Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults

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Highlights

  • Healthy men and women, age 18–69 years, drank 75 ml ketone monoester (KME) daily.

  • Body weights/composition were unchanged by 28 days of three 25 ml KME drinks/day.

  • Blood d-β-hydroxybutyrate concentration increased to ~4.1 mM after each KME drink.

  • Blood glucose, triglyceride, cholesterol, electrolytes and gases remained normal.

  • Kidney function was also normal, so sustained exogenous ketosis using KME is safe.

Abstract

Throughout history, the only way humans could raise their blood ketone levels was by several days of fasting or by following a strict low-carb, high-fat diet. A recently developed, dietary source of ketones, a ketone monoester, elevates d-β-hydroxybutyrate (βHB) to similar concentrations within minutes, with βHB remaining raised for several hours. To date, the longest human safety study of the exogenous ketone ester was for 5 days, but longer consumption times may be desired. Here we report results for 24 healthy adults, aged 18–70 years, who drank 25 ml (26.8 g) of the ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, three times a day for 28 days (a total of 2.1 L). Anthropomorphic measurements, plus fasting blood and urine analyses were made weekly. It was found that elevating blood βHB concentrations from 0.1 to 4.1 (±1.1) mM three times a day for 28 days had no effect on body weights or composition, fasting blood glucose, cholesterol, triglyceride or electrolyte concentrations, nor blood gases or kidney function, which were invariably normal. Mild nausea was reported following 6 of the 2,016 drinks consumed. We conclude that sustained exogenous ketosis using a ketone monoester is safe and well-tolerated by healthy adults.

Introduction

An exogenous, rapidly available, alternative energy source to fatty acids or carbohydrates may alleviate the metabolic abnormalities that underlie many human diseases. The ketone bodies, d-beta-hydroxybutyrate (βHB) and acetoacetate, are not readily available in the human diet, but are produced in the liver from free fatty acids in response to low blood glucose and insulin levels, as an alternative to glucose as an energy supply for the brain (Newman and Verdin, 2014). Until recently, blood ketones could only be raised over several days by fasting or by strictly following low-carb, high-fat diets. Similar blood βHB concentrations can now be attained within 30 min by drinking the ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, which introduces a new metabolic state, termed exogenous nutritional ketosis (Cox et al., 2016). The ketone monoester provides only the d form of βHB and is salt-free (Clarke et al., 2012b). As many chronic diseases are characterised or worsened by metabolic abnormalities, an additional and highly efficient fuel opens potential applications, for example in diabetes (Mizuno et al., 2017), Parkinson's disease (Norwitz et al., 2019), Alzheimer's disease (Murray et al., 2016; Newport et al., 2015) and epilepsy (Gano et al., 2014), for which a ketogenic diet has positive effects (Veech, 2004). Such chronic diseases would require consumption of the ketone ester daily for many days. To date, the continuous consumption of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate has been monitored in two rat studies (during gestation and for twenty-eight days (Clarke et al., 2012a)), and in two human studies (3 drinks/day for five days (Clarke et al., 2012b) and 2 drinks/day for three weeks (Poffé et al., 2019)). Most other studies report single-drink acute effects, such as decreased circulating fatty acid and glucose concentrations (Cox et al., 2016; Kemper et al., 2015; Stubbs et al., 2017). Here, we demonstrate the safety and tolerability of sustained exogenous ketosis, using three ketone monoester drinks per day for 28 consecutive days (2.1 L/participant), in both athletes and sedentary adults as part of their normal, daily routine.

Section snippets

Ethics approval

This study was preregistered (ISRCTN12401551) and the protocol, including amendments and consent forms, was approved by the South Central, Oxford B Research Ethics Committee (18/SC/0064). This study was conducted in accordance with the guidelines set forth by the International Conference on Harmonisation Guidelines for Good Clinical Practice, and the Declaration of Helsinki regarding the treatment of human subjects in a study.

Study design

The aim of this study was to determine whether drinking 75 ml

Results

All 24 participants finished the study with a reported adherence of >90%. Fig. 1 shows that age and gender were evenly distributed throughout the cohort. Drinking three ketone monoester drinks a day (75 ml) for 28 days (2.1 L/person) had no effect on body weights, body mass indices or body composition in either men (age 45 ± 20 years) or women (age 40 ± 16 years) (Table 1).

At weekly intervals, participants recorded their own non-fasting blood βHB and glucose concentrations immediately before,

Discussion

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. It was found that a 25 ml drink of ketone ester increased blood βHB concentrations to between 1.8 and 6.3 mM, the increase being independent of body weight, gender or routine diet. Such a variable βHB increase suggests that other factors, such as

Funding

Dr Adrian Soto Mota thanks the Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) and the Fundación para la Salud y Educación Dr Salvador Zubirán (FUNSAED, Mexico) for support. Hannah Vansant thanks the Minority Health International Research Training (MHIRT) programme for her summer studentship. The ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, was provided for this study by TΔS® Ltd, Thame, UK.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The intellectual property covering the uses of ketone bodies and ketone esters are owned by BTG Plc, Oxford University Innovation Ltd and the US National Institutes of Health. Professor Kieran Clarke, as an inventor, will receive a share of the royalties under the terms prescribed by each institution. Professor Kieran Clarke is a director of TdeltaS Ltd, a

Acknowledgements

The authors thank the late Mrs Yvonne Green whose constant encouragement and enthusiasm made this study possible.

References (17)

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