This guide aims to provide a comprehensive yet concise overview of exogenous ketones, designed specifically for medical professionals. It covers essential information about exogenous ketones, including their types, effects, and safety profile, to help doctors make informed decisions when considering their use for patients.
Medical Disclaimer
The information provided in this guide is intended solely for educational purposes and should not be construed as medical advice. It is not designed to diagnose, treat, cure, or prevent any disease. Instead, this information is meant to assist doctors and clinicians in making more informed decisions for their patients. Always consult with a qualified healthcare professional before adding any new supplement to your daily regime.
2. What are Exogenous Ketones?
Definition
Exogenous ketones are ketone bodies that are ingested through dietary supplements rather than produced endogenously by the liver during periods of low carbohydrate intake or fasting. They provide an alternative energy source for the body and brain other than traditional carbohydrates/glucose.
Background
The discovery and understanding of ketones have a fascinating history intertwined with the study of metabolism and diet. The ketogenic diet, a high-fat, low-carbohydrate diet, was originally developed in the 1920s to treat epilepsy in children who did not respond to conventional therapies. Researchers observed that this diet could induce a state of ketosis, where the body shifts from using glucose as its primary energy source to using fats, resulting in the production of ketone bodies.
Ketone bodies, including beta-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone, are produced in the liver from fatty acids during periods of low carbohydrate availability. The scientific exploration of ketones significantly advanced thanks to the work of Dr. Richard Veech and Sir Hans Krebs. Sir Hans Krebs, a renowned biochemist, made significant contributions to our understanding of cellular respiration and metabolism, including the discovery of the citric acid cycle (Krebs cycle). His work laid the foundation for the metabolic understanding of ketone bodies. Dr. Richard Veech, a prominent researcher, and a student of Krebs furthered this research by isolating and studying the effects of ketone bodies. Dr. Veech and his team showed that ketone supplementation could significantly elevate blood BHB levels, providing a sustained source of energy that could enhance cognitive and physical performance. These findings spurred interest in developing exogenous ketone supplements that could mimic the metabolic state of ketosis without requiring strict dietary restrictions.
Exogenous ketones, therefore, offer a practical way to achieve the benefits of ketosis, including enhanced mental clarity, improved physical performance, and potential therapeutic effects for various metabolic and neurological conditions, without the challenges of adhering to a ketogenic diet. Though the diet and exogenous ketone supplementation differ, exogenous ketones still induce a state of ketosis and ketone availability to the brain, heart, and other tissues. The development of exogenous ketone supplements represents a significant advancement in metabolic health and nutritional science, building on the foundational work of Krebs and Veech.
Dr. Veech’s research focused on the biochemical pathways and the potential therapeutic benefits of ketones. He elucidated the mechanisms by which ketones could improve cellular energy efficiency and reduce oxidative stress, particularly in the brain. In this research, Veech and colleagues demonstrated that ketone bodies could serve as a more efficient fuel source compared to glucose. Specifically, it has been shown that beta-hydroxybutyrate (BHB) produces more ATP per molecule of oxygen consumed, highlighting the potential of ketones to improve cellular energy efficiency [1].
This led to more interest in exogenous ketones, their different forms (esters, salts, etc.) which caught the attention of DARPA and their “Metabolic Dominance” program for soldiers to utilize exogenous ketones [2]. Furthermore, nearly 10 years ago, Pruvit launched the first mass market exogenous ketone salt. Fast forward today and millions of servings of exogenous ketones have been consumed and the scientific research and anecdotal evidence is undeniable.
3. Different Types of Exogenous Ketones
Ketone Salts
Ketone salts are the salt form of beta-hydroxybutyrate, either as a sodium, calcium, potassium, or magnesium salt. They are less expensive to synthesize, are widely available to the public in consumer health products, and modestly increase blood BHB levels.
Benefits: Cost effective, Palatable, Rapid increase in ketones Limitations: Salt content may cause minor GI issues
Ketone Esters
Ketone esters are chemically synthesized compounds in which a ketone body (typically beta-hydroxybutyrate, or BHB) is bound to an ester molecule. When ingested, the ester bond is hydrolyzed by enzymes in the gut, releasing the free ketone bodies into the bloodstream. The most studied ketone ester is (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (BHB monoester). This compound features a molecule of BHB attached to butanediol via an ester linkage.
Benefits: Rapid increase in ketones. No Salt Load Limitations: Costly, Unpalatable, and noticeable GI issues
4. What Do Exogenous Ketones Do?
Metabolic Effects
Exogenous ketones have demonstrated significant potential in improving metabolic health and cardiovascular efficiency, particularly under physically demanding conditions. A notable study by McAllister et al. [3] observed significant reductions in heart rate and improvements in oxidative stress responses in firefighters using ketone salt supplementation during exercise. This suggests that exogenous ketones may help mitigate cardiovascular strain and improve aerobic efficiency in high-stress environments. Furthermore, exogenous ketones can shift the body’s fuel preference from glucose to ketones, promoting a state of ketosis without carbohydrate restriction. This shift can enhance fat oxidation and provide a stable energy supply, particularly beneficial for endurance athletes [4]. Lastly, several studies have shown that ketones may lower blood glucose and insulin levels [5].
