Ketone salts

Ketone Salts

1. Identity: Chemical Names, Natural Sources, and Common Forms

1.1 Chemical Identity

The ketone body β-hydroxybutyrate (BHB) is synthesized in the liver from fatty acids and represents an essential carrier of energy from the liver to peripheral tissues when the supply of glucose is too low for the body's energetic needs, such as during periods of prolonged exercise, starvation, or absence of dietary carbohydrates. Beta-hydroxybutyrate is the deprotonated form of beta-hydroxybutyric acid having the formula CH₃CH₂OHCH₂COOH; the deprotonated form present at typical biological pH levels is CH₃CH₂OHCH₂COO⁻.

The general chemical structure of beta-hydroxybutyrate has a variable substituent X; when X is a hydrogen, the compound is beta-hydroxybutyric acid; when X is a metal ion or an amino cation, the compound is a beta-hydroxybutyrate salt. Ketone salts are therefore mineral or amino-acid-bound forms of BHB, manufactured synthetically for use as dietary supplements. They are not extracted from a botanical source; rather, they are produced through chemical synthesis or fermentation processes.

BHB or BHB precursors are the most commonly administered ketone moiety, as BHB is the ketone body found in circulation in the greatest abundance, is more stable than acetoacetate and acetone, and therefore easier to formulate.

1.2 Mineral Counterions and Chirality

The novel food form of BHB salts that was reviewed by EFSA consists of sodium, magnesium, and calcium BHB salts, and is proposed to be used by adults as a food ingredient in a number of food categories and as a food supplement. The data provided by the applicant about the identity, the production process, and the compositional data over the course of the risk assessment period were overall considered unsatisfactory.

The novel food as intended to be placed on the market was clarified to be a mixture of 59% BHB-Na, 27% BHB-Mg, and 14% BHB-Ca. Some formulations also include potassium as the mineral counterion.

A significant compositional issue relates to stereochemistry. In their original submission, the applicant implied that the individual salts were racemic mixtures of D,L-BHB but did not provide supportive analytical data. Considering the difference in metabolism between the two enantiomers D- and L-BHB reported in the literature, EFSA subsequently asked the applicant to provide analytical data on the chirality of BHB salts. The IV route typically utilizes a mineral salt of BHB, in either a racemic mixture of D-BHB and L-BHB isoforms, or enantiomerically pure, non-racemic salts of the "physiological" D-BHB isoform.

R(D) BHB and S(L) BHB are two stereoisomers — enantiomers, molecules that are mirror images of each other. While R-βHB is the normal product of human metabolism, it is metabolized much faster than S-βHB. S-βHB is not a normal product of human metabolism; however, it is a transient intermediate of β-oxidation of fatty acids, therefore administration of the same amount of S-βHB may lead to higher levels and more sustained blood levels of S-βHB compared to similar administration of R-βHB.

1.3 Common Forms and Preparations

Exogenous ketone supplements are typically taken as a liquid and contain beta-hydroxybutyrate (also known as 3-hydroxybutyrate), which is often attached to an ester — a ketone ester — or a salt — a ketone salt. Some manufacturers produce ketone supplements in powder or tablet form; however, most research studies have used liquid forms.

The first commercially available exogenous ketone supplements were ketone salts and ketone monoesters. Ketone salts are ketone molecules bound to a mineral and are typically (though not exclusively) available in powder form to be mixed with water prior to ingestion.

Exogenous ketones are commercially available as ketone salts, ketone esters, or the combination of the two. Ketone salts are distinguished from ketone esters (such as (R)-3-hydroxybutyl (R)-3-hydroxybutyrate) in that they do not require enzymatic cleavage of an ester bond and carry an inherent mineral (electrolyte) load with each dose.

2. Traditional and Historical Context

2.1 Endogenous Ketosis: A Deep Evolutionary History

Ketone salts as synthetic supplements have no traditional herbal or cultural use in the manner of botanical medicines. Their development is entirely modern and rooted in 20th-century biochemistry. However, the endogenous ketone bodies that these salts mimic represent one of the most ancient metabolic adaptations in human biology.

The human ability to produce and oxidize ketone bodies arguably evolved to enhance survival during starvation by providing an energy source for the brain and slowing the breakdown of carbohydrate and protein stores.

