Keto Lifestyle

Exogenous Ketones – What Are They?

The Charlie Foundation receives questions about ketogenic diet therapy and reaches out to experts to help answer them. A commonly asked question is in regard to ketone supplements. Ketogenic diet therapy has existed nearly 100 years without the use of ketone supplements. We want to make it crystal clear that we don’t endorse using ketone supplements. In addition, the effect of ketone supplements on specific medications or medical conditions is not known. This blog is intended to explain the types of supplements that are on the commercial market and their pros and cons. We urge you to seek the advice of your health care professional if you are considering adding a ketone supplement to your therapy. In addition, it’s important to know that supplements are not regulated and therefore the quality of products can differ.

“The Ketogenic Diet in a Pill” – Is it Possible? 

By Kristi Storoschuk, Dominic D’Agostino and Beth Zupec-Kania

The ketogenic diet has and continues to improve the lives of many across the globe, among all walks of life, and for a growing list of medical conditions. This success has triggered an investigation into whether the barriers that accompany the restrictive nature of the diet can be overcome by a “ketogenic diet in a pill” – and so begins the narrative of something you’ve likely heard of before, exogenous ketones. Exogenous means “outside of” which refers to ketones that you ingest instead of those that you make inside your body.

Brief Introduction to the Ketogenic Diet, Fasting and Ketones 

The ketogenic diet was introduced in the early 1900’s as a dietary method to achieve the success found with fasting for seizure control in epileptic patients. The diet works by shifting the body from using glucose as its primary fuel to fats and ketones – a state referred to as ketosis. This physiological state mimics many aspects of the fasted state, just without the fasting! Carbohydrate restriction, and to some extent limited protein, keeps glucose levels low, thereby suppressing the hormone insulin, and allowing the body to produce ketones from the fat we eat or the fat cells within us. It appears that ketones may be the key players associated with fasting and the ketogenic diet, but research is ongoing to tease out the mechansisms. 

In ketosis, the two primary ketone bodies produced are: beta-hydroxybutyrate (BHB) and acetoacetate (AcAc), the former found in the greatest abundance due to its stability and ability to be transported throughout the body, and the latter being the ketone used as fuel (as BHB must be converted to AcAc to be used by the cell). AcAc can spontaneously decarboxylate (break down) to acetone in small amounts, and this may also have important effects on the body and brain. 

Recognizing that ketones are the common denominator between fasting and the ketogenic diet, and that both produce remarkable seizure control, it was only natural for scientists to look into whether creating ketones outside of the body (exogenous) and having them administered as a supplement would offer the same benefits as the ketones made inside the body (endogenous). Exogenous ketones can also be viewed as “ketogenic food” that may further enhances the physiological state of nutritional ketosis since they are non-glycemic and calorie-containing adjuvants to the ketogenic diet. In other words, they can supplement the effect of a ketogenic diet by providing a boost of ketones.

What are Exogenous Ketones?

The search for ketogenic agents that induce a state of therapeutic ketosis without the need for dietary restriction has been an area of interest for decades. Early research in the 1950’s discovered a certain ketogenic precursor that when taken mimicked certain characteristics of fasting, such as lower blood glucose and an elevation in blood ketones. This opened up a whole new area of research into ketogenic supplements, bringing us to the creation of exogenous ketones in a variety of forms that can be confusing, especially considering some of the marketing tactics of these commercialized supplements. 

Exogenous ketones are synthetic or naturally derived ketones (or ketogenic precursors), that when consumed can elevate blood ketone levels, inducing a state of ketosis. These ketogenic agents can elevate ketone levels independent of carbohydrate restriction and can also be used in addition to a therapeutic ketogenic diet. Therapeutic ketogenic diets are designed with macronutrient (fat, protein, carbohydrate) goals to achieve sustained ketosis.

Types of Exogenous Ketones: 

Ketone Esters 

Ketone esters are created by adding either BHB or AcAc to a “backbone” molecule held together by an “ester” bond. The molecule bound to the ketone can differ depending on the formulation, but ideally is a ketogenic precursor that when released from BHB or AcAc can elevate ketones even further. 

Pros: 

• Most potent form of exogenous ketones, elevating ketones to higher levels and for longer periods of time than any other forms of exogenous ketones
• Greatest potential for anti-seizure/therapeutic purposes 
• No concerns with excess electrolyte mineral (i.e. sodium or potassium) associated with the ketone salt formulations.

Cons: 

• Potential long-term side effects are unknown 
• Commercially available ketone esters are very limited, unpalatable, and relatively expensive 
• Have a strong taste that can be aversive 

Ketones Salts 

Ketone salts are created by adding BHB to an electrolyte mineral, most commonly sodium, potassium, calcium, and magnesium. Ketone salts are widely available exogenous ketones for purchase and come in different forms including pills, powders, beverages, broth and concentrated liquids. 

Pros: 

• Can rapidly induce therapeutic ketosis
• Currently available ketone salts are affordable, palatable, and well-tolerated
• Replenishes lost electrolytes if following a ketogenic/very-low carb diet 

Cons: 

• May require frequent dosing to sustain therapeutic ketosis 
• Can cause GI distress at large or frequent doses 
• Have a strong taste that can be aversive 
• High electrolyte load could be problematic if not diluted or consumedin excess

Medium Chain Triglycerides (MCTs)

MCTs are a type of fat that have very unique properties from other fats, in that they are rapidly absorbed and converted to ketones in the liver. Although MCTs are not technically an exogenous ketone, they can induce ketosis independent of carbohydrate restriction. There are many brands available for purchase and there are different compositions of the carbon content of medium chain fats.

Pros:

• Can promote endogenous ketone production and elevate ketone levels
• Found in nature in foods like coconut oil, palm fruit oil, and small amounts in butter.
• Are easier to digest than long chain fats (which require bile acid for digestion)
• Tasteless and can be added to any food/beverage
• May offer anti-seizure properties outside of metabolism

Cons: 

• Can cause GI distress at large or frequent doses
• To reach therapeutic levels of ketosis would likely require intolerable doses and is therefore recommended to be taken in combination with a ketogenic diet, ketone salts, or ketone esters to further enhance their therapeutic ketogenic potential 

Why Use Exogenous Ketones?

The ketogenic diet, although effective, does not come without limitations. Especially in the young populations, such as pediatric epilepsy, where a diet may be difficult to implement, strategies that allow for a level of “normalcy” can be very impactful. Exogenous ketones are not an immediate or complete replacement for dietary therapies, however when used in conjunction may circumvent some of the practical and social difficulties of a ketogenic diet.  More research supporting therapeutic applications are needed. 

Exogenous Ketones and Epilepsy 

As of now, the research is in its infancy; performed primarily in experimental animal models. However, the results from these studies are promising. In various epilepsy and seizure models, ketone ester, ketone salts, and MCTs have shown anti-seizure effects. Because exogenous ketones allow for a rapid induction and level of ketosis that mimics that achieved with KD treatments for epileptic seizures, it is possible that patients would benefit from these supplements in a variety of ways. 

And although the human clinical evaluation of exogenous ketones for seizure disorders is currently lacking, many positive anecdotes can be found within the online epilepsy forums using exogenous ketones in conjunction with ketogenic diets. With the growing interest and promise of these supplements, we believe evidence will soon emerge on the use and benefits of exogenous ketones, not only in epilepsy but for various other neurological conditions and metabolic disorders that benefit from therapeutic ketosis.  

Clinical trials are underway and will provide insight into their safety and efficacy. These can be found at www.clinicaltrials.gov. 

Reviewed: 08/15/2019 BZK