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A high-fat, low-carbohydrate ketogenic diet alters the way the liver processes alcohol and tends to reduce alcohol consumption in alcohol-dependent male rats. These findings suggest that changing the body’s primary energy source could influence both the rate at which alcohol is broken down and the drive to drink. The research was published in the journal Neuropsychopharmacology.
A ketogenic diet involves eating high amounts of fat and very few carbohydrates and proteins. This nutritional pattern forces the body to stop relying on blood sugar, or glucose, and instead burn fat to produce molecules called ketone bodies. These ketone bodies then serve as an alternative fuel for the brain and body. Previous research indicates that heavy alcohol use reduces the brain’s ability to use glucose, leading to an energy deficit that might drive withdrawal symptoms and the urge to drink.
Researchers from the National Institutes of Health and University of Pennsylvania designed the present study to better understand how this dietary shift interacts with alcohol processing.
“The study builds directly on our previous work showing that a high-fat, low carb ketogenic diet intervention reduced alcohol withdrawal symptoms in human inpatients with AUD, and reduced alcohol intake in rodents,” said Corinde Wiers, an assistant professor of psychiatry and radiology at the Perelman School of Medicine at the University of Pennsylvania who supervised the study along with Leandro Vendruscolo, a Stadtman Investigator and chief of the Stress and Addiction Neuroscience Unit at the National Institute on Drug Abuse.
In their previous experiments, the research team noticed an unexpected pattern. “Interestingly, in that earlier work we also observed that rats on a ketogenic diet had much higher blood alcohol levels compared to chow-fed rats, after receiving the same amount of alcohol,” Wiers explained. “That was an unexpected finding and raised an important question: is the ketogenic diet changing how the liver metabolizes alcohol? The present study was designed to investigate that question and to better understand how ketogenic diets affect both alcohol metabolism and alcohol consumption.”
In the first phase of their research, the scientists maintained eight male and eight female adult rats on a ketogenic diet. A comparison group of eight male and eight female rats ate standard laboratory chow. The ketogenic diet consisted of 93 percent calories from fat, and the standard chow provided 13 percent calories from fat. After eight weeks, the rats on the ketogenic diet had higher blood ketone levels and lower blood glucose levels.
To test alcohol processing, the researchers exposed these rats to a short four-hour session of alcohol vapor. The rats on the ketogenic diet exhibited higher blood alcohol levels compared to the chow-fed group. Upon analyzing the liver tissue, the scientists observed that the ketogenic diet lowered the levels of alcohol dehydrogenase 1, or ADH1, an enzyme responsible for breaking down alcohol. The diet also lowered levels of pyruvate and lactate and increased the ratio of specific coenzymes involved in energy transfer, known as the NAD+/NADH balance.
“The original observation that really motivated this study was that ketogenic-diet-fed rats had much higher blood alcohol levels after alcohol exposure,” Wiers noted. “In the current study, we found evidence that this is related to slower liver alcohol metabolism, including lower levels of the major alcohol-metabolizing enzyme ADH1 and changes in the liver’s NAD+/NADH balance.”
Next, the researchers conducted positron emission tomography scans on a separate group of eight male rats to track how the diet affected brain energy use. They assigned four rats to each diet for eight weeks. The scientists injected the animals with a traceable radioactive sugar to see how much glucose the brain absorbed. The images indicated that the rats on the standard diet had higher sugar absorption across multiple brain regions, while the brains of the ketogenic diet group absorbed less sugar, providing evidence of a shift toward ketone-based energy production.
This shift in fuel sources might play a role in behavioral changes. “We cannot yet say exactly why the ketogenic diet reduced alcohol consumption,” Wiers explained. “In addition to less efficient alcohol metabolism, our findings point to changes in brain energetics as one possible contributor.”
