Are Ketone Esters Safe?

Keto4Life

Well-known member
May 24, 2021
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When it comes to exogenous ketones, Ketone Esters (KE) are the king of exogenous ketones. Compared to other ketone boosting supplements like ketone salts or MCT oils, ketone esters are able to boost physiological ketones to a much higher levels that are often sought in therapeutic applications without the need to maintain a very strict ketogenic diet.

Ketone Ester products have finally made their way into the market over the past few years. The exorbitant cost to produce ketone esters kept it from becoming available commercially for many years after its initial development. Although the cost has decreased substantially, the price of KE still remains fairly high, but interest in the highly potent form of exogenous ketones continues to grow among those in the military, professional sports, medical profession and the general public as well as. As the demand grows, we should see the cost come down further and hopefully the notoriously bad taste (a.k.a “jet fuel”) will be overcome at the same time!

The first and most important question to be answered about any new supplement being sold on the market should always be: “is it safe?”. Several forms of Ketone Ester have been developed that vary slightly in their make-up and are found under different brand names. Not all forms are currently available for sale. The two types of KE currently available (in liquid form) for sale on the market are:
  1. (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (Ketone Monoester)
  2. Bis-Hexanoyl (R)-1,3-Butanediol (C6 Ketone Diester)
Without taking a deep dive into the chemistry of each type of KE, the difference in a “monoester” and a “diester” essentially boils down to the types of ketones produced in the body when they are ingested. There are three types of ketones found in the body: beta-hydroxybutyrate (BHB), acetoacetate (AcAc) and acetone. BHB is the major circulating ketone in the body account for roughly 78% of total ketones followed by AcAc accounting for approximately 20%. Acetone makes up the remaining 2% and is a breakdown product produced from acetoacetate in a process called spontaneous decarboxylation.

As the name hints at, Ketone Diesters will produce BHB and AcAc while a Monoester will only produce BHB in the body. BHB is measured in the blood, whereas AcAc is measured in the urine and acetone in exhaled breath. With this in mind, it’s important to note that, when measuring blood ketone levels after ingesting a Ketone Diester, the total amount of ketones being produced will not be accurate because only BHB will be registered in the blood, missing the AcAc portion that is also being produced.

Returning back to the all-important question of whether Ketone Esters are safe, “Safety & Tolerability” studies have been performed on both of the KEs listed above and are currently being sold on the open market.

Safety & Tolerability of a Ketone Monoester
A study published in 2019 out of the University of Oxford (where the first KE was developed) entitled "Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults" examined (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. The authors point out the potential applications and benefits of sustained ketosis in several disease states via long term consumption of ketone esters without implementing a ketogenic diet:

  • Diabetes (Mizuno et al., 2017)
  • Parkinson's disease (Norwitz et al., 2019)
  • Alzheimer's disease (Murray et al., 2016; Newport et al., 2015)
  • Epilepsy (Gano et al., 2014)
Previous studies had assessed mostly short-term KE consumption in two animal models and two human models. The longest period of consumption previously studied in humans was two drinks/day for 21 days. In this analysis, the researchers set out to examine the safety and tolerability in 24 humans (athletes and sedentary adults) consuming three ketone ester drinks per day for 28 consecutive days. Three of the athletes recruited in the study were already consuming a ketogenic diet and continued to do so for the duration of the study.

Each drink consisted of 25ml of pure ketone monoester or 25ml of pure ketone monoester mixed in an unidentified artificially sweetened drink readily available in the commercial market. The time in between the consumption of the drinks was a minimum of four hours in an attempt to elevate BHB in the blood for at least 12 hours each day for the duration of the study.

All of the study participants completed the 28-day trial with adherence to the protocol exceeding 90%. The recorded levels of BHB in the blood over the duration of the study was found to be from 1.8mmol to 6.3mmol with an average maximum level of approximately 4.1mmol.

