Paoli, 2014; Paoli et al., 2015a). Different hypotheses suggest the indirect and direct mechanisms by which KD/nutritional ketosis/ketone bodies induce and evoke weight loss: (i) Losing energy by excretion of ketone bodies, (ii) gluconeogenesis (which converts protein to glucose and provides a major portion of the glucose needed for fuel during the initial period of KD) is an energy-demanding process leading to a “waste of calories”, (iii) higher satiety effect of proteins, which evoke reductions in appetite, (iv) increased lipolysis and decreased lipogenesis and (v) a possible direct suppressive effect of ketone bodies (e.g., βHB) on appetite/ hunger (Kekwick and Pawan, 1957; Atkins, 2002; Cahill, 2006; Feinman and Fine, 2007; Johnstone et al., 2008; WesterterpPlantenga et al., 2009; Sumithran et al., 2013). In the Kekwick and Pawan study in 1957, the researchers showed that you can consume the same number of calories in fat, protein and carbs, but you expend the most energy (calories) when consuming fat. In other words, a calorie is not a calorie. Also, the ketogenic diet/nutritional ketosis is characterized by increased circulating free fatty acid levels, which may reduce food intake and glucose production through specific neurons from parts of the brain implicated in regulation of satiety and hunger (Paoli et al., 2015a). Thus, among others, beneficial effects of increased levels of both free fatty acids and βHB on body weight suggests that KD/ketosis may be a good way to manage weight.


• Insulin sensitivity: βHB enhances insulin sensitivity (Will et al., 1997; Veech, 2004; Park et al., 2011). 


Improvement of reaction time and exercise performance: βHB may improve them both due to its use as an alternative substrate for ATP (Cox et al., 2016; Egan and D’Agostino, 2016). Additionally, βHB spares glycogen and Leucine (Nair et al, 1988).


• Intermittent fasting: Consumption of βHB may preserve and maintain brain energy metabolism during periods of limited glucose availability.


.• Alleviation of the keto “flu” symptoms: Keto “flu” (or ketogenic/ ketosis flu, low-carb flu, induction flu, Atkins flu) is a withdraw symptom from carbohydrate restriction, which occurs when the body is adapting to burning ketones rather than glucose. Thus, to decrease the symptoms of keto “flu” (e.g., fatigue, headache, nausea, dizziness, sleepiness, and difficulty focusing or brain fog), consumption of more fat, or βHB, may be recommended (Stanton, 2011).




The main benefits to using βHB will be somewhat dependent upon the end-user. We know that βHB has the unique property of enhancing bioenergetic effects (much like creatine, but more versatile), thus consuming βHB as a supplement has the potential to enhance our overall metabolic health and even performance. (Abraham, 2015; Cox et al., 2016; Egan and D’Agostino, 2016; Pinckaers et al., 2017). For example, the use of βHB may be especially beneficial for populations of people that have insulin resistance or carbohydrate intolerance. Evidence suggests that βHB can enhance insulin sensitivity and may improve glucose disposal (Will et al., 1997; Veech, 2004; Park et al., 2011). A large percentage of the population above middle age has either signs of insulin resistance or is considered pre-diabetic. 


It seems that the most promising application of exogenous ketones as a supplement is that it can be used as a source of energy to further augment one’s own diet or perhaps a low-carbohydrate KD (less than 50 g/day carbohydrates) (Veech, 2004; Paoli et al., 2013). When it comes to using βHB as a supplement together with the KD, this may present a number of compelling benefits. For example, when one starts a KD, one’s brain essentially goes through a form of “glucose withdrawal” that can negatively impact physical and cognitive performance. This usually occurs over several days, or as long as two to four weeks, and causes lethargy, headaches and an overall decrease in mental well-being. But after several weeks the body adapts entirely to using fat and ketones (keto-adaptation) more efficiently for energy. Anecdotally, many users report that βHB makes this transition to a keto or lowcarbohydrate diet more seamless by circumventing the need for extreme dietary restriction to elevate βHB levels. This happens by providing an alternative form of energy that can help to restore and preserve normal brain energy metabolism in the face of carbohydrate restriction as described above. If following a KD, the use of βHB helps to bridge the gap into ketosis by supplying ketones to the brain and also supplying a non-gluconeogenic energy precursor that has less insulin potentiating effect than glucose or protein. Oral intake of βHB will not prevent endogenous ketone production from nutritional ketosis. 