In the late 1960s, studies of prolonged starvation in subjects with obesity were the first to establish that the ketone bodies, BHB and AcAc, largely replaced glucose as the brain's primary energy source during starvation. Subjects with obesity were fasted for 38 to 41 days, and this work demonstrated how human beings survive and maintain mental function during physiologic hypoglycemia.

2.2 The Ketogenic Diet: Historical Therapeutic Precursor

The impact of ketone bodies on brain function had been anticipated as early as the 1920s, when it was observed that a low-carbohydrate, high-fat diet was successful in treating pediatric epilepsy. Ketogenic diets have been used as metabolic therapy for over a hundred years; it is well known that ketone bodies and BHB not only serve as ancillary fuel substituting for glucose, but also induce anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone deacetylase (HDAC) and G protein-coupled receptors (GPCRs).

2.3 Development of Exogenous Ketone Salts

Early work by Cahill and Owen demonstrated the degree to which the brain can rely on ketones for energy in the face of a glucose deficit. Obese subjects fasted for 5–6 weeks exhibited high levels of ketosis (~6 mM BHB and 1 mM AcAc), and jugular catheterization was performed to analyze arterio-venous differences in metabolites. These measurements showed that two-thirds of cerebral fuel was being provided by BHB and AcAc.

The use of IV BHB in research has been documented since the 1960s. The transition from intravenous research tools to orally consumed supplements occurred decades later. There has been long-standing interest in the development of ingestible forms of ketone bodies that has recently resulted in the commercial availability of exogenous ketone supplements (EKS).

Produced continuously under physiological conditions, blood ketone concentrations increase during starvation. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate "ketogenic" diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown.

3. Key Constituents, Active Compounds, and Mechanisms of Action

3.1 The Three Ketone Bodies

The three main ketone bodies — beta-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone — circulate through the bloodstream and supply energy to peripheral tissues. BHB is quantitatively the most important form present in ketone salt supplements because it is more chemically stable than AcAc and does not volatilize like acetone. BHB is the most abundant ketone body produced during ketosis, a process initiated by glucose depletion and the β-oxidation of fatty acids in hepatocytes.

3.2 Hepatic Production and the BDH1 Enzyme

The same enzyme, β-hydroxybutyrate dehydrogenase (BDH1; EC 1.1.1.30), interconverts BHB and acetoacetate in both the final step of ketogenesis and the first step of BHB utilization. BDH1 imparts chirality to BHB. Regulation of BHB synthesis is controlled via two principal mechanisms: substrate availability in the form of fatty acids, and expression and activity of the enzyme HMG-CoA synthase (HMGCS2; EC 2.3.3.10). Ketogenesis occurs mostly in the liver, although expression of HMGCS2 may be sufficient to produce ketogenesis in other tissues.

3.3 BHB as a Fuel Substrate

Synthesized in the liver through ketogenesis, BHB serves as an essential energy substrate during glucose deprivation, supporting survival by efficiently utilizing fat reserves. It crosses the blood-brain barrier, providing energy for neuronal function.

Of particular relevance to athletes are the metabolic actions of ketone bodies to alter substrate utilisation through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle.

3.4 Signaling Functions: HDAC Inhibition and GPCR Activation

In addition to its activity as an energetic metabolite, BHB is increasingly understood to have cellular signaling functions. These signaling functions of BHB broadly link the outside environment to epigenetic gene regulation and cellular function, and their actions may be relevant to a variety of human diseases as well as human aging.

BHB influences gene expression, lipid metabolism, and inflammation through its inhibition of Class I Histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs), specifically HCAR2 and FFAR3. These actions lead to enhanced mitochondrial function, reduced oxidative stress, and regulation of inflammatory pathways, with implications for muscle maintenance, neuroprotection, and metabolic regulation.

It has been demonstrated that fatty acid-derived β-OHB specifically activates HCAR2 receptors within physiologically relevant β-OHB concentrations (Ki = 0.7 mM), typically observed in serum during short-term fasting.

3.5 Autophagy, Mitochondrial Biogenesis, and Epigenetic Effects

BHB's impact extends to cellular pathways, including autophagy, mitochondrial biogenesis, and epigenetic regulation. By modulating autophagy, BHB ensures mitochondrial integrity and function through intricate molecular pathways involving AMPK, mTOR, PINK1/Parkin, and others. This regulation plays vital roles in neurodegenerative diseases, metabolic disorders, cancer, and cardiovascular diseases, reducing oxidative stress.

