Can Acetate-Like Drugs Support Sobriety?

Megan Brooks

March 08, 2013

The brains of long-term, heavy drinkers have twice the capacity to take up and metabolize acetate as those of light drinkers, a finding that may have implications for treatment of alcohol problems, new research suggests.

When consumed, alcohol is rapidly converted to acetic acid (acetate), which circulates in the blood and can serve as a source of energy for the brain and other organs.

Dr. Graeme Mason

"Acetate as fuel for the brain may sound like a good thing," but heavy drinkers' brains may adapt to that supply of energy and have a harder time reducing or quitting drinking, senior investigator Graeme F. Mason, PhD, professor of diagnostic radiology and psychiatry, Yale University School of Medicine in New Haven, Connecticut, told Medscape Medical News.

"There may be ways to support early sobriety with acetate or drugs that mimic some effects of acetate, and we need to investigate that with respect to effectiveness, safety, cost, and practicality," Dr. Mason added in a statement.

The study was published online March 8 in the Journal of Clinical Investigation.

New Therapeutic Approach?

The investigators used [2-13C]acetate as a metabolic substrate in combination with in vivo magnetic resonance spectroscopy to compare brain acetate uptake and metabolism in 7 heavy drinkers who regularly consumed at least 8 drinks per week and at least 4 drinks per day at least once weekly, and 7 light drinkers who consumed fewer than 2 drinks per week.

They found that heavy drinkers had roughly 2-fold more brain acetate relative to blood, suggesting that acetate transport and oxidation are faster in heavy drinkers than in light drinkers.

"People who drink heavily have twice the ability to burn acetate as fuel," said Dr. Mason. "We find not only that the acetate is being burned faster [in heavy drinkers] but there is more of the acetate itself."

"We know that in the liver, acetate metabolism causes inflammation, and there is every reason to believe that it does in the brain, too, and that might be one of the ways that when people drink heavily, it damages their brain," he added

Dr. Mason said that another potential adaptation related to acetate may also contribute to dependence. When the brain uses acetate for fuel, it creates adenosine as a by-product, which is sedating. Adaptation to that extra adenosine may also make it more difficult to stop drinking, he said.

The investigators believe their findings suggest that a new therapeutic approach involving supplying acetate to persons with alcoholism during detoxification might be beneficial.

Limitations, Reservations

R. Curtis Ellison, MD, professor of medicine, Boston University School of Medicine in Massachusetts, who was not involved in the study, told Medscape Medical News that "it has been known for a long time that heavy drinkers tend to become habituated to alcohol and react differently to a given amount of it than people who rarely drink. There are probably many mechanisms related to this phenomenon, and the acetate story described in this paper may be one of them."

Harvey Finkel, MD, also from Boston University, cautioned that the study only included 14 participants — "a very small number for such weighty conclusions," and that "the lower limit of the 'heavy' drinker group (8 drinks per week) is hardly abusive." Dr. Finkel, who was not involved in the study, also noted that adaptation "as a general biological phenomenon, and especially in regard to alcohol, has been well known for eons."

Fulvio Ursini, MD, a biochemist from the University of Padova in Italy, who studies the biological and chemical pathways of alcohol in the body but who was not involved in this study, has reservations about it.

"The take-home conclusion is that the story does not stand from a biochemical point of view," said Dr. Ursini.

"Acetate is oxidized in mitochondria, provided a sufficient amount of coenzyme A and oxaloacetic acid (OAA). By no means an increased oxidative capacity can be seen as possibly harmful. Moreover, such a metabolic adaptation, if any, by no means can affect the capacity of quitting drinking," he added

The study was supported by grants from the National Institutes of Health (NIH); the Yale Clinical and Translational Science Award Grant from the National Center for Research Resources and the National Center for Advancing Translational Science; and components of the NIH and NIH Roadmap for Medical Research. Dr. Mason has reported no relevant financial relationships. A complete list of author disclosures is provided in the original article. Dr. Ellison, Dr. Finkel, and Dr. Ursini have reported no relevant financial relationships. All 3 are members of the International Scientific Forum on Alcohol Research.

J Clin Invest. Published online March 8, 2013. Full article

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