Another promising application of exogenous ketones is their consumption during a period of time-restricted eating called intermittent fasting (IF). IF has been shown to have a broad range of health benefits, cognitively, physically and especially for metabolic health in resetting insulin resistance. IF may have therapeutic effect alone or as an adjunct to increase the efficacy of the treatment of different diseases such as cancer, anxiety, neurological diseases and cognitive impairment (Park et al., 2011; Arnason et al., 2017; Hu et al., 2017; O’Flanagan et al., 2017; Singh et al., 2017). Anecdotally, the consumption of small amounts of ketone supplements during a period of intermittent fasting, for example between 10 PM and 4 PM of the next day can provide a person with greater sustained energy without impairing endogenous ketogenesis. Many of the aforementioned benefits are largely a function of preserving and maintaining brain energy metabolism during periods of limited glucose availability and mild hypoglycemia.


One of the main benefits of elevated βHB is that hunger cravings are controlled (satiety) as long as brain energy metabolism is not interrupted by fluctuations in glucose and insulin. Nutritional ketosis plays a vital role in stabilizing and regulating food intake control (Atkins, 2002; Paoli et al., 2015a). Regarding insulin, it has been shown that ingesting sodium-βHB did not change insulin secretion and was well tolerated without adverse effects in human studies (Plecko et al., 2002; Van Hove et al., 2003). More advanced formulas using βHB mineral salts (i.e. in combination with MCTs) and new/more effective methods of their application are being developed to enhance and sustain ketone absorption and utilization and to evolve therapeutic procedures. For example, it has been demonstrated that not only intragastric gavage of βHB salt, but also administration of its 4.2% solution (in drinking water) increased ketonemia/βHB level in rats, which may decrease fat mass and suggests that ketone supplements can increase the effectiveness of the treatment of obesity (Pawan and Semple, 1983; Caminhotto et al., 2017).


When it comes to performance, especially during periods of extreme exertion or extreme environment (e.g., military troops, emergency personnel, etc.), the use of βHB supplementation evoked mild ketosis. This may be leveraged to provide resilience in the face of limited glucose or oxygen levels without elevation of free fatty acids (Veech, 2004). The application of βHB as an exogenous fuel may be perceived as beneficial to exercise enthusiasts, high-performance athletes (e.g., elite athletes, and cyclists) and even to corporate executives functioning under high levels of stress due to limited sleep, limited food consumption and nonstop travel associated with their business activities. Indeed, it has been demonstrated that βHB may have distinct benefits for athletes looking to improve their reaction time and performance (Abraham, 2015; Paoli et al., 2015b; Cox et al., 2016; Egan and D’Agostino, 2016). Moreover, exogenous ketone supplements/ βHB as a food supplement may increase endurance performance of warfighters similar to high-performance athletes, providing an alternative substrate for oxidative phosphorylation (ATP), greater muscle fat oxidation and a sparing of muscle glycogen (Cox et al., 2016; Egan and D’Agostino, 2016). Elevating blood ketones may also enhance cardiac function (Puchalska and Crawford, 2017). For example, ketone bodies increased both the hydraulic efficiency of the heart by 28% and synthesis of adenosine triphosphate (ATP) (Kashiwaya et al., 1994).


However, probably the most promising application of βHB appears to be as a neurocognitive enhancement strategy and perhaps even a nootropic agent for improving cognitive function and maybe reaction time, which has a broad range of implications for agerelated cognitive decline (Newport et al., 2015; Ota et al., 2016; Mamelak, 2017). It has been demonstrated that βHB preserves the rat hippocampus (Izumi et al., 1998), a brain structure, which has a role for example in memory and cognition (it is interesting to note that hippocampus is one of the first structure of the brain, which suffer damage in dementia generating among others short-term memory loss). In human studies, βHB infusion and ketogenic mealsevoked increase in βHB levels improved cognitive functioning (e.g., working memory and executive function) not only in memoryimpaired patients but also in healthy non-demented subjects (Reger et al., 2004; Krikorian et al., 2012; Ota et al., 2016). βHB increased the cerebral blood flow in healthy people (Hasselbalch et al., 1996), which may evoke ameliorating effect on cognitive functions. Moreover, ketone bodies may protect from cognitive impairment and moodiness evoked by obesity and weight gain (Yancy et al., 2009; Davidson et al., 2013).



