Nutritional Ketosis as a Potential Treatment for Alcohol Use Disorder

Abstract

Alcohol use disorder (AUD) is a chronic, relapsing brain disorder, characterized by compulsive alcohol seeking and disrupted brain function. In individuals with AUD, abstinence from alcohol often precipitates withdrawal symptoms than can be life threatening. Here, we review evidence for nutritional ketosis as a potential means to reduce withdrawal and alcohol craving. We also review the underlying mechanisms of action of ketosis. Several findings suggest that during alcohol intoxication there is a shift from glucose to acetate metabolism that is enhanced in individuals with AUD. During withdrawal, there is a decline in acetate levels that can result in an energy deficit and could contribute to neurotoxicity. A ketogenic diet or ingestion of a ketone ester elevates ketone bodies (acetoacetate, β-hydroxybutyrate and acetone) in plasma and brain, resulting in nutritional ketosis. These effects have been shown to reduce alcohol withdrawal symptoms, alcohol craving, and alcohol consumption in both preclinical and clinical studies. Thus, nutritional ketosis may represent a unique treatment option for AUD: namely, a nutritional intervention that could be used alone or to augment the effects of medications.

Keywords: alcohol dependence; alcohol metabolism; alcohol withdrawal; alcoholism; ketogenic diet; ketone ester.

Figure 1

(A) Hepatic metabolism of ethanol and fatty acids and ketogenesis are shown. (B) Non-hepatic metabolism of D-BHB, acetate, and glucose in the cytosol and mitochondria converge on acetyl-CoA which enters the tricarboxylic acid (TCA) cycle. Within neurons, acetoacetate and D-BHB are transported into the mitochondria via monocarboxylate transporters. Abbreviations: TCA Cycle, tricarboxylic acid cycle/the citric acid cycle/Kreb's cycle; D-BHB, D-β-Hydroxybutyrate; NAD(H), nicotinamide adenine dinucleotide; SCOT, 3-ketoacid CoA transferase; ACAT, acetyl-CoA acetyltransferase; I, NADH ubiquinone oxireductase; II, succinate dehydrogenase; III, CoQH₂-cytochrome c reductase; IV, cytochrome c oxidase; ATP Synthase, F_OF₁ ATP synthase; PDC, pyruvate dehydrogenase complex.

Figure 2

Schematic overview of the shift from high acetate utlization to low brain acetate avaliability with slow recovery of brain glucose metabolism in chronic AUD during detoxification. This shift is hypothesized to produce a central energy deficit that could contribute to alcohol withdrawal symptoms and associated neurotoxicity.