SK. Elvig, A. McGinn, X. Li, JCM. Vendruscolo, JL. Gomez, R. Pawlosky, B. Mackowiak, L. Gonzalez, MT. King, M. Michaelides, B. Gao, ND. Volkow, GF. Koob, CE. Wiers, et al. (2026). A ketogenic diet reduces hepatic alcohol metabolism and alcohol consumption in rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 51(9), 1568-1576. https://doi.org/10.1038/s41386-026-02383-5

PubMed 41862734

[Abstract]
Previous work showed that rats that were exposed to a high-fat, low-carbohydrate/protein ketogenic diet (KD) exhibited elevated blood alcohol levels following alcohol exposure compared with rats fed regular chow. Additionally, the administration of a KD prior to alcohol exposure (i.e., a history of KD) reduced alcohol consumption in alcohol-dependent rats that were no longer on the diet. In the present study, we investigated the mechanisms by which a KD alters alcohol metabolism and tested whether ongoing KD exposure reduces alcohol consumption in rats. We hypothesized that chronic KD exposure alters hepatic alcohol-metabolizing enzymes, slows alcohol metabolism, and reduces alcohol self-administration in alcohol-dependent rats. We found that male and female rats maintained on a KD had higher blood alcohol levels, lower hepatic alcohol dehydrogenase 1 protein levels, and a higher nicotinamide adenine dinucleotide [NAD+]/[NADH] ratio in the liver cytoplasm compared with chow-fed control rats. Furthermore, KD-fed rats demonstrated lower brain glucose uptake relative to chow-fed control rats. In a model of alcohol dependence, the KD reduced alcohol consumption in male, but not female, rats compared with chow-fed rats. These findings suggest that a KD alters brain energetics and alcohol metabolism, which may contribute to reduced alcohol consumption in male rats.