{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T20:17:53Z","timestamp":1791577073786,"version":"4.3.4"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:00:00Z","timestamp":1687910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> A study was undertaken to determine the acute effects of a beverage made with Avela\u2122 (<jats:italic>R<\/jats:italic>)-1,3-butanediol, on blood beta-hydroxybutyrate (BHB) levels (using the Keto-Mojo monitor), gastrointestinal (GI) tolerability (using the modified visual analogue scale GI Symptoms Tool), and sleepiness (using the Stanford Sleepiness Scale).<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Following a 12-h overnight fast, 26 healthy adults consumed one beverage containing 11.5\u00a0g of (<jats:italic>R<\/jats:italic>)-1,3-butanediol at each of 0, 30, and 60\u00a0min, culminating in a total intake of 34.5\u00a0g of (<jats:italic>R<\/jats:italic>)-1,3-butanediol. Blood BHB levels, GI tolerability, and sleepiness were assessed at baseline (0\u00a0min), and at 30, 60, 90, 120, 180, 240, and 300\u00a0min. At 240\u00a0min, a protein bar was consumed.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The mean (\u00b1SD) BHB fasting baseline level, maximal concentration, time at maximal concentration, and incremental area under the curve over 300\u00a0min were 0.23 \u00b1 0.21\u00a0mmol\/L, 2.10 \u00b1 0.97\u00a0mmol\/L, 133.85 \u00b1 57.07\u00a0min, and 376.73 \u00b1 156.76\u00a0mmol\/L*min, respectively. BHB levels at each time point were significantly increased relative to baseline. In females, BHB T<jats:sub>max<\/jats:sub> was significantly greater (<jats:italic>p<\/jats:italic> = 0.046), and BHB iAUC<jats:sub>0\u2013300\u00a0min<\/jats:sub> nearly significantly greater (<jats:italic>p<\/jats:italic> = 0.06) than in males.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> The beverage formulated with Avela\u2122 had no impact on sleepiness and was generally well-tolerated, with no or mild GI symptoms reported in most participants. Mild headaches were reported as an adverse event by five participants and judged possibly related to the study product in two of the participants.<\/jats:p>","DOI":"10.3389\/fphys.2023.1195702","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T14:37:35Z","timestamp":1687963055000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["An open-label, acute clinical trial in adults to assess ketone levels, gastrointestinal tolerability, and sleepiness following consumption of (R)-1,3-butanediol (Avela\u2122)"],"prefix":"10.3389","volume":"14","author":[{"given":"James","family":"Lowder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shafagh","family":"Fallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Venditti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Musa-Veloso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassili","family":"Kotlov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"9136","DOI":"10.3168\/jds.2016-11077","article-title":"Technical note: Comparison of 4 electronic handheld meters for diagnosing hyperketonemia in dairy cows","volume":"99","author":"Bach","year":"2016","journal-title":"J. Dairy Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1097\/SGA.0b013e3182945881","article-title":"Further validation of the visual analogue scale for irritable bowel syndrome after use in clinical practice","volume":"36","author":"Bengtsson","year":"2013","journal-title":"Gastroenterol. Nurs."},{"key":"B3","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.mehy.2006.07.043","article-title":"Low-carb diets, fasting and euphoria: Is there a link between ketosis and \u03b3-hydroxybutyrate (GHB)?","volume":"68","author":"Brown","year":"2007","journal-title":"Med. Hypotheses"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1146\/annurev.nutr.26.061505.111258","article-title":"Fuel metabolism in starvation","volume":"26","author":"Cahill","year":"2006","journal-title":"Annu. Rev. Nutr."},{"key":"B5","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.yrtph.2012.04.008","article-title":"Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects","volume":"63","author":"Clarke","year":"2012","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.cmet.2016.07.010","article-title":"Nutritional ketosis alters fuel preference and thereby endurance performance in athletes","volume":"24","author":"Cox","year":"2016","journal-title":"Cell. Metab."