UT Southwestern scientists discover agent that reverses effects of intoxication

DALLAS – March 07, 2023 – A shot of a liver-produced hormone called FGF21 sobered up mice that had passed out from alcohol, allowing them to regain consciousness and coordination much faster than those that didn’t receive this treatment, UT Southwestern researchers report in a new study. The findings, published in Cell Metabolism, could lead to effective treatments for acute alcohol intoxication, which is responsible for about 1 million emergency room visits in the U.S. each year.

“Humans have long searched for agents that could reverse drunkenness, and now we have discovered something to achieve this effect that’s been in our bodies the whole time,” said David Mangelsdorf, Ph.D., Chair and Professor of Pharmacology, Professor of Biochemistry at UTSW, and a Howard Hughes Medical Institute Investigator. Dr. Mangelsdorf co-led the study with his longtime collaborator, Steven Kliewer, Ph.D., Professor of Molecular Biology and Pharmacology, and Mihwa Choi, Ph.D., an Instructor of Pharmacology.

Dr. Kliewer explained that for thousands of years, humans have attempted to speed up the sobering process after drinking too much alcohol. For example, the ancient Greeks believed that amethyst could protect people from drunkenness, so they drank out of chalices carved from this semiprecious stone. But there is no treatment for alcohol intoxication. Other than removing undigested alcohol by pumping the stomach and preventing people from aspirating their own vomit, getting sober takes time, Dr. Mangelsdorf said.

In recent years, Drs. Mangelsdorf, Kliewer, and their colleagues discovered that FGF21 discouraged alcohol drinking in sober mice and encouraged water drinking to prevent dehydration in intoxicated mice. Other researchers discovered that this hormone appears to protect against alcohol-related liver injury.

While further exploring the hormone, UTSW scientists discovered that mice genetically altered to delete the gene that produces FGF21 took far longer than unaltered mice to become sober after acute alcohol poisoning.

As part of this latest study, the researchers delivered enough alcohol to mice to render them unconscious, mimicking a binge drinking session. They then injected some of the animals with FGF21. While those that didn’t receive this agent took about three hours to regain consciousness and stand upright, those that received FGF21 were able to accomplish this feat in half the time.

When the researchers delivered smaller amounts of alcohol more akin to typical human drinking – enough to significantly affect the animals’ coordination – the mice that received FGF21 injections also regained their coordination much faster than those that didn’t receive the hormone.

Further investigations showed that FGF21 acts on noradrenergic neurons, a type of nerve cell in the brain that promotes wakefulness. The hormone didn’t affect alcohol metabolism, though, as both treated and untreated mice showed the same blood alcohol concentrations.

FGF21 appears to specifically affect intoxication from alcohol, Dr. Kliewer said. Animals that received other types of sedatives did not become alert any faster than usual when given this hormone.

Dr. Mangelsdorf added that FGF21 has already been explored in clinical trials involving diabetes, weight loss, and nonalcoholic fatty liver disease and has shown a good safety profile. Eventually, he said, FGF21 could be developed into a drug that could be delivered to patients in hospital emergency rooms, college campuses, or elsewhere akin to the way Narcan is used to treat opiate overdoses, potentially saving countless lives.

“We don’t want to send the signal that it’s OK to get drunk because a drug can undo it,” Dr. Kliewer said. “But FGF21 may eventually be able to prevent some negative consequences for people incapacitated from alcohol.”

Other UTSW researchers who contributed to this study are Wei Fan, Abhijit Bugde, Laurent Gautron, Kevin Vale, Robert E. Hammer, and Yuan Zhang.

This study was supported by grants from the National Institutes of Health (K99 DK120869, R01 AA028473, 1P30 CA142543, and 1S10 RR029731), the Robert A. Welch Foundation (I-1275 and I-1558), and the Howard Hughes Medical Institute.

Dr. Hammer holds the Graydon Heartsill Professorship in Medical Science. Dr. Kliewer holds the Diana K. and Richard C. Strauss Distinguished Chair in Developmental Biology. Dr. Mangelsdorf, an Investigator in the Peter O’Donnell Jr. Brain Institute, holds the Alfred G. Gilman Distinguished Chair in Pharmacology and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, Ph.D. Drs. Mangelsdorf and Kliewer are members of the National Academy of Sciences.

Drs. Mangelsdorf and Kliewer are founders of Atias Pharma LLC and members of the advisory board.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.