Ketone supplementation as an intervention to alleviate alcohol withdrawal and improve brain energetics in Alcohol Use Disorder

PROJECT SUMMARY/ABSTRACT Alcohol Use Disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths globally. There is an urgent need to test interventions that reduce withdrawal symptoms such as tremor and delirium and improve brain health. Recent observations on brain energetics suggest that a shift from brain glucose to acetate

metabolism occurs in individuals with AUD that persists beyond the acute intoxication state. That is, individuals with AUD show poor brain glucose utilization and enhanced levels of brain acetate, a metabolite of alcohol. During alcohol detoxification, brain acetate levels decrease in the absence of alcohol, leading to an energy-

deficit state that may contribute to neurotoxicity and withdrawal severity in AUD. Ketone bodies (β- hydroxybutyrate [BHB]), acetoacetate, and acetone) are structurally similar to acetate and provide an alternative to glucose as an energy source in the brain. We recently found that a Ketogenic Diet intervention reduced the

need for benzodiazepine medications to treat alcohol withdrawal and elevated brain utilization of ketone bodies in AUD inpatients. Because a Ketogenic Diet is rigid and difficult to maintain, we started evaluating a BHB ketone supplement drink (KS) in humans, which reduced alcohol withdrawal in rodent models of alcohol dependence.

Thus, KS supplementation appears to be sufficient to reduce withdrawal symptoms without requiring a special dietary regimen. Here we propose to evaluate the clinical efficacy of ketone supplementation during the alcohol withdrawal state and its effect on improving brain ketone, and GABA metabolism in patients with AUD during

inpatient detoxification. The proposed study aims to determine: (1) the extent to which KS reduces the need for benzodiazepine treatment and alleviates withdrawal symptoms in AUD inpatients during alcohol detoxification, and (2) the effects of KS on brain ketone and GABA metabolism in individuals with AUD measured with high-

field strength proton magnetic spectroscopy (1H-MRS) imaging. To this end, we propose to randomize AUD inpatients to receive a KS supplement or a taste-matched Placebo by mouth three times daily during a 4-day alcohol detoxification treatment. Withdrawal signs and symptoms will be monitored every four hours using the

Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar), and benzodiazepines will be prescribed by a clinician for a CIWA-Ar score ≥8. After the 4-day intervention, participants in the KS and Placebo groups will complete a 1H-MRS scan at 7 Tesla to measure brain ketone and GABA metabolism. We hypothesize that KS

will reduce the need for benzodiazepine medication and alcohol withdrawal symptoms during alcohol detoxification and improve ketone, GABA and glutamate metabolism compared to Placebo, as evidenced by higher brain ketone, GABA, and glutamate levels. Documenting the beneficial clinical effects of KS in humans

with AUD (e.g., reducing withdrawal and improving brain metabolism) would be promising for the development of new ketone-based interventions during alcohol treatment to enhance success in recovery from AUD and to elucidate brain metabolism in the context of AUD.