},{"key":"B7","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3389\/fnut.2020.00013","article-title":"Metabolism of exogenous D-beta-hydroxybutyrate, an energy substrate avidly consumed by the heart and kidney","volume":"7","author":"Cuenoud","year":"2020","journal-title":"Front. Nutr."},{"key":"B8","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1042\/bj2850647","article-title":"Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats","volume":"285","author":"Desrochers","year":"1992","journal-title":"Biochem. J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.cmet.2016.08.021","article-title":"Fueling performance: Ketones enter the mix","volume":"24","author":"Egan","year":"2016","journal-title":"Cell. Metab."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2330","DOI":"10.1249\/mss.0000000000001700","article-title":"Intermittent running and cognitive performance after ketone ester ingestion","volume":"50","author":"Evans","year":"2018","journal-title":"Med. Sci. Sports Exerc."},{"key":"B11","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/s40279-022-01756-2","article-title":"Exogenous ketone supplements in athletic contexts: Past, present, and future","volume":"52","author":"Evans","year":"2022","journal-title":"Sports Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1080\/17461391.2017.1421711","article-title":"Effect of acute ingestion of \u03b2-hydroxybutyrate salts on the response to graded exercise in trained cyclists","volume":"18","author":"Evans","year":"2018","journal-title":"Eur. J. Sport Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1093\/advances\/nmac036","article-title":"Effects of exogenous ketone supplementation on blood glucose: A systematic review and meta-analysis","volume":"13","author":"Falkenhain","year":"2022","journal-title":"Adv. Nutr."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/19390211.2023.2179152","article-title":"The effect of novel exogenous ketone supplements on blood beta-hydroxybutyrate and glucose","volume":"2023","author":"Falkenhain","year":"2023","journal-title":"J. Diet. Suppl."},{"key":"B15","doi-asserted-by":"publisher","first-page":"732120","DOI":"10.3389\/fnmol.2021.732120","article-title":"Ketone bodies in the brain beyond fuel metabolism: From excitability to gene expression and cell signaling","volume":"14","author":"Garc\u00eda-Rodr\u00edguez","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1123\/ijsnem.2018-0215","article-title":"Test-retest reliability of a modified visual analog scale assessment tool for determining incidence and severity of gastrointestinal symptoms in response to exercise stress","volume":"29","author":"Gaskell","year":"2019","journal-title":"Int. J. Sport Nutr. Exerc. Metab."},{"key":"B17","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.eplepsyres.2011.04.017","article-title":"The effects of the ketogenic diet on behavior and cognition","volume":"100","author":"Hallb\u00f6\u00f6k","year":"2012","journal-title":"Epilepsy Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0026-0495(82)90024-5","article-title":"Differences in circulating gluconeogenic substrates during short-term fasting in men, women, and children","volume":"31","author":"Haymond","year":"1982","journal-title":"Metabolism"},{"key":"B19","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1111\/j.1469-8986.1973.tb00801.x","article-title":"Quantification of sleepiness: A new approach","volume":"10","author":"Hoddes","year":"1973","journal-title":"Psychophysiology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1093\/ajcn\/73.3.517","article-title":"Whole-body and adipose tissue glucose metabolism in response to short-term fasting in lean and obese women","volume":"73","author":"Horowitz","year":"2001","journal-title":"Am. J. Clin. Nutr."},{"key":"B21","doi-asserted-by":"publisher","first-page":"E278","DOI":"10.1152\/ajpendo.1999.276.2.E278","article-title":"Effect of short-term fasting on lipid kinetics in lean and obese women","volume":"276","author":"Horowitz","year":"1999","journal-title":"Am. J. Physiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1781","DOI":"10.1515\/cclm.2010.351","article-title":"Accuracy of the Precision\u00ae point-of-care ketone test examined by liquid chromatography tandem-mass spectrometry (LC-MS\/MS) in the same fingerstick sample","volume":"48","author":"Janssen","year":"2010","journal-title":"Clin. Chem. Lab. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1093\/jn\/103.8.1155","article-title":"Utilization of 1,3-butanediol and nonspecific nitrogen in human adults","volume":"103","author":"Kies","year":"1973","journal-title":"J. Nutr."