Ketone-sup before Pub: Effects of ketone supplementation on brain energetics and alcohol consumption in alcohol use disorder

Enter the text here that is the new abstract information for your application. Alcohol Use Disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths globally. Available treatments are not efficacious for all patients or not well tolerated, thus there is a critical need to identify novel, well-tolerated treatments to reduce alcohol craving and consumption. Individuals with AUD have low brain glucose and a high rate of acetate metabolism that persist beyond acute intoxication. Ketones (β-hydroxybutyrate [BHB] and acetoacetate) structurally resemble acetate and provide an alternative to glucose as a source of energy to the brain. We and others have found that elevating ketones with a ketogenic diet reduced alcohol consumption and signs of alcohol withdrawal in alcohol-dependent rodents, and alcohol craving and alcohol withdrawal in human patients with AUD. Because a ketogenic dietary regimen is difficult to maintain, we have begun to evaluate a ketone supplement drink (KS), which increases blood ketone levels within 30 min of administration without the need for a special dietary regimen. The main goal of this proposal is to examine the efficacy and tolerability of KS in reducing alcohol craving and consumption among individuals with AUD by (1) improving brain energetics and (2) affecting the pharmacokinetic effects of alcohol and subjective responses. Our preliminary data demonstrate that KS reduced alcohol consumption in alcohol-dependent rodents. In humans, a single dose of KS rapidly increased blood and brain BHB levels while decreasing brain glucose metabolism, and pairing KS with alcohol significantly blunted breath and blood alcohol concentrations two-fold and reduced self-reported ratings of alcohol liking and “wanting” more alcohol. Here, we propose a randomly ordered, 2-session crossover study in which 60 nontreatment seeking individuals with AUD will receive a single dose of KS and a matched placebo during two separate study visits. On each visit, participants will undergo a Proton Magnetic Resonance Spectroscopy scan edited for the detection of brain BHB, the consumption of an oral alcohol priming dose, and an alcohol bar lab choice paradigm. Consumption of KS vs placebo is expected to (1) rapidly elevate BHB metabolism, (2) result in lower breath alcohol levels and subjective alcohol liking and wanting, and in (3) lower alcohol craving and consumption. We will test the degree to which the KS-induced shift in brain energetics and -reductions in breath alcohol levels will mediate reductions in alcohol craving and consumption. Demonstrating the beneficial effects of KS on alcohol craving and consumption in human AUD would support the development of new ketone-based interventions that may significantly enhance brain health and success in recovery from AUD.