In a third experiment, lead authors Sophie K. Elvig and Adrienne McGinn along with the rest of the team tested how the diet influenced the motivation to drink alcohol in dependent rats. They trained 20 male and 31 female rats to press a lever to receive a small dose of alcohol. The rats were then split into ketogenic and standard diet groups. To induce physical dependence on alcohol, the researchers exposed the animals to daily cycles of 14 hours of alcohol vapor followed by 10 hours of regular air.
Because the earlier experiment showed that a ketogenic diet slows alcohol breakdown, the researchers controlled for this metabolic difference. They adjusted the vapor chambers to deliver about 40 percent less alcohol to the ketogenic diet group. This adjustment successfully equalized the blood alcohol levels between the two groups.
During the daily withdrawal periods, the rats were given 30-minute sessions where they could press the lever for alcohol. The researchers found that male rats on the ketogenic diet pressed the lever fewer times and drank less alcohol per gram of body weight compared to the male rats on the standard diet. However, the diet did not alter alcohol consumption in the female rats. The ketogenic diet did not affect lever pressing for water in either sex, which indicates that the reduction in drinking among males was specific to alcohol.
“It was also interesting that the reduction in alcohol consumption occurred in male but not female rats, suggesting that sex may be an important factor in how metabolic interventions affect alcohol use, at least in rats,” Wiers told PsyPost.
These parallel changes in liver function and behavior highlight the complex nature of alcohol dependence. “I think this study illustrates why it is important to look at the whole body when studying addiction,” Wiers said. “Alcohol use is influenced not only by the brain, but also by peripheral metabolism and the interaction between the brain and organs such as the liver.”
The slowed alcohol metabolism suggests a potential risk for people attempting this diet. “Our findings suggest that a metabolic intervention can have effects in both directions, potentially reducing alcohol consumption while also slowing alcohol metabolism,” Wiers added. “That combination makes it especially important to study these interventions carefully before assuming that a ketogenic diet is necessarily beneficial or harmful for people who drink alcohol.”
The most relevant limitation is that these effects were observed in an animal model. “The most important caveat is that these are findings in rats, and we cannot assume that the same effects occur in humans,” Wiers cautioned. “We need a lot more work to determine the mechanisms and whether they are relevant to individuals with alcohol use disorder.”
A direct comparison to human metabolism is still pending. “If these findings translate to humans, the same amount of alcohol could result in greater alcohol exposure while following a ketogenic diet,” Wiers said. “This was an animal study, so we don’t yet know whether these effects occur in people. But we do know that increased sensitivity to alcohol is an anecdotally reported side effect of ketogenic diets.”
To explore this in humans, Wiers noted that her lab is currently conducting a clinical trial, led by postdoctoral fellow Xinyi Li, testing the effects of a four-week ketogenic diet on alcohol intoxication.
Looking ahead, the research team aims to evaluate several diet-based and pharmacological approaches to treating addiction. “Our broader goal is to understand how the body’s metabolic state influences addiction,” Wiers said. “Ketogenic diets fundamentally change the fuels available to the brain, shifting it away from glucose toward ketone bodies. We are particularly interested in whether these changes in brain energetics can influence alcohol craving, withdrawal, and alcohol consumption.”
Some scientists are already exploring whether metabolic medications used for diabetes and weight loss, known as GLP-1 receptor agonists, might also reduce drinking. “Ultimately, we want to determine whether metabolic interventions, including the ketogenic diet, ketone supplement drinks, and GLP-1 receptor agonist medications, can be developed into useful treatments for alcohol use disorder, while also understanding their potential effects on alcohol intoxication and other risks,” Wiers concluded.
The study, “A ketogenic diet reduces hepatic alcohol metabolism and alcohol consumption in rats,” was authored by Sophie K. Elvig, Adrienne McGinn, Xinyi Li, Janaina C. M. Vendruscolo, Juan L. Gomez, Robert Pawlosky, Bryan Mackowiak, Luis Gonzalez, M. Todd King, Michael Michaelides, Bin Gao, Nora D. Volkow, George F. Koob, Corinde E. Wiers, and Leandro F. Vendruscolo.