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]

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]

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.

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.