Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults

Abstract

Nutritional ketosis is a state of mildly elevated blood ketone concentrations resulting from dietary changes (e.g., fasting or reduced carbohydrate intake) or exogenous ketone consumption. In this study, we determined the tolerability and safety of a novel exogenous ketone diester, bis-hexanoyl-(R)-1,3-butanediol (BH-BD), in a 28-day, randomized, double-blind, placebo-controlled, parallel trial (NCT04707989). Healthy adults (n = 59, mean (SD), age: 42.8 (13.4) y, body mass index: 27.8 (3.9) kg/m2) were randomized to consume a beverage containing 12.5 g (Days 0-7) and 25 g (Days 7-28) of BH-BD or a taste-matched placebo daily with breakfast. Tolerability, stimulation, and sedation were assessed daily by standardized questionnaires, and blood and urine samples were collected at Days 0, 7, 14, and 28 for safety assessment. There were no differences in at-home composite systemic and gastrointestinal tolerability scores between BH-BD and placebo at any time in the study, or in acute tolerability measured 1-h post-consumption in-clinic. Weekly at-home composite tolerability scores did not change when BH-BD servings were doubled. At-home scores for stimulation and sedation did not differ between groups. BH-BD significantly increased blood ketone concentrations 1-h post-consumption. No clinically meaningful changes in safety measures including vital signs and clinical laboratory measurements were detected within or between groups. These results support the overall tolerability and safety of consumption of up to 25 g/day BH-BD.

Keywords: beta-hydroxybutyrate; exogenous ketone; gastrointestinal symptom; ketone diester; ketone ester; ketones.

Conflict of interest statement

This work was funded by BHB Therapeutics (Ireland) Ltd. (“BHB Therapeutics”), which is commercializing products that will contain BH-BD. BHB Therapeutics provided the study beverages used in this work. J.C.N. and E.V. are co-founders with equity interest in BHB Therapeutics Ltd. J.C.A. holds stock options in Juvenescence Limited and Juvenescence Life Sciences Limited and serves as Chief Scientific Officer of the JuvLife Division. B.J.S. holds stock options in BHB Therapeutics Ltd. and Juvenescence Ltd. J.C.N., E.V. and B.J.S. are inventors on patents related to the use of ketone bodies and BH-BD. B.W., K.N. and were scientific consultants in the design, review, and audit of these studies. They derive no direct financial benefit from the results of this research. O.C., T.B., E.M., K.S. and D.B. are employees of Biofortis Research, which received funding to conduct these studies. Biofortis Research derives no direct financial benefit from the results of this research.

Figures

Figure 1

Schematic illustrating endogenous and exogenous ketosis and bis-hexanoyl-(R)-1,3-butanediol (BH-BD) metabolism. Created with Biorender.Com. Abbreviations: BHB, beta-hydroxybutyrate.

Figure 2

Study design schematic. Abbreviations B-BAES, Brief Biphasic Alcohol Effect Scale; BH-BD, bis-hexanoyl (R)-1,3-butanediol; BTQ, beverage tolerability questionnaire.

Figure 3

Daily beverage tolerability composite scores for healthy adults consuming up to 25 g/day of BH-BD or placebo. 10 tolerability issues (gas/flatulence, nausea, vomiting, abdominal cramping, stomach rumbling, burping, reflux/heartburn, diarrhea, headache, and dizziness) were scored 0 = none, 1 = mild, 2 = moderate and 3 = severe, giving a maximal composite score of 30. (A) Pre-beverage composite score; (B) Post-beverage composite score. Dots indicate statistical outliers identified by the 1.5 x interquartile (IQR) rule.