Ketone esters show promise as a new treatment for alcohol use disorder

A small study comparing individuals with alcohol use disorder and healthy participants found that a single dose of a ketone ester supplement significantly reduced alcohol cravings in participants with alcohol use disorder and shifted brain energy use from glucose to ketones. The paper was published in Psychiatry Research: Neuroimaging.

Ketone esters are synthetic compounds designed to raise the level of ketone bodies in the blood without requiring fasting or a strict ketogenic diet. Ketones are alternative energy molecules produced naturally by the liver when carbohydrate intake is low, especially during fasting or prolonged exercise.

The rationale behind the study stems from how alcohol changes the brain’s metabolism. People who drink heavily adapt to using acetate (a byproduct of alcohol) for brain energy instead of glucose. When a person stops drinking, the sudden lack of acetate creates a brain energy deficit that is believed to trigger withdrawal symptoms and severe alcohol cravings. Researchers hypothesized that ketones, which act similarly to acetate, could serve as an alternative brain fuel to safely close this energy gap.

A ketone ester supplement typically contains molecules such as β-hydroxybutyrate (BHB) bound to an alcohol, which the body rapidly converts into usable ketones. These supplements can quickly induce a state of nutritional ketosis within minutes of ingestion.

Unlike ketone salts, ketone esters do not contain large amounts of minerals and therefore can deliver higher ketone levels more efficiently. They are sometimes used by athletes to (potentially) enhance endurance performance by providing an alternative fuel source. Some research suggests they may also affect cognitive function by supplying the brain with a steady energy substrate. However, the taste of ketone ester supplements is unpleasant (for most people), and they can cause gastrointestinal discomfort in some users.

Study author Xinyi Li and colleagues wanted to explore the effects of a single dose of a ketone ester supplement. They note that previous studies showed a single dose of ketone ester supplements to elevate BHB levels in blood 30 minutes after intake, with the effects peaking 45-60 minutes after intake. In this study, they investigated the effects on brain glucose metabolism in individuals with alcohol use disorder and healthy individuals. They also looked into how alcohol cravings changed after intake of this supplement.

Study participants included 5 individuals with alcohol use disorder and 5 healthy individuals. Participants were between 21 and 65 years of age; 3 of them were women and 7 were men. Healthy participants’ average age was 36 years, while the average age of individuals with alcohol use disorder was 31 years.

There were two treatment conditions – receiving no ketone ester supplement (baseline) and receiving 395 mg/kg of a ketone ester supplement. All participants went through both conditions in two visits to the laboratory, but the order in which they received the treatments was randomly determined for each participant. On each visit, they completed a PET scan.

The ketone ester supplement participants took was diluted with diet soda or sparkling water and given to participants 1 hour before they had a PET scan. The PET scan portion of the study was open-label, meaning no intervention was provided at the baseline visit and participants knew when they were receiving the supplement. Study participants gave blood samples at arrival to the laboratory, prior to injection of the radioactive glucose (that is needed for PET scans to work), 30 minutes later, and 60 minutes later.

Participants with alcohol use disorder also underwent magnetic resonance spectroscopy (MRS), allowing study authors to directly measure BHB levels inside the brain. Unlike the PET scans, this MRS portion of the study was double-blind and placebo-controlled; participants received either the ketone ester or a taste-matched, bitter dextrose placebo 45 minutes prior to the scan.

Results showed that the ketone ester supplement lowered blood glucose levels and increased BHB levels in both groups. Brain scans revealed a 17% reduction in glucose metabolism, especially in the frontal, occipital, and cingulate cortices of the brain, as well as in the hippocampus, amygdala, and insula regions.

The ketone ester supplement significantly reduced self-reported alcohol cravings in participants with alcohol use disorder. It also tripled BHB levels in the cingulate cortex region of their brains, proving the supplement successfully crossed the blood-brain barrier.

“These findings suggest that a single KE [ketone ester] dose can rapidly shift brain energy use from glucose to ketones, and may help reduce cravings in AUD [alcohol use disorder], supporting its potential as a therapeutic approach,” the study authors concluded.

The study contributes to the scientific understanding of the physiological and psychological effects of ketone ester supplements. However, it should be noted that the study was conducted on a very small group of participants. Because of this, effects needed to be of very substantial magnitude to be detectable.

The paper, “Pharmacokinetic effects of a single dose nutritional ketone ester supplement on brain glucose and ketone metabolism in alcohol use disorder,” was authored by Xinyi Li, Anthony J. Young, Zhenhao Shi, Juliana Byanyima, Sianneh Vesslee, Rishika Reddy, Timothy Pond, Mark Elliott, Ravinder Reddy, Robert K. Doot, Jan-Willem van der Veen, Henry R. Kranzler, Ravi Prakash Reddy Nanga, Jacob G. Dubroff, and Corinde E. Wiers.