The participants each consumed 2.1 liters of KE over the 28 days. Among the study points examined the following unremarkable effects were observed:
  • No effect on body weights.
  • No effect on body composition.
  • No effect blood pH (metabolic acidosis).
  • No effect HCO−3, electrolyte, or metabolite concentrations.
  • There was no evidence of acute kidney injury or urinary bleeding, and urinary pH, specific gravity, glucose, leukocytes, nitrite, protein and urobilinogen were invariably normal.
  • Fasting blood samples, taken at the start and end of the 28 days, showed normal circulating glucose, triglycerides, cholesterol, HDL, ApoB, HbA1c and C-reactive protein.
The adverse events reported among the total of 2,016 drinks consumed included:
  • Mild nausea shortly after consuming 6 drinks (6/2,016 drinks).
  • Mild headache was reported after 3 drinks (3/2,016 drinks).
  • Mild diarrhea and abdominal pain in two participants.
  • These mild adverse events amounted to 0.75% of the total drinks consumed (14/2,106 drinks).
Conclusions

Safety

The authors concluded:

The most important finding of this study was that sustained exogenous ketosis for 28 days was safe for healthy adults in that it had no effect on any physical, blood or urine parameter, and was independent of age, level of physical activity and diet.

Tolerability
When discussing the tolerability of the chronic ingestion of KE for 28 days the authors state:

The ketone ester was well-tolerated given the high adherence of the participants, both to consumption of the drink and record keeping, so the low frequency and intensity of adverse effects were not due to missed drinks or poor recording. As most of the participants worked in healthcare or were athletes, it is unlikely that adherence of the general population would be as high.”

Safety & Tolerability of a Ketone Diester
When considering the safety and tolerability of a ketone diester a study published in June 16, 2021 entitled “Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults” addressed this form of KE.

Similar to the ketone monoester study previously discussed, the authors here examined the effects of consuming Bis-Hexanoyl (R)-1,3-Butanediol (BH-BD) ketone diester for 28 days. However, one major difference in the two studies was the total daily intake of the diester studied was much less. The study included 59 healthy participants implementing the following randomized consumption protocol:
  • Consume a beverage containing 12.5 g (Days 0–7) and
  • 25 g (Days 8–28) of BH-BD or
  • a taste-matched placebo daily with breakfast.
Like in the monoester study, the authors first discuss the potential applications of using exogenous ketones as an alternate way of achieving the therapeutic ketosis versus the implementation of ketogenic diet, stating:
  • “…it is increasingly understood that ketones function as a signal that link the environment to diverse molecular responses (i.e., oxidative stress and inflammatory pathways) increasing resilience.
  • Importantly, ‘physiological’ levels of BHB (regulated ≤ 7mmol) the major circulating ketone, are safe and likely played a role in the survival of early man.
  • Endogenous ketosis has historically been used to treat intractable seizures, and is under investigation for use in other clinical conditions such as type 2 diabetes, migraine, and glioblastoma.
  • Evidence suggests ketone bodies could be directly responsible for some of the beneficial molecular changes associated with dietary modifications (i.e., caloric restriction and time-restricted feeding) that can increase health span and lifespan across a variety of species.
The study was a “randomized, double-blind, placebo-controlled, parallel study in healthy adults to evaluate the tolerability and safety of BH-BD compared to placebo”. Unlike the monoester study, participants only consumed one BH-BD drink per day. The KE was a “chocolate flavored beverage matrix (water, whey protein concentrate, modified gum acacia, natural and artificial flavors, cocoa powder) with a total volume of 75ml” yielding 12.5g of BH-BD for the first seven days and 25g of BH-BD for the remaining duration (day 8-28) of the study.

Tolerability
High compliance to the given protocol was observed among the participants with 99.9 ± 2.2% adhering to the regimen. Only one adverse event (constipation) was reported and surprisingly this actually occurred after ingesting the placebo-controlled group. No adverse events were reported in the group consuming the BH-BD beverage mix, obviously indicating a high tolerability of the KE mixture over the 28-day period of consumption and examination.

Safety
When examining the safety parameters measured during the study it was found that “there were no clinically meaningful changes in laboratory results from baseline, supporting the safety of BH-BD.”

Conclusions
In the final analysis, the authors conclude:

the results of this study demonstrate the safety and tolerability of up to 25 g/day of the ketone diester, BH-BD in healthy adults. These findings will be foundational for the design of future clinical research studies using BH-BD as a tool to induce a metabolic switch to nutritional ketosis and facilitate the study of ketosis for health and resilience.”

So, there you have it, in at least the two ketone esters studied here in humans for a period of 28-days, ketone esters (monoester and C6 diester) appear to be well tolerated and most importantly safe to consume.