Human Study: Safety and Tolerability

Kieran Clarke, Kirill Tchabanenko, Robert Pawlosky, Emma Carter, M. Todd King, Kathy Musa-Veloso, Manki Ho, Ashley Roberts, Jeremy Robertson, Theodore B. VanItallie, Richard L. Veech,

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects,

Regulatory Toxicology and Pharmacology,

Volume 63, Issue 3,


Pages 401-408,

Abstract: Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1–2h, reaching 3.30mM and 1.19mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8–3.1h for β-hydroxybutyrate and 8–14h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714mg/kg body weight, three times daily, over 5days (equivalent to 0.42, 1.07, and 2.14g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.

Keywords: (R)-3-hydroxybutyl (R)-3-hydroxybutyrate; Ketone; β-Hydroxybutyrate; Acetoacetate; Kinetics; Safety; Tolerability

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