βHB is attached to minerals through an ionic bond because βHB is not stable on its own in powder form. The βHB “salt” (calcium, sodium, magnesium or potassium) makes the molecule more palatable, and it’s also a convenient way to deliver critical electrolytes that may otherwise be depleted under conditions of low-carbohydrate dieting. Specifically, the consumption of βHB in a mineral salt form buffers the ketone molecule to reduce the mild acidity that’s associated with the free acid form while supplying free-form electrolytes to help promote a low-carb diet.


It is important to consume βHB with balanced minerals in order to help absorption and maintain increased βHB levels as described in animal studies (Paoli et al., 2015b; Kesl et al., 2016; Caminhotto et al., 2017) (Figure 3.). Combining βHB with mineral salts also allows βHB consumption in effective concentrations without leading to gastrointestinal (GI) distress It is interesting to note that ketone salts may be effective in different intravenous and dialysis fluid therapies such as application of sodium- βHB in resuscitation fluids in combat casualties (Veech, 2004). There is currently a patent application that covers the mixture of all four of the BHB salts used together (calcium, magnesium, potassium, sodium).





One way to balance βHB mineral salts is to have sodium as the predominant mineral, since that can facilitate absorption of many molecules in the gut through co-transporter activation. Potassium, magnesium and calcium would represent at least 50% of the mineral content of the ketone salt in a balanced ratio. This is one general guideline for formulation of a ketone salt that is palatable and tolerable (Plecko et al., 2002; Van Hove et al., 2003; Azzam and Azar, 2013; Kesl et al., 2016). However, due to Potassium βHB’s hygroscopicity (absorbs water and causes clumping in powder formulas), most βHB formulas don’t contain Potassium βHB. Instead, it’s possible to add potassium chloride, for example, to balance the minerals. Or, you could use sodium, calcium and magnesium in a powder, and have a separate liquid Ready-To-Drink (RTD) product using Potassium βHB to stack. RTDs also allow for all four βHB salts to be used without stability issues.


βHB salts contain βHB and sodium (Na+), potassium (K+), calcium (Ca2+) and/or magnesium (Mg2+) ions. As ketone bodies have diuretic effects and cause a loss of certain amounts of salts, βHB “salt” content helps compensate for the loss without serious side effects if keeping to normal dosing (Veech, 2004). It should be noted that the sodium in sodium βHB is not sodium chloride (aka, table salt), the type of sodium people normally attribute to a rise in blood pressure.




The best dosing strategy for βHB salts is to start at a relatively low dose - about 6 g per serving. Gradually increase the dose every three days in order to achieve the desired energy performance and GI tolerability. However, to achieve therapeutic level of ketone bodies (1-5 mM) in the blood of a 70 kg man, it can range from 5.6 g to 63 g/day of βHB salts (Veech, 2004), depending on the goal of the user and/or type of disease state. In dietary supplements, the typical therapeutic dose is in the 12 g range, and some combine it with 3-7 g of MCT for higher and more sustained levels of blood ketones. After ingesting a βHB supplement, increased levels of blood ketones may decrease to the normal physiological levels within several hours (Figure 3.). Thus, to achieve and maintain desired therapeutic levels of βHB, it’s wise to time your ketogenic/ βHB supplement to achieve your goal (e.g., before a meal, during intermittent fasting, prior to exercise, before difficult cognitive tasks, for long-lasting energy and other goals unique to you). 




The combination of βHB with medium chain triglycerides (MCTs) enhances the overall elevation of βHB in the blood by facilitating endogenous ketone production (from MCTs) in addition to the exogenous βHB source. It delays gastric absorption to extend and sustain the elevation of blood ketone levels over a longer period of time (Kesl et al., 2016). Therefore, it is easier to achieve a higher level of blood βHB then if they used either βHB salt orMCT alone. Emerging data on a number of animal models and anecdotal reports in humans have validated the combination of βHB with MCT as being superior (Azzam and Azar, 2013; Kesl et al., 2016). It was also described that the combination of MCT oil with βHB mineral salt effectively increased the level of βHB and abolished the adverse GI effects of MCT oil alone such as diarrhea and flatulence (Azzam and Azar, 2013; Kesl et al., 2016). However, more studies are needed to determine what dosage and ratio is optimal. Other ingredients that go well with βHB include branched-chain amino acids for buffering and an anti-catabolic affect, as well as various digestion-resistant prebiotic soluble fibers to ensure a healthy and robust gut microbiome (Stilling et al., 2016). 



