Exogenous Ketones

    Researchedby:
    Thomas Solomon

    Fact-checked

    by:

    Katie Jantz, Conni Covington
    Last Updated: March 27, 2025

    Exogenous ketones are supplements that mimic ketosis by increasing ketone bodies in the blood. Supplementation with exogenous ketones might improve glycemic control, cognition, and heart function.

    What are exogenous ketones?

    Exogenous ketones are synthetic ketones consumed in supplement form that mimic the state of ketosis — i.e., they cause a temporary increase in the concentration of beta-hydroxybutyrate (a ketone body) in the blood.[19][11][10][20] Such supplements are called “exogenous” because they come from an external source (e.g., a supplement) rather than being produced naturally by the body.

    The active ingredient in exogenous ketone supplements is typically beta-hydroxybutyrate (a.k.a. 3-hydroxybutyrate), which is often attached to an ester — a ketone ester — or a sodium/potassium/magnesium salt — a ketone salt.[21][22][23] However, some exogenous ketone supplements contain a ketone precursor (e.g., 1,3-butanediol) that is metabolized by the liver after ingestion to produce beta-hydroxybutyrate.[21][22][23]

    What are exogenous ketones’s main benefits?

    Cognitive function

    Preclinical studies in rodents have shown that exogenous ketones can enhance cognitive function.[24][25][26][27] Some randomized controlled trials have also found that supplementation with exogenous ketones can improve aspects of cognitive function in people under conditions of metabolic stress (e.g., fasting, exercise, or hypoxia, which is a condition when the body is deprived of an adequate oxygen supply)[1][2][3][4][5][6] and in people with neurodegenerative conditions (e.g., Alzheimer’s disease).[28] However, the effects in humans vary considerably, and some clinical trials have found no benefit of exogenous ketones on cognitive function.[7][8][9] Further high-quality randomized controlled trials are needed to understand the therapeutic efficacy of ketones in people with mild cognitive impairment or Alzheimer's disease.

    Glycemic control

    Two meta-analyses have found that supplementation with exogenous ketones can lower blood glucose and increase insulin in people with obesity and prediabetes and in people without known health conditions.[10][11] Some,[12][13] but not all,[14][15] randomized controlled trials have found similar effects in people with type 2 diabetes. More research is needed to determine the efficacy of exogenous ketones in treating diabetes.

    Heart failure

    One meta-analysis has shown that exogenous ketones can increase the left ventricular ejection fraction, cardiac output, and stroke volume — signs of improved cardiac function — in people with heart failure, without influencing the heart rate or blood pressure.[16] A subgroup analysis in that study found that exogenous ketones can also enhance cardiac function in people without heart failure.[16] However, there was a high risk of bias among the included studies, and the analysis combined different types of ketone delivery: intravenously infused beta-hydroxybutyrate and orally administered ketone esters. That said, two further randomized controlled trials that used an orally ingested ketone ester have confirmed the findings of the meta-analysis described above in heart failure patients and people with type 2 diabetes.[17][18]

    Which type of exogenous ketone is most effective: a ketone salt, a ketone ester, or a ketone precursor (a pro-ketone)?Are ketone precursors (pro-ketones) an effective alternative to exogenous ketones?Do exogenous ketones cause weight loss?Do exogenous ketones improve exercise performance?Do exogenous ketones increase erythropoietin (EPO)?Are exogenous ketones effective for treating McArdle disease?Do exogenous ketones treat multiple acyl-coA dehydrogenase deficiency (MADD)?

    What are exogenous ketones’s main drawbacks?

    The main adverse effects of taking exogenous ketones include headaches and gastrointestinal problems like nausea, diarrhea, flatulence, belching, heartburn, abdominal pain, and bloating.[10][11][29][30][20][31] However, these side effects are typically mild, and exogenous ketones are generally considered to be safe for consumption.[30][20][31] That said, there is a lack of studies thoroughly examining the dose-response relationship and pharmacokinetics of exogenous ketones in humans, and their safety is not fully understood.

