Pharmacokinetic effects of a single-dose nutritional ketone ester supplement on brain ketone and glucose metabolism in alcohol use disorder

Acute alcohol intake decreases brain glucose metabolism and increases brain uptake of acetate, a metabolite of alcohol. This shift in energy utilization persists beyond acute intoxication in individuals with alcohol use disorder (AUD), and may contribute to alcohol craving. We recently found that ketone therapies decrease alcohol withdrawal and alcohol craving in AUD. Here, we studied the effects of a single-dose ketone ester (KE) supplement on brain energy metabolism and alcohol craving. Five AUD and five healthy control (HC) participants underwent two 18F-fluorodeoxyglucose positron emission tomography (PET) scans, after consumption of 395 mg/kg KE or without (baseline), in randomized order. In the AUD group, KE reduced alcohol craving scores compared to baseline. KE decreased blood glucose levels and elevated blood {beta}-hydroxybutyrate (BHB) levels compared to baseline in both groups. Whole-brain voxel-wise maps of the cerebral metabolic rate of glucose (CMRglc) decreased by 17% in both groups, with the largest KE-induced CMRglc reductions in the frontal, occipital, and cingulate cortices, hippocampus, amygdala, and insula. There were no group differences between AUD and HC in blood or FDG measures, and no correlations between reductions in craving with CMRglc. Cingulate BHB levels, as assessed with 1H-magnetic resonance spectroscopy in 5 participant with AUD, increased 3-fold with KE compared to baseleline. In sum, administration of a single dose of KE rapidly shifted brain energetics from glucose to ketone metabolism in HC and AUD. KE also reduced ratings of alcohol craving, demonstrating its potential clinical effectiveness for supporting brain health and alcohol craving in AUD.