3.6 Effects on Neurotransmitters

BHB crosses the blood-brain barrier, providing energy for neuronal function, enhancing cognitive processes such as learning and memory, and offering neuroprotection by modulating synaptic plasticity and neurotransmitter levels.

BHB and AcAc reduce firing rates in neurons of the dentate gyrus by favoring the opening state of the potassium ATP-sensitive (K-ATP) channels, which can be blocked by intracellular ATP. This ion channel modulation is one proposed mechanism underlying the anti-seizure properties of ketone bodies.

4. Scientific Evidence by Area of Use

4.1 Elevation of Blood Ketone Levels: Established Pharmacokinetics

In healthy human volunteers taking part in three randomized metabolic studies of drinks containing a ketone ester (KE) or ketone salts (KS; sodium plus potassium βHB), both drinks delivering ~12 or ~24 g of βHB 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.

Ketone salts are composed of BHB bound to mineral ions such as sodium, potassium, calcium, or magnesium. These salts are generally more palatable and accessible to consumers but deliver lower peak ketone levels — typically 0.5 to 1.0 mmol/L after ingestion. While ketone salts can increase circulating BHB levels, the effects are comparatively modest — typically peaking around 0.5 to 1.0 mmol/L — due to slower absorption rates and lower overall bioavailability.

A randomized crossover pilot study of 13 healthy adults (mean age 21.6 ± 4.3 years) using a triple-blind placebo-controlled design investigated changes in circulating acetoacetate following ketone salt supplementation. Participants consumed either KS or flavor-matched placebo with a one-week washout period, and blood samples were taken before and 30 minutes after consuming each supplement, with plasma acetoacetate and BHB levels measured by gas chromatography/mass spectrometry.

4.2 Athletic and Exercise Performance

Evidence strength: Mixed to weak for salts specifically; predominantly null for performance enhancement.

Exogenous ketone supplements in the form of ketone salts and ketone esters, in addition to ketogenic compounds such as 1,3-butanediol and medium chain triglycerides, facilitate an acute transient increase in circulating AcAc and βHB concentrations, which has been termed "acute nutritional ketosis" or "intermittent exogenous ketosis."

Some studies have suggested beneficial effects of EKS to endurance performance, recovery, and overreaching, although many studies have failed to observe benefits of acute nutritional ketosis on performance or recovery.

A meta-analysis cited in the literature found no overall performance benefit: a meta-analysis including 13 studies in total found that acute ketone supplementation exerts no effects on overall performance (Hedges' g = −0.05; 95% CI: −0.30 to 0.20; P = 0.682). The lack of performance-enhancing effect was confirmed when analyzing separately endurance time-trial performance (Hedges' g = −0.04; 95% CI: −0.35 to 0.28; P = 0.820).

A systematic review aimed to determine the effects of both ketone precursors and monoesters on endurance exercise performance; a systematic search was conducted in PubMed, SPORTDiscus, and CINAHL for randomized controlled trials investigating endurance performance outcomes in response to ingestion of a ketone supplement compared to a nutritive or nonnutritive control in humans. The search yielded 569 articles, of which eight were included (80 participants; 77 men and three women).

One study specifically examining ketone salts — rather than the more potent esters — in a short-term physical performance context reported that blood β-OHB was elevated with KS, peaking at 0.76 ± 0.32 mM. Blood glucose was lower with KS compared with placebo. There were no differences between the treatments for heart rate, rating of perceived exertion, mental arithmetic challenge, or Stroop Color Word. Overall, this study suggests that KSs are not effective aids for enhancing cognitive performance during a dual-stress challenge, which might partially be explained by the inability of currently available commercial KS supplements to elevate β-OHB blood concentrations above ~1.0 mM.

A 2025 systematic review of aerobic performance in endurance runners evaluated the effects of ketogenic diets or ketone supplements (ketone esters or ketone salts, medium-chain triglycerides, or 1,3-butanediol) on the aerobic performance of adult endurance runners, with a systematic search conducted in PubMed, Web of Science, ProQuest, and Science Direct for publications up to October 2023, including human studies after independent screening by two reviewers.

4.3 Blood Glucose and Glycemic Control

Evidence strength: Moderate for acute glucose lowering; preliminary for clinical glycemic benefit in disease.

Recently developed ketone (monoester or salt) supplements acutely elevate blood β-hydroxybutyrate (BHB) exogenously without prolonged periods of fasting or carbohydrate restriction. Previous (small-scale) studies have found a blood glucose-lowering effect.