    Another drawback of exogenous ketones is that, although consuming them can mimic signs of ketosis (a raised beta-hydroxybutyrate concentration in the blood),[19][11][10][20] unlike other interventions that induce ketosis (a ketogenic diet or fasting), exogenous ketones do not cause the body to burn its own fat stores. Therefore, exogenous ketones are not a replacement for interventions designed to induce weight loss. See Do exogenous ketones cause weight loss? for more details.

    It is also important to note that much of the evidence about the benefits of exogenous ketones has a moderate to high risk of bias because there are few studies,[28][16] small sample sizes,[28] inadequate reporting about randomization and blinding,[16] a high level of heterogeneity between the studies,[28][10][11] and potential conflicts of interest (studies being funded/authored by manufacturers of exogenous ketone supplements).[10][11] Furthermore, many studies use an off-the-shelf consumer product containing exogenous ketones but do not independently analyze the product to confirm its composition and purity. Doing this would increase confidence in the study findings.

    How do exogenous ketones work?

    During periods of low glucose availability, e.g., fasting, ketogenic diet, or long-duration exercise, the endogenous (in-the-body) production of ketone bodies increases to maintain an adequate supply of energy. Ketone bodies like beta-hydroxybutyrate act as a transportable form of acetyl-CoA that can be converted into adenosine triphosphate (ATP) in organs of the body.[34][35][36][37] Beta-hydroxybutyrate can also regulate gene expression, neuronal function, and metabolic rate, either directly or indirectly through the metabolites into which it is converted.[35][38][37] Furthermore, beta-hydroxybutyrate can inhibit the activity of histone deacetylases, which means it may play a role in epigenetics, a process where modifications to DNA regulate whether genes are turned on or off.[35][38][37] Consequently, because consuming exogenous ketones[19][11][10][20] (including ketone precursors like 1,3-butanediol)[21][22][23] increases the circulating concentration of beta-hydroxybutyrate in the blood, exogenous ketones could provide energy to the body and regulate gene expression, etc.

    How do exogenous ketones improve cognitive function?

    Because exogenous ketones increase beta-hydroxybutyrate levels, it is plausible that they provide an additional source of energy for the brain during periods of high energy demand, like during stressful cognitive tasks.[36][39][40] Additionally, intravenous infusion of beta-hydroxybutyrate in humans has been shown to increase blood flow and oxygen uptake in the brain,[41] which might help improve nutrient and oxygen delivery to the brain during cognitive tasks. Studies in rodents and other preclinical models have also shown that ketones can reduce inflammation in the brain by blunting the release of glutamate from astrocytes (cells in the central nervous system).[27]

    How do exogenous ketones improve glycemic control?

    Meta-analyses have found that exogenous ketones can increase serum insulin,[10][11] a hormone that increases glucose uptake, which potentially explains how ketones can lower blood glucose. However, clinical studies have also shown that ketones can decrease the blood concentrations of alanine,[42] which is a precursor for gluconeogenesis (the production of new glucose). This is relevant because reducing gluconeogenesis would lower the amount of glucose released by the liver into the blood and thus lower blood glucose.

    How do exogenous ketones improve cardiac function?

    By raising beta-hydroxybutyrate levels in the blood, exogenous ketones might provide an additional source of energy for the contractile muscles in the heart to help increase the left ventricular ejection fraction and cardiac output in people with heart failure.[16] Furthermore, in vitro studies in cardiac muscle cells have shown that ketone bodies can regulate the production of reactive oxygen species,[37][43][44] which are involved in oxidative stress. However, the precise mechanisms for the effect of exogenous ketones on cardiac function and other outcomes, like cognitive function and blood glucose control, need further exploration.

    What are other names for Exogenous Ketones?

    Note that Exogenous Ketones is also known as:

    • Ketone salt
    • Ketone ester
    • Ketone monoester
    • 3-hydroxybutyrate
    • 3-hydroxybutyric acid
    • Beta-hydroxybutyrate (β-hydroxybutyrate)
    • Beta-hydroxybutyric acid (β-hydroxybutyric acid)
    • D,L-3-hydroxybutyrate
    • 1,3-butanediol (a ketone precursor)
    • R-1,3-butanediol (a ketone precursor)

    Exogenous Ketones should not be confused with:

    Dosage information

    Formulation:

    Exogenous ketone supplements are typically taken as a liquid and contain beta-hydroxybutyrate (a.k.a. 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.

