Side effects of exogenous ketones

Exogenous ketones are usually positioned as safe “natural” molecules, since the body itself produces beta-hydroxybutyrate. However, taking several dozen grams of ketones at once is not the same as gradual endogenous ketogenesis. The editorial team has gathered the documented side effects and explained what they depend on.

Gastrointestinal symptoms

The most frequent complaint when taking exogenous ketones is discomfort from the digestive system. Study participants describe nausea, bloating, cramps, belching, reflux, and diarrhea. The severity of symptoms depends on the dose, the type of product, and whether it was taken on an empty stomach or with food.

In the study by Clarke and colleagues (2012), where healthy adults received a ketone monoester in several doses, the product was generally tolerated satisfactorily, but at the highest dose gastrointestinal complaints were recorded more often. This is a typical dose-dependent pattern, characteristic of other products in this group as well.

For sport these symptoms are especially critical. In the work of Leckey and colleagues (2017), professional cyclists after a ketone diester not only felt worse but also showed a poorer result in a time trial. The authors directly linked the worsening to digestive discomfort.

During physical exertion, blood flow in the gut decreases, and the stomach handles concentrated solutions worse. Therefore a product that is tolerated normally at rest may cause problems during training or competition.

Mineral load from ketone salts

Ketone salts are BHB bound to cations of sodium, potassium, calcium, or magnesium. To obtain a noticeable amount of ketones, a person simultaneously consumes a significant amount of these minerals. For sodium this may amount to a noticeable part of the recommended daily allowance in just one serving.

For a healthy person with normal kidney function, a single serving is usually not dangerous. However, people with arterial hypertension, chronic kidney disease, heart failure, or those who limit salt on a doctor's advice should take this aspect into account. Repeated intake throughout the day is especially risky.

In addition, magnesium and some other salts have a laxative effect, which intensifies gastrointestinal symptoms. That is precisely why some people tolerate even small servings of salt products poorly.

Another detail is that many salt products contain a racemic mixture of D- and L-BHB. The L-form is metabolized more slowly, and although no direct harm from it has been described in human studies, the long-term safety of regular intake of this form has not been studied sufficiently.

Metabolic effects: glucose, acidity, appetite

Exogenous ketones temporarily lower blood glucose. In the study by Myette-Côté and colleagues (2018), prior intake of a ketone monoester softened the rise in glucose during a glucose tolerance test in healthy young people. For healthy people this is a neutral or even favorable effect, but for people taking glucose-lowering drugs it may increase the risk of hypoglycemia.

Ketone bodies are organic acids. Taking an ester in a large dose can temporarily lower blood pH and bicarbonate levels. In healthy people, buffer systems quickly compensate for this shift, and it has no clinical significance. However, this is not a product it is advisable to use for people with disturbances of acid-base balance.

The effect on appetite is worth mentioning separately. A ketone ester in the study by Stubbs and colleagues (2018) lowered ghrelin levels and the feeling of hunger. For people losing weight this may seem a plus, but for athletes during periods of heavy loads an undesirable decrease in appetite can deepen an energy deficit.

In people taking SGLT2 inhibitors for the treatment of diabetes, there is a described risk of so-called euglycemic ketoacidosis (Peters et al., 2015). There is no direct data on combining these drugs with exogenous ketones, so the editorial team considers such a combination unacceptable without agreement with a doctor.

Taste, 1,3-butanediol, and other features of esters

Ketone esters are known for an extremely unpleasant bitter and burning taste. This is not only a matter of comfort: a strong taste reaction can provoke nausea and vomiting, especially on an empty stomach or before training.

The monoester contains 1,3-butanediol, which is converted into ketones in the liver. This compound is an alcohol, and in large doses it can cause sensations similar to mild intoxication. Products based on free butanediol require special caution, particularly before driving.

Short-term intake of esters in controlled studies was tolerated acceptably, but there is much less data on the safety of many months of daily use in the general population. This also applies to pregnant and breastfeeding women, children, and older people, who were practically not represented in the studies.

• Gastrointestinal symptoms — the most common side effect of all forms.
• Salt products — a load of sodium and other minerals.
• Esters — unpleasant taste, temporary lowering of pH, effects of butanediol.
• All forms — reduction of glucose and appetite, possible interactions with medications.

How to reduce the risks

If a person still decides to try ketones, the editorial team advises starting with the minimum serving indicated by the manufacturer and not combining the first intake with an important workout or competition. Tolerability should be tested on a quiet day.

It is better to take the product not on an empty stomach, diluting it with a sufficient amount of water. Concentrated solutions irritate the stomach more strongly. You should not exceed the recommended number of servings per day in the hope of a stronger effect.

When choosing salt products, it is worth looking at the amount of sodium and other minerals per serving and accounting for it in the overall diet. People with chronic kidney or heart disease, diabetes, or those taking regular medications should make the decision to take them together with a doctor.

If severe abdominal pain, vomiting, rapid breathing, marked weakness, or confusion occurs, intake must be stopped and medical help sought. Such symptoms are not typical for healthy people and may indicate a serious metabolic disturbance.

Editorial conclusions

Exogenous ketones in short-term studies on healthy adults are mostly tolerated acceptably, but have a predictable set of side effects. Most often these are gastrointestinal symptoms, which depend on the dose and can worsen athletic performance.

Salt products add a significant mineral load, and esters stand out for their unpleasant taste and the effects of 1,3-butanediol. The effect on glucose and appetite requires special attention in people with diabetes and in athletes with high energy needs.

The long-term safety of regular intake has still not been studied sufficiently, so a sensible approach is minimal servings, testing tolerability, and consulting a doctor if chronic diseases are present.

For more on who ketones are contraindicated for, read the article “Who should not take exogenous ketones,” and on choosing a product — the materials “Exogenous ketones: forms and which to choose” and “How to take exogenous ketones: dosage, timing, duration.”

References

1. Clarke K, Tchabanenko K, Pawlosky R, et al. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012;63(3):401–408.
2. Leckey JJ, Ross ML, Quod M, Hawley JA, Burke LM. Ketone diester ingestion impairs time-trial performance in professional cyclists. Front Physiol. 2017;8:806.
3. Stubbs BJ, Cox PJ, Evans RD, et al. On the metabolism of exogenous ketones in humans. Front Physiol. 2017;8:848.
4. Myette-Côté É, Neudorf H, Rafiei H, Clarke K, Little JP. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. J Physiol. 2018;596(8):1385–1395.
5. Stubbs BJ, Cox PJ, Evans RD, et al. A ketone ester drink lowers human ghrelin and appetite. Obesity (Silver Spring). 2018;26(2):269–273.
6. Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1687–1693.
7. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 2017;25(2):262–284.