Exogenous Ketones
What You Need To Know

What are Ketones?

To better understand exogenous ketones, we first need to look at exactly what ketone bodies are. When we restrict carbohydrates in the diet, we need to obtain fuel from alternative sources. Once the body is fully depleted of glycogen, it will then begin to break down fatty acids in the liver, to eventually produce ketone bodies. It is the ketone bodies that then act as an alternative fuel to glucose.

There are three different types of ketone bodies produced in the liver:

1. Acetone (can be measured using breath ketone meter)
2. Acetoacetate (can be measured using ketone urine strips)
3. Beta hydroxybutyrate (BHB, can be measured using blood ketone meter) Side note: Technically speaking, BHB is not a ketone body as it contains a reactive OH-group in place of where a double bonded oxygen normally would be.

BHB does still act like a ketone in the body and is often the ketone body that is most utilised for energy.

What are Exogenous Ketones?

The word exogenous means to obtain something from out with the body. Unlike endogenous ketones that are produced by the liver from fatty acids, exogenous ketones are ingested through a form of supplementation.

Ketone Salts vs Ketone Esters

Regardless of the type of ketone supplements, all of them contain that of BHB.

There exists 2 different type of exogenous ketones:

• Ketone salts - these are naturally derived BHB that is bound to a salt such as sodium, potassium or calcium.
• Ketone esters - these are synthetically made and exhibit BHB in its raw form. These are more potent than salts and can raise the ketone levels higher than that of salts. However, they can be very unpalatable and cause gastrointestinal distress.

At the minute, it is only ketone salts that are commercially available with ketone esters mostly being used in research.

Potential Areas of Application

Whilst ketone supplementation appears to have gained in popularity, we need to better understand why and how they should be used. The below will look at the applications that currently have scientific evidence and clinical data.

Alzheimer's Disease (AD)

A feature of Alzheimer's disease (AD) is region-specific declines in brain glucose metabolism. Normally the brain is not able to switch effectively between using glucose or fat for energy and predominantly relies on that of glucose. Therefore, the problems with glucose metabolism in the brains of AD patients can have a significant impact on its function.

Replacing the normal glucose supply with that of ketone bodies may offer a therapeutic alternative. When ketone bodies have been used in animals and cell cultures, they have demonstrated neuroprotective qualities such as improving cell survival and cognitive performance ( 1).

In humans, a crossover study looked to examine the effects of acute elevation of the ketone body, BHB, on the cognitive function of 20 AD patients ( 2). They gave the patients 40 g of MCT oil and noticed a significant increase in BHB levels after 2 hours. After 90-minutes they were tested for changes in cognitive performance using a specific AD questionnaire. A significant correlation between performance on the cognitive test and BHB levels were observed, with those presenting with the highest BHB levels showing the most improvement.

Another randomised, double blind, placebo controlled trial was carried out in 152 patients to evaluate administration of a ketone based supplement ( 3). Serum ketone bodies were significantly elevated 2 hours after administration compared to a placebo. A significant correlation was observed between BHB levels and change in AD cognition scores. This essentially means that the more elevated the level of ketone bodies, the greater improvement in AD related cognition symptoms.

The exact level that BHB needs to be raised to get these benefits is still not fully known. One case study reports that for ketone bodies to provide energy to the glucose deprived parts of the AD brain, BHB levels must rise above 0.2 mM ( 4). In this patient, after 6-8 weeks of ingesting a ketone ester, there were marked improvements in activities of daily living.

Parkinson's Disease (PD)

Due to the proposed impact that ketone bodies can have in the brain, it is hypothesised that the ketogenic diet may be an effective treatment for PD.

Researchers have looked at the impact of ketone bodies in animals and cell cultures. In one study, they showed that administering exogenous ketones for 7 days offered protection against structural and functional effects that occur in PD ( 5).

To date, there has been no human clinical study utilising exogenous ketones in patients with PD. However, there is a growing body of case studies using exogenous ketones for PD. The results of the case studies are showing some promising results. One case study which was carried out at the ASPI facility in Tampa, Florida provided one patient with 10 g of BHB. After 30 minutes the patient reported vast improvements in eye movement which is a characteristic in PD.

Athletic Performance

One of the main reasons that exogenous ketones have been developed was for use in athletes. In sport science, it is believed that when performing, the body operates best by using glucose as its main fuel. A recent study ( 6) which compared athletes who followed a habitual high carbohydrate diet to that of a low carbohydrate diet showed this to not be the case. It showed that individuals who are keto-adapted, can operate at a high athletic level by gaining most of their energy through that of fat and ketone bodies.

A study carried out in rats supplemented 30% of their diet with a ketone ester. For 5 days, the rats ran 32% further on a treadmill than did the control rats and outperformed on cognitive tests ( 7).

