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

Regul Toxicol Pharmacol. 2019 Dec;109:104506. doi: 10.1016/j.yrtph.2019.104506. Epub 2019 Oct 23.


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.

Keywords: Ketone bodies; Ketone monoester; Safety; Tolerability; Toxicity.

Publication types

  • Clinical Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Chronic Disease / therapy*
  • Diet, Ketogenic
  • Dietary Supplements / toxicity*
  • Esters / administration & dosage
  • Esters / toxicity*
  • Fasting
  • Healthy Volunteers
  • Humans
  • Hydroxybutyrates / administration & dosage
  • Hydroxybutyrates / toxicity*
  • Ketones / administration & dosage
  • Ketones / toxicity*
  • Ketosis / blood
  • Ketosis / chemically induced
  • Ketosis / urine
  • Male
  • Middle Aged
  • Toxicity Tests, Subacute / methods
  • Young Adult


  • (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
  • Esters
  • Hydroxybutyrates
  • Ketones