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Ketone bodies are produced by the liver during periods of food scarcity or severe carbohydrate restriction. Blood ketones are an alternative fuel source used by the brain, heart, and skeletal muscle during periods of fasting. Further, ketones bodies act as a signalling molecule that have pleiotropic effects that upregulate cellular stress-resistance pathways throughout the body.
Oral supplements containing exogenous ketones have recently become available and represent a novel tool for increasing plasma ketone bodies without the need for dietary restriction. Early evidence suggests that oral ketone supplements may enhance cerebral blood flow and improve cognition. However, the dose-dependent effects of a single ketone supplement on cerebral blood flow and cognition in young adults is currently unknown.
The purpose of this study is to characterize the effects of ingesting a high versus low dose of an oral ketone monoester on cerebral blood flow, circulating blood markers, and cognition in young adults.
As an exploratory aim, this study will investigate how oxygen uptake kinetics during submaximal exercise are impacted 2 hours after ingestion of a ketone supplement. Recent findings indicate that ketone supplementation may impair exercise performance due to the physiological stress (i.e., pH disturbances) imposed by an acute ketone dose. Delaying exercise onset by 2 hours after ingestion of a ketone supplement may enhance oxygen kinetics in a dose-dependent manner.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Single dose of a taste-matched calorie-free placebo |
|
| High Dose β-OHB | Experimental | Single dose of a ketone monoester ([R]-3-hydroxybutyl [R]-3-hydroxybutyrate; 0.6 g β-OHB/kg body weight) |
|
| Low Dose β-OHB | Experimental | Single dose of a ketone monoester ([R]-3-hydroxybutyl [R]-3-hydroxybutyrate; 0.3 g β-OHB/kg body weight) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Low Dose β-OHB | Dietary Supplement | Ingestion of a low dose [R]-3-hydroxybutyl [R]-3-hydroxybutyrate (0.3 g β-OHB/kg body weight) followed by 2-hours of rest. Submaximal exercise to be performed following 2-hour resting measures. |
| Measure | Description | Time Frame |
|---|---|---|
| Resting cerebral blood flow (CBF) | Measured via duplex ultrasound of the extra-cranial arteries (internal carotid and vertebral arteries). | 2-hour |
| Measure | Description | Time Frame |
|---|---|---|
| Cognitive Function | The MST (Mnemonic Similarity Task) will be used to assess hippocampal-dependent memory and pattern separation. | 2-hour |
| Plasma beta-hydroxybutyrate area under the curve | Venous blood samples will be obtained via intravenous catheter |
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Inclusion Criteria:
- Between the ages of 18 and 35
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jeremy J Walsh, PhD | McMaster University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| McMaster University | Hamilton | Ontario | L8S 4K1 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40349325 | Derived | Rourke AJ, Yong CMS, Coombs GB, Odisho AR, Nash JA, Bone J, Al-Khazraji BK, Walsh JJ. Acute ketone monoester ingestion lowers resting cerebral blood flow: a randomized cross-over trial. J Physiol. 2026 Mar;604(6):2525-2541. doi: 10.1113/JP287320. Epub 2025 May 11. |
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The investigators will share individual patient data (de-identified) with researchers upon request
Beginning 12 months and ending 36 months following article publication.
Anyone who wishes to access the data.
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A randomized double-blind placebo-controlled crossover design will be used to test 3 conditions. Participants will consume 60 mL of a supplement containing: 1) a low β-OHB dose (0.3g/kg) body weight of the ketone monoester; [R]-3-hydroxybutyl [R]-3-hydroxybutyrate); 2) a high β-OHB dose (0.6g/kg body weight); or 3) a taste-matched calorie-free inert placebo drink.
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| High Dose β-OHB | Dietary Supplement | Ingestion of a high dose [R]-3-hydroxybutyl [R]-3-hydroxybutyrate (0.6 g β-OHB/kg body weight) followed by 2-hours of rest. Submaximal exercise to be performed following 2-hour resting measures. |
|
| Placebo | Other | Ingestion of a taste-matched calorie-free placebo drink followed by 2-hours of rest. Submaximal exercise to be performed following 2-hour resting measures. |
|
| 2-hour |
| Brain-derived neurotrophic factor (BDNF) | Serum and plasma BDNF measured in venous blood samples will be obtained via intravenous catheter | 2-hour, then following completion of submaximal exercise bout |
| Oxygen uptake (VO2) | Breath-by-breath analysis performed via metabolic cart | 2-hour, then during submaximal exercise (performed after 2-hour rest period) |
| End-tidal CO2 | Breath-by-breath analysis performed via PowerLab Gas Analyzer (AD Instruments) | 2-hour, then during submaximal exercise (performed after 2-hour rest period) |
| Mean arterial pressure (MAP) | Automated blood pressure cuff measurement of brachial artery pressure in mmHg. | 2-hour |