    Range of dosages studied:

    Ketone esters: 115 to 1,500 milligrams per kilogram of body weight or a total of 12 to 25 grams.

    Ketone salts: 140 to 468 milligrams per kilogram of body weight or a total of 6 to 36 grams.

    Effective Dosages:

    Cognitive function

    Adults: The effective dosage for improving cognitive function in people under conditions of metabolic stress (e.g., fasting, hypoxia, or exercise) is a single dose of ketone ester (375 to 750 milligrams per kilogram of body weight or a total of 25 grams) taken by mouth 20 to 30 minutes before testing.[1][2][3][4] Benefits have also been found with daily use of a ketone salt (12 grams twice a day) or a ketone ester (12 grams three times a day) taken by mouth for 2 to 6 weeks.[5][6]

    Special considerations: In studies that show a benefit, ketone supplements are typically taken without food. However, the effects in humans vary considerably, and not all the trials find a benefit.[7][8][9] Furthermore, due to a lack of dose-response studies and meta-analyses, the precise effective dose and most effective type of ketone are uncertain. Additionally, further research is needed to understand the therapeutic efficacy of ketones in people with mild cognitive impairment or Alzheimer's disease.

    Glycemic control

    Adults: The effective dosage for improving glycemic control (lowering blood glucose) is a single dose of ketone ester (250 to 1,500 milligrams per kilogram of body weight or a total of 12 to 25 grams) or a ketone salt (140 to 468 milligrams per kilogram of body weight or a total of 6 to 36 grams) taken by mouth before a meal.[10][11] Benefits have also been found with daily use (12 to 25 grams of a ketone ester or 12 grams of a ketone salt) taken by mouth one to three times per day for 2 to 6 weeks.[10][11]

    Special considerations: Some trials have found similar effects in people with type 2 diabetes,[12][13] but outcomes are mixed,[14][15] and more research is needed. Meta-regression analyses are also needed to determine the optimal dose and ketone type. Ketone supplements are not typically taken with food in the studies that have tested their effects.

    Heart failure

    Adults: The effective dosage for improving cardiac function (increases left ventricular ejection fraction, cardiac output, and stroke volume) is a single dose of ketone ester (115 to 500 milligrams per kilogram of body weight or a total of 25 grams) taken by mouth before the test.[16][17][18] Benefits have also been found with daily use of a ketone ester (25 grams four times a day) taken by mouth for 2 weeks.[16][17]

    Special considerations: Ketone supplements are not typically taken with food in the studies that have tested their effects. However, due to the scarcity of studies, future research is needed to clarify the optimal dose and type of ketone for improving cardiac function.

    Other Considerations:

    Frequently asked questions

    What are exogenous ketones?

    Exogenous ketones are synthetic ketones consumed in supplement form that mimic the state of ketosis — i.e., they cause a temporary increase in the concentration of beta-hydroxybutyrate (a ketone body) in the blood.[19][11][10][20] Such supplements are called “exogenous” because they come from an external source (e.g., a supplement) rather than being produced naturally by the body.

    The active ingredient in exogenous ketone supplements is typically beta-hydroxybutyrate (a.k.a. 3-hydroxybutyrate), which is often attached to an ester — a ketone ester — or a sodium/potassium/magnesium salt — a ketone salt.[21][22][23] However, some exogenous ketone supplements contain a ketone precursor (e.g., 1,3-butanediol) that is metabolized by the liver after ingestion to produce beta-hydroxybutyrate.[21][22][23]

    What are exogenous ketones’s main benefits?

    Cognitive function

    Preclinical studies in rodents have shown that exogenous ketones can enhance cognitive function.[24][25][26][27] Some randomized controlled trials have also found that supplementation with exogenous ketones can improve aspects of cognitive function in people under conditions of metabolic stress (e.g., fasting, exercise, or hypoxia, which is a condition when the body is deprived of an adequate oxygen supply)[1][2][3][4][5][6] and in people with neurodegenerative conditions (e.g., Alzheimer’s disease).[28] However, the effects in humans vary considerably, and some clinical trials have found no benefit of exogenous ketones on cognitive function.[7][8][9] Further high-quality randomized controlled trials are needed to understand the therapeutic efficacy of ketones in people with mild cognitive impairment or Alzheimer's disease.