Yes, there are patents concerning BHB, the combination of BHB and MCT, and patent-pending on the combination of all four BHB salts. Compound Solutions is the official distributor of patented BHB and MCT under the trademarks goBHB™ and goMCT™



More research is needed to determine whether D-βHB or DLβHB is superior. DL is known as racemic (DL indicates an equal (1:1) mixture of dextro and levo isomers). There is some evidence to suggest that the D form may be superior for enhancing mitochondrial function whereas some evidence suggests the DL form is superior for specific types of neurological diseases and cancer (Van Hove et al., 2003; Veech, 2004; Taggart et al., 2005; Gautschi et al., 2015). The body converts some portion of L-BHB to D-BHB; and L-BHB is thought to be a signaling molecule to reduce the inflammation associated with the diseases above. But experiments are ongoing to determine if one form is more beneficial than the other. To the best of our knowledge at this time, there is no comprehensive study to determine if D-βHB is more beneficial than DL regarding general use applications, or value to the consumer from a financial perspective. In regards to elevating blood ketone levels, D-βHB will appear to generate a higher level of blood βHB because the commercially available measurement devices only measure the D form of βHB, not the L form. If ketone blood measurements are done using gas chromatography or mass spectrography, the total level of βHB including D and L will be measured correctly and the rise in βHB from consuming D or consuming DL should be identical.



The primary potential downside of ketone supplementation is GI discomfort which is associated with the mineral load that can cause an osmotic diarrhea (Plecko et al., 2002; Van Hove et al., 2003; Azzam and Azar, 2013; Kesl et al., 2016). It typically occurs with higher levels of βHB and MCT combined. This side effect of βHB supplementation can be significantly reduced by consuming adequate amounts of water, limiting the dosage and gradually increase the dosage over time to improve tolerability. Consuming ketone salts with a meal can also improve tolerability.



As the effectiveness of ketone bodies and their tolerability may vary in each person, GI distress can occur at dosages as little as  5 g/day in the most sensitive populations. But dosages as high as 50 g/day are well tolerated in many people using βHB supplements. In terms of recommended βHB dosage, it is 11 – 13 g/serving (Denton, 2016). 



“Gradualism” is the key. At levels of about 5g each of βHB and MCT, some very sensitive people start to feel GI distress. Individual sensitivity requires starting at lower doses and gradually adding ketones until striking a balance between effectiveness and GI tolerability.



Yes, taking exogenous ketone supplements will elevate normal blood plasma βHB levels into a range that is clinically accepted as being in a state of ketosis (>0.5 mM) (Achanta and Rae, 2017). 

It must be recognized that nutritional/physiological ketosis is much different from pathological ketosis (“ketoacidosis”) that is a consequence of type I diabetes (and type 2 diabetes to a lesser extent) and other pathological states. For example, in physiological ketosis (e.g. during very-low-calorie KD and use of exogenous ketone supplements), the level of ketones are not able to go higher than 7-8 mM because, cells of the CNS use ketone bodies efficiently for energy production. Thus, under nutritional ketosis or supplemental ketones, blood pH does not change. Ketoacidosis cannot occur. In the case of diabetic ketoacidosis, ketone body levels can increase up to 20-25 mM, which decreases blood pH (Paoli et al., 2013, 2015b).



Yes, someone not eating a KD or carbohydrate-restricted diet can benefit from consumption of βHB salts due to the fact that this will allow an elevation of βHB in the blood, which we know is linked to many health benefits described above; some of which have been documented in humans (Pinckaers et al., 2017). More research is needed to move the preclinical animal studies into human clinical studies to validate the use of βHB supplementation.



The use of exogenous ketones for performance applications has been exclusively in the realm of special operations forces and elite level endurance athletes that have described significant benefits for specific applications (Egan and D’Agostino, 2016; D’Agostion et. al., 2013; Abraham, 2015; Pinckaers et al., 2017). Similar to creatine supplementation, we will elucidate what types of exercise and what types of sports will benefit most from ketone supplementation as the science progresses (Cox et al., 2016). It will be important for the end-user to experiment with the dosing of ketones according to their own performance regimen since other factors, - including body size, type of exercise, duration, existing nutrition strategy and other supplements - will influence the performance-enhancing benefits of βHB supplementation (Pinckaers et al., 2017). Those already in a state of nutritional ketosis can also benefit from βHB supplementation by allowing the user to optimize blood levels of ketones that they have found correlate with optimal mental and cognitive performance.



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