Performance Enhancement
Ketones serve as a rapid and efficient energy source for the brain, potentially enhancing various aspects of cognitive function. Research indicates that supplementation with ketones can improve performance and cognitive processing speed, focus, and memory retention, especially in situations where glucose availability is compromised. A study by Cox et al. [7] demonstrated that ketone esters improved exercise performance by increasing efficiency and endurance in athletes. A study by Clarke et al. [8], Murray et al [9], and Saito [10] demonstrated that exogenous ketones significantly enhance cognitive function by providing an efficient energy source for the brain. Participants who ingested ketone esters showed improved cognitive performance in tasks requiring mental clarity and focus, indicating the potential of exogenous ketones to support brain health and cognitive function. Lastly, a study at Ohio State University showed that a ketone salt formula increased cycling performance in recreationally trained men and women [11].
Potential Therapeutic Uses
Exogenous ketones have shown promise in various therapeutic applications, including:
Neurological Conditions: Ketones can provide an alternative energy source for the brain. Studies demonstrated that ketones could reduce oxidative stress and improve mitochondrial function in neuronal cells. This research provided a basis for the potential use of exogenous ketones in assisting with improving neurodegenerative diseases such as Alzheimer’s and Parkinson’s [12][13]. Further, there have been studies showing promise for Traumatic Brain Injury (TBI) with exogenous ketones [15]
Weight Management: In the context of weight management, exogenous ketones can play a role in reducing appetite and enhancing lipolysis, thereby supporting fat loss efforts. Studies have shown that ketone supplementation can lead to a decrease in ghrelin (the hunger hormone) and an increase in satiety, reducing overall caloric intake [16]. Additionally, Poff et al. found that all ketogenic agents tested induced weight loss and voluntary caloric restriction in animals [17].
Cardiovascular Health: Ketones may offer cardiovascular benefits. In another study, Veech (2001) explored the effects of ketone bodies on heart metabolism. He found that ketones could improve cardiac efficiency and function, particularly under conditions of ischemia (restricted blood supply). This study along with several others [20][19] suggest that ketone bodies could be beneficial in treating heart conditions by providing an efficient and protective fuel source for cardiac cells.
Cancer Therapy: Exogenous ketones may play a role in oncology, particularly in relation to metastatic cancer. Research by Poff et al. [21] demonstrated that ketone supplementation could decrease tumor cell viability and significantly prolong survival in mice with metastatic cancer. This suggests that ketones might play a role in inhibiting cancer cell growth and could be considered as a complementary approach to traditional cancer treatments under proper supervision.
Inflammatory Diseases: Ketones also show potential in inflammatory conditions such as Crohn’s disease. A case study by Lowery et al. [22] illustrated that exogenous ketone supplementation could positively affect biomarkers of Crohn’s disease, suggesting an improvement in the inflammatory profile (specifically CRP). This highlights the potential of ketones to modulate immune response and inflammation, providing a novel approach to managing autoimmune conditions.
Metabolic Disorders: Severe MADD: In the context of metabolic disorders, particularly Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), ketones have been used as an alternative energy source to support metabolic processes. Fischer et al. [23] documented the therapeutic use of D/L-BHB acid in severe MADD, noting improvements in clinical outcomes. This underscores the potential of ketone bodies to provide critical energy substrates for individuals with impaired fatty acid oxidation. The therapeutic use of exogenous ketones across these sensitive populations showcases their potential beyond typical nutritional supplementation. By providing an alternative energy source, reducing inflammation, and potentially modulating disease progression, exogenous ketones offer a promising adjunct to traditional treatment modalities. These findings encourage further research and consideration in clinical settings, supporting the integration of ketone supplementation in therapeutic protocols, particularly for conditions where current treatments are limited or not fully effective.
5. Safety of Exogenous Ketones
General Safety Profile
Overall, exogenous ketones are considered safe for most individuals when used appropriately. Exogenous ketones have received GRAS (Generally Recognized as Safe) approval.
Safety Studies in Adolescents and Adults
Extensive studies by Stefan et al [24][25]. have evaluated the safety profile of exogenous ketones in both adolescents and adults, demonstrating that these supplements do not adversely affect vital signs, blood markers, or metabolic functions. These findings support the safe use of exogenous ketones in a controlled setting.
6. Conclusion
Exogenous ketones offer a versatile and safe supplement option that can enhance physical performance, cognitive function, and metabolic health. The current body of research supports their use in various therapeutic and wellness applications, making them a valuable tool for those seeking to improve their health and longevity. Medical professionals should consider these findings while monitoring and guiding patients interested in or currently using exogenous ketone supplements.
Dr. Ryan P. Lowery is the CEO of ketogenic.com, author of The Ketogenic Bible, President of the Applied Science and Performance Institute and KetoPhD™. His mission is to spread awareness around the Ketogenic Lifestyle and its’ many benefits beyond body composition. He earned his BS and MS in exercise physiology and exercise and nutrition science from the University of Tampa and completed his doctorate work at Concordia University in Health and Human Performance with a focus on “The Effects of a Well-Formulated Ketogenic Diet and Exogenous Ketone Supplementation on Various Markers of Health and Body Composition in Healthy and Diseased Populations.” Over his career, Ryan has published over 150 papers, abstracts, and book chapters on human performance and sports nutrition and has dedicated his life to educating the masses. In his free time, Ryan enjoys spending time with his best friend, Scoot the Keto Pup, jet skiing, and traveling around the world. The way to his heart is through a good glass of wine and Keto desserts.
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