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.

Influence of Nutritional Ketosis Achieved through Various Methods on Plasma Concentrations of Brain Derived Neurotropic Factor

“…Second, in Study 3 it was demonstrated that weight loss achieved over 6-weeks was a robust stimulus to uniformly decrease plasma BDNF regardless of the macronutrient distribution of the diet or level of ketosis. Thus, circulating BDNF levels can be modulated in healthy adults, but unlike the results from many animal studies [ 11 , 27 ] the results from our work do not support a major effect of nutritional ketosis achieved through a low-carbohydrate eating pattern or exogenous ketone consumption on plasma BDNF in healthy adults.…”

Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future

“…Ingestion in the fed state produces a rapid and dose-responsive increase in plasma [R-βHB] [ 39 , 106 ] e.g…”

The janus face of ketone bodies in hypertension

“…For example, recent studies demonstrate that a ketone monoester drink effectively improves glucose clearance in healthy young adults [59], and in participants with obesity [60]. Regarding longer term studies, two 1-month studies in which healthy participants consumed ketone esters daily found that despite regular elevations in βOHB, the ketone esters had no effect on body weight or body composition, fasting blood glucose, cholesterol, or triglyceride concentrations [52]. In a similar study design, patients with type 2 diabetes experienced modest improvements in markers of glycemic control, including mean blood glucose and HbA1c [61].…”

“…For example, ingestion of a ketone monoester acutely reduces ghrelin (a gut hormone that stimulates the desire to eat), self-reported hunger, and enhances satiation [65]. Despite these promising findings acutely, longer term studies of ketone supplementation have reported no change in bodyweight [52], and therefore, the limited data available suggest that long-term ketone supplementation may not have an appreciable effect on caloric intake.…”