    Glycemic control

    Two meta-analyses have found that supplementation with exogenous ketones can lower blood glucose and increase insulin in people with obesity and prediabetes and in people without known health conditions.[10][11] Some,[12][13] but not all,[14][15] randomized controlled trials have found similar effects in people with type 2 diabetes. More research is needed to determine the efficacy of exogenous ketones in treating diabetes.

    Heart failure

    One meta-analysis has shown that exogenous ketones can increase the left ventricular ejection fraction, cardiac output, and stroke volume — signs of improved cardiac function — in people with heart failure, without influencing the heart rate or blood pressure.[16] A subgroup analysis in that study found that exogenous ketones can also enhance cardiac function in people without heart failure.[16] However, there was a high risk of bias among the included studies, and the analysis combined different types of ketone delivery: intravenously infused beta-hydroxybutyrate and orally administered ketone esters. That said, two further randomized controlled trials that used an orally ingested ketone ester have confirmed the findings of the meta-analysis described above in heart failure patients and people with type 2 diabetes.[17][18]

    Which type of exogenous ketone is most effective: a ketone salt, a ketone ester, or a ketone precursor (a pro-ketone)?

    While some evidence shows that ketone esters have a greater effect than ketone salts on increasing ketone body concentrations and lowering blood glucose,[11] not all the studies show this difference.[10] However, the precise type of ketone being studied is often unclear because the terms “exogenous ketone” and “ketone ester” are used interchangeably to describe isolated ketone bodies (e.g., beta-hydroxybutyrate), ketone esters (e.g., beta-hydroxybutyrate attached to 1,3-butanediol), and ketone precursors (isolated 1,3-butanediol).[45][46] Consequently, the comparative effects of ketone salts vs. ketone esters vs. ketone precursors (sometimes called pro-ketones) have not been adequately studied to determine which type of exogenous ketone supplement might have the greatest efficacy.

    Are ketone precursors (pro-ketones) an effective alternative to exogenous ketones?

    Ketone precursors — sometimes called pre-ketones — include 1,3-butanediol, bis hexanoyl (R)-1,3-butanediol, and bis octanoyl (R)-1,3-butanediol, which are metabolized in the liver to produce the ketone bodies beta-hydroxybutyrate and acetoacetate.[21][22][23][47][48][49][50][51] Therefore, ingesting a ketone precursor increases the concentration of beta-hydroxybutyrate in the blood and mimics ketosis.[52][51][53][54][55] Companies like ketone-IQ (formerly HVMN) sell products containing 1,3-butanediol and claim a wide variety of benefits. However, as described below, there are few clinical studies.

    A single dose of 1,3-butanediol increased cardiac output, stroke volume, and the left ventricular ejection fraction in men with heart failure in a small randomized controlled trial.[56] Further larger studies are needed to confirm these effects.

    Ingesting a single dose of 1,3-butanediol either before or before and during exercise did not affect aerobic exercise performance during running or cycling, as shown by two small randomized controlled trials.[57][58]

    The effects on blood glucose are mixed. One small study found that a single dose of bis octanoyl (R)-1,3-butanediol did not affect fasting blood glucose in older adults.[54] However, this study did not include a control group,[54] so firm conclusions cannot be made. Another study found that a single dose of bis hexanoyl (R)-1,3-butanediol lowered postprandial blood glucose when taken before a carbohydrate-containing meal.[51] However, this study also lacked a control group.[51] A follow-up study that included a control group found no effect on blood glucose.[53]

    Generally, there are very few randomized controlled trials on ketone precursors, and much of the existing work is of low quality. Further high-quality research is needed to make firm conclusions about the effects of ketone precursors on health and performance.

    Do exogenous ketones cause weight loss?