},{"key":"B24","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1186\/s12916-021-02185-0","article-title":"Ketone bodies: From enemy to friend and guardian angel","volume":"19","author":"Kolb","year":"2021","journal-title":"BMC Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1002\/(sici)1520-7560(199911\/12)15:6<412::aid-dmrr72>3.0.co;2-8","article-title":"Ketone bodies: A review of physiology, pathophysiology and application of monitoring to diabetes","volume":"15","author":"Laffel","year":"1999","journal-title":"Diabetes Metab. Res. Rev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"806","DOI":"10.3389\/fphys.2017.00806","article-title":"Ketone diester ingestion impairs time-trial performance in professional cyclists","volume":"8","author":"Leckey","year":"2017","journal-title":"Front. Physiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1093\/jn\/nxz308","article-title":"The ketogenic diet: Evidence for optimism but high-quality research needed","volume":"150","author":"Ludwig","year":"2020","journal-title":"J. Nutr."},{"key":"B28","doi-asserted-by":"publisher","first-page":"613648","DOI":"10.3389\/fphys.2020.613648","article-title":"Ketones for post-exercise recovery: Potential applications and mechanisms","volume":"11","author":"Mansor","year":"2021","journal-title":"Front. Physiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1210\/jcem-37-5-698","article-title":"Homeostasis during fasting. II. Hormone substrate differences between men and women","volume":"37","author":"Merimee","year":"1973","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B30","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1210\/jcem-46-3-414","article-title":"Sex variations in free fatty acids and ketones during fasting: Evidence for a role of glucagon","volume":"46","author":"Merimee","year":"1978","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B31","doi-asserted-by":"publisher","first-page":"E1333","DOI":"10.1152\/ajpendo.2001.281.6.E1333","article-title":"Gender differences in lipid and glucose kinetics during short-term fasting","volume":"281","author":"Mittendorfer","year":"2001","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"B32","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s12970-020-00404-2","article-title":"Reliability and diagnostic performance of a new blood ketone and glucose meter in humans","volume":"18","author":"Moore","year":"2021","journal-title":"J. Int. Soc. Sports Nutr."},{"key":"B33","doi-asserted-by":"publisher","first-page":"4021","DOI":"10.1096\/fj.201600773R","article-title":"Novel ketone diet enhances physical and cognitive performance","volume":"30","author":"Murray","year":"2016","journal-title":"FASEB J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1801171","DOI":"10.1002\/mnfr.201801171","article-title":"Oral ketone supplementation acutely increases markers of NLRP3 inflammasome activation in human monocytes","volume":"63","author":"Neudorf","year":"2019","journal-title":"Mol. Nutr. Food. Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"8818","DOI":"10.3168\/jds.2015-9667","article-title":"Technical note: Validation of a handheld meter for measuring \u03b2-hydroxybutyrate concentrations in plasma and serumfrom dairy cows","volume":"98","author":"Pineda","year":"2015","journal-title":"J. Dairy Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"783659","DOI":"10.3389\/fnut.2021.783659","article-title":"Ketone supplementation: Meeting the needs of the brain in an energy crisis","volume":"8","author":"Poff","year":"2021","journal-title":"Front. Nutr."},{"key":"B37","first-page":"11","article-title":"Employees as research participants: Ethical and policy issues","volume":"38","author":"Resnick","year":"2016","journal-title":"IRB Ethics Hum. Res."},{"key":"B38","article-title":"Caffeine withdrawal","volume-title":"StatPearls","author":"Sajadi-Ernazarova","year":"2022"},{"key":"B39","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.jsams.2018.11.027","article-title":"The effect of 1,3-butanediol and carbohydrate supplementation on running performance","volume":"22","author":"Scott","year":"2019","journal-title":"J. Sci. Med. Sport"},{"key":"B40","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/978-1-4419-9893-4","article-title":"Stanford sleepiness scale (SSS)","volume-title":"Stop that! And one hundred other sleep scales","author":"Shahid","year":"2012"},{"key":"B41","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1123\/ijsnem.2018-0284","article-title":"The effect of 1,3-butanediol on cycling time-trial performance","volume":"29","author":"Shaw","year":"2019","journal-title":"Int. J. Sport Nutr. Exerc. Metab."