A systematic review and meta-analysis published in Advances in Nutrition (2022) examined this effect across a range of study types. Across both analyses, significantly greater effects were seen with ketone monoesters compared with salts (P < 0.001). The available evidence indicates that acute ingestion of exogenous ketones leads to increased blood BHB and decreased blood glucose. Limited evidence on prolonged ketone supplementation was found.

Overall, these findings show that exogenous ketones are capable of both lowering blood glucose in the fasted state and attenuating postprandial glucose excursions, with a recent meta-analysis suggesting a strong linear relationship between plasma β-OHB exposure (i.e., measures of peak concentration as well as the area under the curve) and the extent of the glucose-lowering effect. It has repeatedly been demonstrated that exogenous ketones — either intravenously or orally administered — decrease endogenous glucose production.

These studies highlight the therapeutic potential of exogenous ketone supplementation for hyperglycaemia-related conditions such as insulin resistance and type 2 diabetes. However, most evidence for meaningful glucose lowering comes from ketone ester studies achieving higher peak BHB concentrations; the more modest BHB elevations produced by commercially available ketone salts show correspondingly smaller effects.

4.4 Cognitive Function and Brain Metabolism

Evidence strength: Preliminary in healthy adults; some signal in populations with metabolic or cognitive impairment.

When glucose availability is acutely reduced by experimental hypoglycemia, additional provision of ketones either by infusion or ingestion of medium-chain fatty acids preserves cognitive functions in patients with type 1 diabetes and healthy individuals, and increases the glycemic threshold for symptoms and the counter-regulatory hormone response. This suggests that ketone bodies are not only able to save glucose, but also support brain metabolism during energy crises without prior adaptations from fasting.

In 1967, ketone bodies were discovered to replace glucose as the major fuel of the brain in situations of prolonged fasting or glucose shortage, being able to supply up to 60% of the energy needs of the brain.

A 2025 systematic review and meta-analysis on exogenous ketone bodies and cognition identified a range of outcomes. The most common outcomes evaluated focused on cognitive function and physical performance. Cognitive function was assessed using various tools, with the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) being the most frequently used. Neuropsychological tests such as the Trail Making Test and Stroop Test were also commonly employed. These assessments were applied across diverse populations, including healthy adults, individuals with MCI, and patients with AD.

One randomized crossover trial of ketone ester (not salt) in 20 subjects (10 with metabolic syndrome, 10 without) found that cognitive function, subjective appetite, and respiratory gases were measured at baseline and for 2 hours following ingestion of a randomly assigned KE or placebo drink, and that post-trial food intake was also collected. Independent of metabolic syndrome group, indices of working memory significantly improved (p ≤ .035), and blood glucose significantly decreased (p < .001), following KE ingestion. This finding is from a ketone ester study and may not generalize to the lower BHB concentrations typically achieved with ketone salts.

A study in a mild cognitive impairment context found: in a randomized controlled trial, six months of consuming an MCT-based ketogenic drink improved recall, verbal fluency, confrontation naming, and visual attention and task switching in humans with MCI. Some of the observed benefits correlated positively with blood ketone concentration, supporting a potential central role. This study used an MCT-based formulation, not BHB salts directly.

For healthy adults without neurological impairment, a study specifically using commercial ketone salt supplements concluded: KSs are not effective aids for enhancing cognitive performance during a dual-stress challenge, which might partially be explained by the inability of currently available commercial KS supplements to elevate β-OHB blood concentrations above approximately 1.0 mM.

4.5 Neurological Disease: Alzheimer's Disease and Mild Cognitive Impairment

Evidence strength: Emerging for ketone-based interventions broadly; insufficient clinical data specific to ketone salts.

Elevated ketones are associated with improved cognitive performance and associated cognitive impairments such as Alzheimer's Disease. Improvements in metabolic health such as improved glucose tolerance and insulin sensitivity and reduced blood pressure may also be relevant.

Most age-related neurodegenerative diseases are characterized by cognitive impairment, with one of the most common being Alzheimer's disease (AD). The theoretical basis for using exogenous ketones in AD rests on evidence of brain glucose hypometabolism in AD patients, with ketones proposed as an alternative fuel. However, the published human trial evidence in this area uses primarily ketone esters or MCT supplementation; direct evidence from ketone salt supplementation in AD or MCI populations specifically remains limited at the time of this writing.

