Acute ketone monoester ingestion lowers resting cerebral blood flow: a randomized cross-over trial

Exogenous ketone monoester (KME) supplements rapidly increase plasma beta-hydroxybutyrate (β-OHB) and may impact cerebral blood flow (CBF). However, it is currently unknown how acute KME ingestion impacts resting CBF and whether differences in KME dose have differential effects on CBF regulation. The purpose of this study was to investigate the effect of two separate KME doses on resting CBF in young adults. On separate days and in a double-blind, placebo-controlled, cross-over design, 20 participants (10 females; aged 23 ± 3 years) ingested either: (1) High-KME (0.6 g kg^-1 β-OHB); (2) Low-KME (0.3 g kg^-1 β-OHB); or (3) placebo drink, and quietly rested for 120 min. Global CBF (gCBF) was assessed using duplex ultrasound of the internal carotid and vertebral arteries, and transcranial Doppler ultrasound was used to assess middle cerebral artery blood velocity at baseline, 45 min and 120 min post-ingestion. End-tidal CO₂ ( $P_{\mathrm{ETC}{O}_2}$ ) was measured using a gas analyser. β-OHB was measured in venous blood. At 45 min post-ingestion, gCBF was significantly reduced by 10.6% in Low-KME and by 14.6% in High-KME compared to baseline. At 120 min, gCBF returned towards baseline in Low-KME, whereas gCBF was further reduced by 19.1% in High-KME compared to baseline. KME dose-dependent reductions in $P_{\mathrm{ETC}{O}_2}$ may have contributed to these reductions in gCBF following KME ingestion. These novel findings provide a foundational characterization of the impact of KME on resting CBF, which prompts further investigation building on these results to isolate underlying mechanisms and develop dosing protocols to mitigate potential CO₂ disruptions. KEY POINTS: Beta-hydroxybutyrate (β-OHB) is a signalling molecule and β-OHB infusion increases cerebral blood flow (CBF) in humans. Ingestion of higher doses of a ketone monoester (KME) supplement have been shown to lower blood pH and arterial CO₂, which are important regulators of CBF. This double-blind and placebo-controlled cross-over study tested the effects of two separate KME doses (Low-KME and High-KME) on resting CBF, end-tidal CO₂ and systemic haemodynamics over a 2 h period post-ingestion in young adults. Low-KME reduced CBF 45 min post-ingestion and High-KME reduced CBF at both 45 and 120 min post-ingestion, which corresponded with dose-dependent reductions in end-tidal CO₂. The findings from this trial represent a foundational characterization of the effects of KME dose on resting CBF.