A lab based in Oxford, England has carried out a series of studies in high-performing athletes utilising ketone esters. From their work, they have shown that having higher circulating levels of ketone bodies in athletes can cause physiological alterations which may improve physical performance in some athletes ( 8). It appears to do this through the ketone bodies offering an effective alternative energy source for the body during exercise.

Further to improving performance, nutritional ketosis is hypothesised to help facilitate muscle recovery from intense exercise ( 9). One study gave eight athletes a novel oral ketone ester drink every 60 minutes during the initial 5 hour of recovery, following a glycogen depleting maximal exercise bout ( 10). They found that BHB levels reached an average level of 5mM which was able to increase a muscle signalling pathway known as mTORC1. This pathway induces leucine-mediated protein synthesis. Essentially this means that ketone esters could promote muscle building following exercise.

It should be noted that most of the evidence we have in athletes, have been done with ketone esters and not salts (as noted earlier the only commercially available exogenous ketone supplements). As ketone esters are much more potent than that of salts, it may mean the salts do not provide the same therapeutic potential.

Weight Management

One area of use with exogenous ketones that is being mostly misunderstood is its role in weight management. There are many people out there claiming that by ingesting exogenous ketones it will somehow cause you to lose weight at a faster rate. It is important to note that this claim is completely unsubstantiated.

Why Ketone Esters Won't Promote Fat Loss

There is a belief that people think the higher their ketone levels, then the greater rate of weight loss. Where this comes from is the understanding of how your body gets into ketosis and how this can promote weight loss.

As we know, when you restrict carbohydrates from the body, it forces it to get energy from someplace else, enter ketosis. Eventually after all your glycogen stores are depleted your body will turn to its fat stores to break it down and produce ketone bodies, providing it with the energy it needs.

Therefore, to lose weight, the ketone bodies produced need to be coming from your body stores not that of exogenous ketones. If you provide the body with the energy it needs from ketones out with the body, it has no need to break down its own body fat and therefore, it will won't result in a weight loss.

Now that we've cleared up the issue of ketone supplements not causing weight loss, let's look at how these could help to potentially aid it in other ways.

Keto-flu

When you first begin with a low carbohydrate approach, you can encounter what is known as keto-flu. Simply put, this is a list of side effects including (but not limited to):

• Headaches
• Nausea
• Lethargy
• Bad breath
• Heart palpitations
• Muscle cramps

There can be a variety of reasons for this going on but namely it is down to the water loss and subsequent change in electrolytes (including sodium, potassium and magnesium), that occurs when you first start on a low carbohydrate diet.

Normally speaking, supplementing with some additional salt or 1 cup of bone broth per day can help to alleviate these symptoms. For some people though, this can sometimes not be enough to alleviate the side-effects. Case study reports have now shown that the ketone salts can help stop people experiencing some of the side-effects listed above.

To date, there are no clinical studies that have looked at this, but hypothesis would suggest that it could be due to the salts contained in some of the supplements and providing the body with a higher BHB level could also be helping.

Appetite Suppression

One area that supplementing with ketones could potentially help with, is around appetite control. Normally, diet-induced weight loss causes the body to experience increased hunger and advanced feelings of fullness through appetite-based hormones ( 11).

The ketogenic diet alone has been reported to be extremely satiating, with one study demonstrating the impact that ketone bodies can have on the hunger stimulating hormone, ghrelin ( 12).

In a study that looked at the timeline of changes in appetite during weight loss with a KD, it showed that a 10% weight loss did not result in an increase in appetite, that is often seen when losing weight ( 13).

One study has looked at the specific effects of administering a ketone ester drink on appetite ( 14). In comparison to a sugar based solution, those who consumed the ketone ester had significantly lower levels of hunger stimulating hormones. They also reported a suppression in hunger and a desire to eat 1.5 hours after consuming the esters.

Potential Side Effects of Exogenous Ketones

Whilst the area of supplementing with ketones does appear to be promising, there are some potential side effects that people may encounter.

Gastrointestinal Problems

The first thing that appears to be getting reported is the impact that the supplements can have on the GI tract. This is mostly the esters that are causing this upset, likely due to their potency and so impact when the body must digest and absorb them through the gut.

As with other supplements, like MCT, the answer to this may be to lower the dose until the body builds up a little more tolerance to the supplements.

Dehydration

This side effect is more aimed at the ketone salts. Since the BHB in these supplements are bound to that of a salt, this could cause a further change in the electrolyte balance in the body, particularly promoting that of dehydration. Likewise, the increase in ketone level could cause the body to dump more of these out of the kidney which could cause excess urination and again lead to dehydration.

Long-term Safety

One area that we lack any data on at the minute is the long-term use of these supplements. Again, whilst they are showing potential benefits in certain areas, we do not know what impact constantly ingesting and having a higher level of BHB in the body will do. In time, more longer-term trials in larger populations are needed.

However, a study has been carried out to look at the safety and tolerability of exogenous ketones in humans in the short term. It reports that GI distress can be caused at a high dose, but overall, they are very well tolerated in the human body ( 15).