4.6 Cardiovascular and Metabolic Health

Evidence strength: Preliminary; largely mechanistic and short-term.

Improvements in metabolic health such as improved glucose tolerance and insulin sensitivity and reduced blood pressure, circulating triglycerides, and inflammation may occur with elevated ketone levels, thereby improving related conditions such as cardiovascular disease and type 2 diabetes. However, these are largely hypothesized associations based on short-term biomarker changes, not established outcomes from long-term trials of ketone salt supplementation.

BHB's ability to modulate adipose tissue lipolysis and immune responses highlights its broader potential in managing chronic metabolic conditions and aging.

4.7 Seizure Disorders and Neuroprotection

Evidence strength: Established for the ketogenic diet; very limited and indirect for exogenous ketone salts specifically.

In the 1920s, researchers developed a fat-based diet that induces the same metabolic shift without the need for calorie restriction. The ketogenic diet, as it is known, has since been used as a non-pharmaceutical treatment of pediatric epilepsy.

Ketone diet emulsions and combined ketone diet emulsion plus MCT combination treatments were effective in preventing hyperbaric oxygen-induced tonic-clonic seizures in rats, but BHB in ketone salt form and 1,3-butanediol were not. This animal study specifically found ketone salts to be less effective than other ketone formulations in a seizure model, underscoring the importance of distinguishing between different exogenous ketone preparations.

5. Body Systems and Health Areas

Based on the published mechanistic and clinical literature, ketone salts and their active component BHB are associated with the following body systems and health domains:

• Central Nervous System: BHB crosses the blood-brain barrier, providing energy for neuronal function, enhancing cognitive processes such as learning and memory, and offering neuroprotection by modulating synaptic plasticity and neurotransmitter levels.
• Metabolic/Endocrine System: BHB influences gene expression, lipid metabolism, and inflammation through its inhibition of Class I HDACs and activation of GPCRs, specifically HCAR2 and FFAR3.
• Cardiovascular System: Cardiac output has been found to increase with increasing BHB concentration during IV infusion, and cognitive function improved with increasing BHB concentration with oral ketone supplementation.
• Skeletal Muscle: Ketone bodies may attenuate proteolysis in skeletal muscle, which has implications for muscle preservation during caloric restriction or metabolic stress.
• Adipose Tissue: β-OHB activates HCAR2 receptors and reduces lipolysis in adipocytes, possibly creating a negative feedback mechanism to regulate availability of fat.
• Mitochondrial and Cellular Homeostasis: By modulating autophagy, BHB ensures mitochondrial integrity and function through intricate molecular pathways involving AMPK, mTOR, PINK1/Parkin, and others.

6. Dosage Forms and Dosages Reported in Studies

Exogenous ketone supplements are typically taken as a liquid and contain beta-hydroxybutyrate, often attached to a salt. Some manufacturers produce ketone supplements in powder or tablet form; however, most research studies have used liquid forms.

The dosage range reported across human studies for ketone salts is wide. For ketone salts specifically, dosages used in studies range from 140 to 468 milligrams per kilogram of body weight, or a total of 6 to 36 grams.

In the Stubbs et al. comparison study of a ketone ester versus ketone salts (KS; sodium plus potassium BHB), 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations, with KE achieving D-βHB Cmax of 2.8 mM and KS achieving D-βHB Cmax of 1.0 mM, which returned to baseline within 3–4 h.

In a tolerability and acceptability study, the purpose was to examine the tolerability, acceptability, and circulating R-beta-hydroxybutyrate and glucose responses to a ketone monoester and ketone monoester/salt combination at 5 g and 10 g total R-βHB compared with placebo control. The five study conditions included placebo control, 5 g ketone monoester, 10 g ketone monoester, 5 g ketone monoester/salt, and 10 g ketone monoester/salt.

In a safety and tolerability study of free D-BHB (not bound as a salt), the investigators evaluated the safety and tolerability of orally administered free D-BHB in a gender- and age-balanced sample of 24 asymptomatic and overtly healthy adults. The study monitored clinical parameters over 4 weeks.

While the number of published studies in humans is limited, most studies show that exogenous ketones can safely and effectively increase circulating ketone concentrations without introducing extensive dietary changes such as energy or carbohydrate restriction.

