Intravenous Acetate as an Adjunctive Treatment for Alcohol Withdrawal in Hospitalized Patients

Alcohol withdrawal syndrome manifests in up to 30% of hospitalized patients with severealcohol use disorders (AUD), and is a potentially life‐threatening, highly morbidcondition. Standard medications to treat alcohol withdrawal (e.g. benzodiazepines) caninduce respiratory depression and prolong hospitalization, while medications used asadjuncts (e.g. dexmedetomidine) are also sedating and necessitate intensive monitoring.Therefore, alternative treatments targeting novel pathways in alcohol withdrawal areneeded to address this treatment gap and improve patient care. Although alcoholwithdrawal symptoms arise from counterregulatory neuroadaptations in γ‐aminobutyric acid(GABA) and glutamate signaling, homeostatic alterations in the brain's fuel preferenceand sudden changes in its fuel supply have also been implicated that are not addressed bycurrent treatment paradigms. Longstanding AUD diminishes the brain's ability tometabolize glucose, enhancing its metabolic preference for the alcohol metaboliteacetate. Acetate is converted to acetyl‐CoA, which is used for fuel and neurotransmitterproduction. When a person with AUD is hospitalized, stopping alcohol consumption, acetatesupply ceases at a time when the brain has a reduced preference for glucose, potentiallydriving withdrawal symptoms. Investigations in patients with alcohol withdrawal thatadministered alternative energy substrates via oral ketogenic diet (which also generatesacetyl‐CoA) reported symptom improvement; however, prominent gastrointestinal symptoms inacute, severe alcohol withdrawal limit their use in this setting. Notably, we have shownthat intravenous (IV) acetate administration to participants with AUD was feasible andsafe and had a demonstrable physiological effect on cerebral blood flow (CBF), measuredby magnetic resonance arterial spin labeling, including increased CBF to thalami,cerebellum, and cortex, which was not observed in healthy controls. Since metabolism andblood flow are tightly linked in the brain, our results support metabolic adaptations inAUD, paving the way for future investigations of acetate's efficacy as an adjunctivetreatment in alcohol withdrawal that will be refined in this R34 proposal. We willconduct a single‐ center, placebo‐controlled randomized clinical trial (RCT) of IVacetate in patients hospitalized at a large academic university hospital who arereceiving inpatient standard of care treatment for alcohol withdrawal syndrome.Aim 1 will optimize screening, recruitment, informed consent, and enrollment strategies.Aim 2 will establish processes to ensure protocol fidelity, safety, and patientretention, to include collection of outcome variables reflecting patient symptoms andmedication administration for alcohol withdrawal, and healthcare resource utilization.Aim 3 will use qualitative methods to incorporate the experiences and perceptions ofpatients hospitalized with alcohol withdrawal to improve study design and magnify theimpact of the research.Results of this study will inform the final protocol and procedures for a futuremulti‐center RCT focused on determining efficacy of adjunctive acetate treatment inpatients admitted for alcohol withdrawal syndrome.