1. Introduction
gastrointestinal distress, weight loss, chronic disease
ADVERSE EVENTS, SECONDARY, CHRONIC DISEASE
Exogenous ketone ester and ketone ester mixed with ketone free acid formulations are rapidly entering the commercial marketspace. Short-term animal and human studies using these products suggest significant potential for primary or secondary prevention of a number of chronic disease conditions. However, a number of questions need to be addressed by the field for optimal use in humans, including variable responses among available exogenous ketones at different dosages; frequency of dosing; and their tolerability, acceptability, and efficacy in long-term clinical trials. The purpose of the current investigation was to examine the tolerability, acceptability, and circulating R-beta-hydroxybutyrate (R-βHB) and glucose responses to a ketone monoester (KME) and ketone monoester/salt (KMES) combination at 5 g and 10 g total R-βHB compared with placebo control (PC). Fourteen healthy young adults (age: 21 ± 2 years, weight: 69.7 ± 14.2 kg, percent fat: 28.1 ± 9.3%) completed each of the five study conditions: placebo control (PC), 5 g KME (KME5), 10 g KME (KME10), 5 g (KMES5), and 10 g KMES (KMES10) in a randomized crossover fashion. Circulating concentrations of R-βHB were measured at baseline (time 0) following an 8–12 h overnight fast and again at 15, 30, 60, and 120 min following drink ingestion. Participants also reported acceptability and tolerability during each condition. Concentrations of R-βHB rose to 2.4 ± 0.1 mM for KME10 after 15 min, whereas KMES10 similarly peaked (2.1 ± 0.1 mM) but at 30 min. KME5 and KMES5 achieved similar peak R-βHB concentrations (1.2 ± 0.7 vs. 1.1 ± 0.5 mM) at 15 min. Circulating R-βHB concentrations were similar to baseline for each condition by 120 min. Negative correlations were observed between R-βHB and glucose at the 30 min time point for each condition except KME10 and PC. Tolerability was similar among KME and KMES, although decreases in appetite were more frequently reported for KMES. Acceptability was slightly higher for KMES due to the more frequently reported aftertaste for KME. The results of this pilot investigation illustrate that the KME and KMES products used increase circulating R-βHB concentrations to a similar extent and time course in a dose-dependent fashion with slight differences in tolerability and acceptability. Future studies are needed to examine variable doses, frequency, and timing of exogenous ketone administration for individuals seeking to consume ketone products for health- or sport performance-related purposes.During periods of low glucose availability, long-chain fatty acids are partially oxidized to water-soluble four-carbon molecules referred to as ketones, which include acetoacetate (AcAc) and beta-hydroxybutyrate (βHB) [Several studies show that a standard low-carbohydrate (<5% by kcals), high-fat (≥80% fat ketogenic diet (KD) increases circulating ketone concentrations and consistently produces weight loss [A number of studies from our laboratory and others have shown that exogenous ketones produce consistent and robust effects on energy homeostasis, energy metabolism, and body composition in rodents [While the number of published studies in humans is limited, most studies show that exogenous ketones can safely and effectively increase circulating ketone concentrations without introducing extensive dietary changes such as energy or carbohydrate restriction. Exogenous ketones are commercially available as ketone salts, ketone esters, or the combination of the two. Veech and colleagues showed that the ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KME), increased R-βHB and acetoacetate concentrations in a dose-dependent fashion at 140 mg/kg, 357 mg/kg, and 714 mg/kg body weight [Most studies conducted in humans today have examined high concentrations of exogenous ketones in the range of 10–50 g when consumed as a single dose or short term (less than one month) [The purpose of the current investigation was to examine the responses to a single dose of the KME at lower doses (5 and 10 g) and to compare those responses with a ketone ester + R-βHB salt (single enantiomer) mixture (KMES) at 5 and 10 g doses. The primary outcome variables for this study were whole-blood concentrations of R-βHB and glucose produced by condition and over time. Because the KME drink contained a higher concentration of KME, compared with KMES and PC, we hypothesized that the KME would raise circulating ketone concentrations to a greater magnitude and duration than KMES and PC. We also hypothesized that both exogenous ketones would lower circulating ketone concentrations. Secondary outcomes included tolerability, acceptability, and assessment of adverse events. A limited number of past studies in exogenous ketones have reported adverse side effects and severity of such effects. While high doses of KME have been associated with mild gastrointestinal distress [