7. Safety Considerations and Interactions

7.1 EFSA Regulatory Assessment

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens was asked to deliver an opinion on β-hydroxybutyrate salts as a novel food pursuant to Regulation (EU) 2015/2283. The novel food consists of sodium, magnesium and calcium BHB salts and is proposed to be used by adults as a food ingredient in a number of food categories and as food supplement. The data provided by the applicant about the identity, the production process and the compositional data over the course of the risk assessment period were overall considered unsatisfactory.

The EFSA Panel noted inconsistencies in the reporting of the test item used in the subchronic toxicity study and human studies provided by the applicant.

7.2 Gastrointestinal Adverse Effects

A study by Stubbs and colleagues found that lower GI symptoms were more frequent and severe for ketone salts compared with ketone monoester. Ultimately, the higher salt load of ketone salts may result in lower tolerability compared with KME, although KME may be less acceptable due to its strong, unpleasant flavor.

In the tolerability study of free D-BHB over 4 weeks: the most reported secondary effects (19/720 or 2.6%) were gastrointestinal discomfort, headache (7/720 or 1%), and loss of appetite (7/720 or 1%). The rest of the reported secondary symptoms were reported less than 1% of the time.

No participant showed acid-base abnormalities or electrolyte abnormalities. Secondary symptoms were reported after only 6.2% of all drink takes, and none of the reports described the symptom as "severe."

7.3 Electrolyte Load and Cardiovascular Considerations

Because ketone salts deliver minerals like sodium, calcium, magnesium, and potassium, frequent or high-dose use may disrupt electrolyte balance, especially in people with kidney or heart conditions.

In an adolescent safety study using BHB bound to sodium, calcium, and magnesium salts: the study found that systolic blood pressure, diastolic blood pressure, heart rate, and oxygen saturation were unaffected in the resting state. Previous research had found that IV infusion of ketone salts raised heart rate. This contrary finding may be attributed to the ingestion method, health and age of the subjects, and the combination of ketone salts with glucose that was infused.

The big safety gap is long-term data. Most trials last hours to weeks. We lack high-quality evidence about chronic daily use over months or years and effects on kidney function, mineral balance, cardiovascular risk, or metabolic regulation.

7.4 Blood Glucose Lowering and Hypoglycemia Risk

Exogenous ketones can lower blood glucose levels. For patients with diabetes on insulin or oral medications, this may increase the risk of hypoglycemia if not carefully monitored.

This glucose-lowering effect has been demonstrated consistently. A recent meta-analysis suggested a strong linear relationship between plasma β-OHB exposure (i.e., measures of peak concentration as well as the area under the curve) and the extent of the glucose-lowering effect.

7.5 Racemic Mixtures and the L-BHB Question

Most commercially available ketone salts were originally reported as racemic mixtures of D,L-BHB. EFSA subsequently asked applicants to provide analytical data on the chirality of BHB salts, given the difference in metabolism between the two enantiomers reported in the literature. R(D) BHB and S(L) BHB are two stereoisomers. While R-βHB is the normal product of human metabolism, it is metabolized much faster than S-βHB. S-βHB is not a normal product of human metabolism; however, it is a transient intermediate of β-oxidation of fatty acids, and administration of the same amount of S-βHB may lead to higher levels and more sustained blood levels of S-βHB. The long-term safety profile of circulating L-BHB in humans has not been systematically established.

7.6 Populations Requiring Caution

Ketone salts can increase electrolyte levels. Higher levels can be harmful if a person has a medical condition, such as kidney disease, that affects their ability to regulate electrolytes.

A number of questions need to be addressed by the field for optimal use in humans, including variable responses among available exogenous ketones at different dosages, frequency of dosing, and their tolerability, acceptability, and efficacy in long-term clinical trials.

7.7 Evidence Gaps and Limitations

While findings show BHB as a promising therapeutic agent, further research is required to determine optimal dosing strategies, long-term effects, and its translational potential in clinical settings. Understanding BHB's mechanisms will facilitate its development as a novel therapeutic strategy for multiple organ systems affected by aging and disease.

It is important to note that the majority of the mechanistic literature concerns BHB generally — whether produced endogenously, delivered intravenously, or via ketone esters. Human clinical trials specifically and exclusively using oral ketone salt formulations remain comparatively limited, and the peak BHB concentrations achievable with ketone salts (~0.5–1.0 mM) are consistently lower than those from ketone esters (~1.5–3.0 mM), which may limit the magnitude of physiological effects observed in salt-specific studies.

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