{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:55:57Z","timestamp":1790085357772,"version":"4.0.1"},"reference-count":62,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T00:00:00Z","timestamp":1623801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"BHB Therapeutics (Ireland) LTD","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>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\u20137) and 25 g (Days 7\u201328) 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.<\/jats:p>","DOI":"10.3390\/nu13062066","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T21:58:32Z","timestamp":1623880712000},"page":"2066","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6273-9017","authenticated-orcid":false,"given":"Oliver","family":"Chen","sequence":"first","affiliation":[{"name":"Biofortis Research, Addison, IL 60101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1346-988X","authenticated-orcid":false,"given":"Traci","family":"Blonquist","sequence":"additional","affiliation":[{"name":"Biofortis Research, Addison, IL 60101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunice","family":"Mah","sequence":"additional","affiliation":[{"name":"Biofortis Research, Addison, IL 60101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Sanoshy","sequence":"additional","affiliation":[{"name":"Biofortis Research, Addison, IL 60101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Beckman","sequence":"additional","affiliation":[{"name":"Biofortis Research, Addison, IL 60101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7529-0872","authenticated-orcid":false,"given":"Kristin","family":"Nieman","sequence":"additional","affiliation":[{"name":"Katalyses, Ankeny, IA 50023, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Winters","sequence":"additional","affiliation":[{"name":"Winters Nutrition Associates, S Abington Township, PA 18411, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Anthony","sequence":"additional","affiliation":[{"name":"Nlumn LLC, Princeton, NJ 08543, USA"},{"name":"Juvenescence Ltd., Princeton, NJ 08540, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Verdin","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, Novato, CA 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-0100","authenticated-orcid":false,"given":"John","family":"Newman","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, Novato, CA 94945, USA"},{"name":"Division of Geriatrics, UCSF, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9566-9134","authenticated-orcid":false,"given":"Brianna","family":"Stubbs","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, Novato, CA 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1152\/physrev.1980.60.1.143","article-title":"Physiological roles of ketone bodies as substrates and signals in mammalian tissues","volume":"60","author":"Robinson","year":"1980","journal-title":"Physiol. 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