Nutritional Ketosis as a Potential Treatment for Alcohol Use Disorder.

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, ß-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.

Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet.

We measured the effects of a diet in which D-ß-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood d-ß-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [(18)F]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement.

A ketone ester diet increases brain malonyl-CoA and Uncoupling proteins 4 and 5 while decreasing food intake in the normal Wistar Rat.

Three groups of male Wistar rats were pair fed NIH-31 diets for 14 days to which were added 30% of calories as corn starch, palm oil, or R-3-hydroxybutyrate-R-1,3-butanediol monoester (3HB-BD ester). On the 14th day, animal brains were removed by freeze-blowing, and brain metabolites measured. Animals fed the ketone ester diet had elevated mean blood ketone bodies of 3.5 mm and lowered plasma glucose, insulin, and leptin. Despite the decreased plasma leptin, feeding the ketone ester diet ad lib decreased voluntary food intake 2-fold for 6 days while brain malonyl-CoA was increased by about 25% in ketone-fed group but not in the palm oil fed group. Unlike the acute effects of ketone body metabolism in the perfused working heart, there was no increased reduction in brain free mitochondrial [NAD(+)]/[NADH] ratio nor in the free energy of ATP hydrolysis, which was compatible with the observed 1.5-fold increase in brain uncoupling proteins 4 and 5. Feeding ketone ester or palm oil supplemented diets decreased brain L-glutamate by 15-20% and GABA by about 34% supporting the view that fatty acids as well as ketone bodies can be metabolized by the brain.