    A ketogenic diet, which induces a state of ketosis (raised concentrations of ketone bodies in the blood), is often used to help with weight loss. Supplementation with exogenous ketones, which also increases blood concentrations of ketone bodies, has been touted as a simple alternative to a ketogenic diet. However, is this approach an effective tool for weight loss?

    Evidence from in vitro studies shows that beta-hydroxybutyrate, a ketone body, can regulate pathways involved in sympathetic nervous system (“fight or flight”) activation and energy expenditure.[59] Preclinical studies in rats have also found that infusing beta-hydroxybutyrate can stimulate leptin — a hormone that regulates food and energy intake — and decrease body weight.[60] Further studies in rodents have shown that short-term feeding with a ketone ester can decrease ad libitum food intake[61] and cause weight loss.[62][63][64] However, not all preclinical studies have found beneficial effects of exogenous ketones on total daily energy expenditure or body weight.[65]

    Although preclinical studies show promise, the clinical effects of exogenous ketones on energy intake and weight loss are not well understood. A series of small randomized controlled trials has found that a single dose of exogenous ketones (either beta-hydroxybutyrate or a ketone ester) can slow the gastric emptying rate,[66] lower feelings of hunger and appetite,[67][68] increase feelings of satiety and fullness,[68] and decrease energy intake during ad libitum eating.[14]

    However, some trials do not support the findings described above, showing no effects on hunger,[14] fullness,[14] or appetite.[66] Furthermore, there are mixed effects on the plasma concentrations of gut hormones that regulate appetite and satiety. For example, exogenous ketones do not affect glucose-dependent insulinotropic polypeptide [66][68] but can decrease ghrelin[68][67] and peptide YY.[67] Meanwhile, there was an increase in cholecystokinin in some[66] but not all[68] studies and a decrease in glucagon-like peptide 1 (GLP-1) in some[67] but not all[66][68] studies.

    Additionally, the clinical effects on weight loss are also mixed. One randomized controlled crossover study found that 14 days of daily supplementation with beta-hydroxybutyrate led to an approximately 1 kg (2 lb) decrease in body weight in 15 people with obesity,[69] but another trial in 20 women did not find that beta-hydroxybutyrate influenced diet-induced weight-loss.[70]

    In summary, while preclinical evidence is compelling, clinical evidence is sparse, and larger, high-quality randomized controlled trials are needed to make conclusions about the efficacy of exogenous ketones on weight loss and the regulation of energy intake.

    Do exogenous ketones improve exercise performance?

    While some small studies have shown the benefits of exogenous ketones on exercise performance, meta-analyses have found that supplementation with exogenous ketones does not improve aerobic exercise performance.[29][71][72] This includes both running and cycling performance (as measured by time trials and time to exhaustion tests) and aerobic exercise metrics such as VO2max, economy/efficiency, and RPE. Meta-analyses have also found that exogenous ketones do not improve anaerobic exercise performance such as during sprinting.[71] However, as described below, there are some important caveats.

    Firstly, several studies have provided an exogenous ketone combined with carbohydrates and lack a comparator group who did not take carbohydrates.[72][29][71][73] This approach could mask any potential benefit of ketones, because ingesting carbohydrates during exercise has a powerful beneficial effect on performance.[74][75][76][77][78][79]

    Secondly, many studies have examined the effect of exogenous ketones on exercise performance when participants are fresh and not fatigued.[72][29][71][73] Because ketone bodies become a primary fuel source for tissues during hypoglycemia (when blood glucose concentrations are low) and because hypoglycemia can arise during long-duration aerobic exercise, it would be prudent to study the effects of exogenous ketone supplementation under these conditions. Only one study to date has examined the efficacy of exogenous ketone for improving cycling time trial performance following a fatiguing long-duration bout (4 hours of cycling) and found no benefit.[80] Additional randomized controlled trials are needed to understand whether exogenous ketones can improve performance when people are fatigued and/or hypoglycemic. This would help answer whether exogenous ketones can improve performance during long-duration bouts such as ultra-distance events.

    Do exogenous ketones increase erythropoietin (EPO)?