},{"key":"B42","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1042\/BST20190240","article-title":"Why a d-\u03b2-hydroxybutyrate monoester?","volume":"48","author":"Soto-Mota","year":"2020","journal-title":"Biochem. Soc. Trans."},{"key":"B43","doi-asserted-by":"publisher","first-page":"111859","DOI":"10.1016\/j.fct.2020.111859","article-title":"In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol","volume":"147","author":"Stubbs","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"848","DOI":"10.3389\/fphys.2017.00848","article-title":"On the metabolism of exogenous ketones in humans","volume":"8","author":"Stubbs","year":"2017","journal-title":"Front. Physiol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1123\/ijsnem.2019-0014","article-title":"Gastrointestinal effects of exogenous ketone drinks are infrequent, mild, and vary according to ketone compound and dose","volume":"29","author":"Stubbs","year":"2019","journal-title":"Int. J. Sport Nutr. Exerc. Metab."},{"key":"B46","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1046\/j.1528-1157.44.s7.4.x","article-title":"Assessing the efficacy of antiepileptic treatments: The ketogenic diet","volume":"44","author":"Thiele","year":"2003","journal-title":"Epilepsia"},{"key":"B47","first-page":"2171","article-title":"Nutritional and metabolic studies in humans with 1,3-butanediol","volume":"34","author":"Tobin","year":"1975","journal-title":"Fed. Proc."},{"key":"B48","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1007\/s11916-010-0119-5","article-title":"Fasting headache","volume":"14","author":"Torelli","year":"2010","journal-title":"Curr. Pain Headache Rep."},{"key":"B49","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1123\/ijspp.2019-0918","article-title":"Acute ketone supplementation and exercise performance: A systematic review and meta-analysis of randomized controlled trials","volume":"15","author":"Valenzuela","year":"2020","journal-title":"Int. J. Sports Physiol. Perform."},{"key":"B50","doi-asserted-by":"publisher","first-page":"310","DOI":"10.3389\/fphys.2017.00310","article-title":"Intake of a ketone ester drink during recovery from exercise promotes mTORC1 signaling but not glycogen resynthesis in human muscle","volume":"8","author":"Vandoorne","year":"2017","journal-title":"Front. Physiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1139\/apnm-2017-0724","article-title":"Exogenous ketone salts do not improve cognitive responses after a high-intensity exercise protocol in healthy college-aged males","volume":"43","author":"Waldman","year":"2018","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"B52","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1249\/mss.0000000000002517","article-title":"Acute ketogenic diet and ketone ester supplementation impairs race walk performance","volume":"53","author":"Whitfield","year":"2021","journal-title":"Med. Sci. Sports Exerc."},{"key":"B53","doi-asserted-by":"publisher","first-page":"600","DOI":"10.23736\/s0022-4707.18.08318-4","article-title":"Low-carbohydrate, ketogenic diet impairs anaerobic exercise performance in exercise-trained women and men: A randomized-sequence crossover trial","volume":"59","author":"Wroble","year":"2019","journal-title":"J. Sports Med. Phys. Fit."},{"key":"B54","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1111\/j.1399-5448.2011.00768.x","article-title":"Clinical utility of Abbott Precision Xceed Pro\u00ae ketone meter in diabetic patients","volume":"12","author":"Yu","year":"2011","journal-title":"Pediatr. Diabetes"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1660","DOI":"10.1016\/j.jacc.2020.12.065","article-title":"Therapeutic potential of ketone bodies for patients with cardiovascular disease: JACC state-of-the-art review","volume":"77","author":"Yurista","year":"2021","journal-title":"J. Am. Coll. Cardiol."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2023.1195702\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T14:37:41Z","timestamp":1687963061000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2023.1195702\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,28]]},"references-count":55,"alternative-id":["10.3389\/fphys.2023.1195702"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2023.1195702","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,28]]},"article-number":"1195702"}}