    Erythropoietin (EPO) is a hormone primarily produced by the kidneys that stimulates the production of red blood cells in the bone marrow, a process known as erythropoiesis.[81][82] This process is typically triggered when oxygen levels in the blood drop, and it helps maintain oxygen delivery throughout the body.[81][82]

    Some trials have examined the effect of exogenous ketones on serum EPO concentrations. A small randomized controlled trial in 17 adults found an increase in EPO following an intravenous infusion of beta-hydroxybutyrate administered the morning after an overnight fast (no breakfast).[83] Another randomized controlled trial in 20 recreationally active men found an increase in EPO following 3 weeks of endurance training during which ketone ester was consumed daily after each training session and before sleep.[84] Similarly, a small randomized controlled crossover study in 9 recreationally active men found that consuming a ketone ester after a 1-hour exercise bout without eating breakfast increased EPO for up to 4 hours.[85] However, another trial found that when carbohydrates are consumed before exercise, consuming a ketone ester after exercise does not affect EPO.[86] Because these outcomes are somewhat mixed and because the trials are small, more research is needed to determine whether exogenous ketones have a robust stimulating effect on serum EPO concentrations.

    As a side note, EPO is on the World Anti-Doping Agency prohibited list because it is a performance-enhancing drug.[87] So, if consuming an exogenous ketone had a meaningful effect on EPO, we would also expect to see an increase in exercise performance. However, the current evidence shows that supplementation with exogenous ketones does not improve exercise performance (see Do exogenous ketones improve exercise performance?).

    Are exogenous ketones effective for treating McArdle disease?

    McArdle disease is a rare genetic condition that prevents the body from breaking down glycogen. Therefore, people with McArdle disease have a limited exercise capacity because, although they can burn glucose in the blood, they cannot break glycogen down into glucose so it can be used as a fuel. Consequently, providing an alternative fuel may improve the quality of life for people with McArdle disease.

    Only two studies have examined the effect of exogenous ketones on exercise capacity in people with McArdle disease. A randomized crossover study by Valenzuela et al. found that ingesting a single dose of a ketone ester before an exercise test impaired maximal exercise capacity (lowered peak power output) compared to a placebo.[88] Neither the maximal heart rate nor the rating of perceived exertion (RPE) during this test were affected by the ketone ester.[88] Another randomized crossover study by Løkken et al. did not find an effect of a ketone ester on aerobic exercise metrics (e.g., heart rate and RPE) during submaximal exercise compared to a placebo.[89] Consequently, the current evidence does not support a beneficial effect of ketone supplementation on exercise capacity in people with McArdle disease.

    Notably, the study by Valenzuela et al. also found that people with McArdle disease who ingested a carbohydrate-containing drink before the exercise test showed an increase in VO2max compared to a placebo.[88] Other studies confirm that carbohydrate supplementation before exercise[90][91] and a carbohydrate-rich diet[92][93] can improve exercise capacity in McArdle disease.

    Do exogenous ketones treat multiple acyl-coA dehydrogenase deficiency (MADD)?

    Multiple acyl-coA dehydrogenase deficiency (MADD) is a rare inherited metabolic condition that reduces the body's ability to break down fats and proteins to produce adenosine triphosphate (ATP; i.e., energy).[94] MADD is caused by mutations in genes involved in mitochondrial electron transfer, which is crucial for energy production.[94] Without appropriate treatment, MADD can cause metabolic acidosis, hypoglycemia (low blood sugar), skeletal abnormalities, myopathy (muscle weakness), fatigue, poor exercise capacity, hepatomegaly (liver enlargement), and cardiomyopathy (heart defects), and it can be fatal.[94]

    Standard treatment includes supplementation with riboflavin (vitamin B2) and L-carntine, a high-carbohydrate diet, and the avoidance of fasting.[94] However, a retrospective cohort study of 23 people with MADD found that supplementation with D,L-3-hydroxybutyrate improved cardiomyopathy, liver symptoms, muscle symptoms, and respiratory failure in some of the participants.[95] While this sounds promising, high-quality randomized controlled trials are needed to adequately determine the efficacy of exogenous ketones in the treatment of MADD.

    What are exogenous ketones’s main drawbacks?

    The main adverse effects of taking exogenous ketones include headaches and gastrointestinal problems like nausea, diarrhea, flatulence, belching, heartburn, abdominal pain, and bloating.[10][11][29][30][20][31] However, these side effects are typically mild, and exogenous ketones are generally considered to be safe for consumption.[30][20][31] That said, there is a lack of studies thoroughly examining the dose-response relationship and pharmacokinetics of exogenous ketones in humans, and their safety is not fully understood.

    Another drawback of exogenous ketones is that, although consuming them can mimic signs of ketosis (a raised beta-hydroxybutyrate concentration in the blood),[19][11][10][20] unlike other interventions that induce ketosis (a ketogenic diet or fasting), exogenous ketones do not cause the body to burn its own fat stores. Therefore, exogenous ketones are not a replacement for interventions designed to induce weight loss. See Do exogenous ketones cause weight loss? for more details.

    It is also important to note that much of the evidence about the benefits of exogenous ketones has a moderate to high risk of bias because there are few studies,[28][16] small sample sizes,[28] inadequate reporting about randomization and blinding,[16] a high level of heterogeneity between the studies,[28][10][11] and potential conflicts of interest (studies being funded/authored by manufacturers of exogenous ketone supplements).[10][11] Furthermore, many studies use an off-the-shelf consumer product containing exogenous ketones but do not independently analyze the product to confirm its composition and purity. Doing this would increase confidence in the study findings.

    How do exogenous ketones work?

    During periods of low glucose availability, e.g., fasting, ketogenic diet, or long-duration exercise, the endogenous (in-the-body) production of ketone bodies increases to maintain an adequate supply of energy. Ketone bodies like beta-hydroxybutyrate act as a transportable form of acetyl-CoA that can be converted into adenosine triphosphate (ATP) in organs of the body.[34][35][36][37] Beta-hydroxybutyrate can also regulate gene expression, neuronal function, and metabolic rate, either directly or indirectly through the metabolites into which it is converted.[35][38][37] Furthermore, beta-hydroxybutyrate can inhibit the activity of histone deacetylases, which means it may play a role in epigenetics, a process where modifications to DNA regulate whether genes are turned on or off.[35][38][37] Consequently, because consuming exogenous ketones[19][11][10][20] (including ketone precursors like 1,3-butanediol)[21][22][23] increases the circulating concentration of beta-hydroxybutyrate in the blood, exogenous ketones could provide energy to the body and regulate gene expression, etc.

    How do exogenous ketones improve cognitive function?

    Because exogenous ketones increase beta-hydroxybutyrate levels, it is plausible that they provide an additional source of energy for the brain during periods of high energy demand, like during stressful cognitive tasks.[36][39][40] Additionally, intravenous infusion of beta-hydroxybutyrate in humans has been shown to increase blood flow and oxygen uptake in the brain,[41] which might help improve nutrient and oxygen delivery to the brain during cognitive tasks. Studies in rodents and other preclinical models have also shown that ketones can reduce inflammation in the brain by blunting the release of glutamate from astrocytes (cells in the central nervous system).[27]

    How do exogenous ketones improve glycemic control?

    Meta-analyses have found that exogenous ketones can increase serum insulin,[10][11] a hormone that increases glucose uptake, which potentially explains how ketones can lower blood glucose. However, clinical studies have also shown that ketones can decrease the blood concentrations of alanine,[42] which is a precursor for gluconeogenesis (the production of new glucose). This is relevant because reducing gluconeogenesis would lower the amount of glucose released by the liver into the blood and thus lower blood glucose.

    How do exogenous ketones improve cardiac function?

    By raising beta-hydroxybutyrate levels in the blood, exogenous ketones might provide an additional source of energy for the contractile muscles in the heart to help increase the left ventricular ejection fraction and cardiac output in people with heart failure.[16] Furthermore, in vitro studies in cardiac muscle cells have shown that ketone bodies can regulate the production of reactive oxygen species,[37][43][44] which are involved in oxidative stress. However, the precise mechanisms for the effect of exogenous ketones on cardiac function and other outcomes, like cognitive function and blood glucose control, need further exploration.