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The anti-anxiety reducing effects of metformin during nicotine withdrawal are dependent on hippocampal AMPKα. Representative GFP expression of AMPK in the hippocampus at 10× magnification (green). Julie Blendy, PhD, Perelman School of Medicine, University of Pennsylvania; PNAS

PHILADELPHIA – Metformin, the most widely used medication for diabetes, has also been shown to help treat dementia and some cancers. New research from the Perelman School of Medicine at the University of Pennsylvania and Johns Hopkins Medicine shows smoking cessation may be added to that list.

In a new study in the Proceedings of the National Academy of Sciences the research team found that after giving mice metformin the animals displayed reduced symptoms when going through nicotine withdrawal.

“Although we are just beginning to characterize this new role for metformin, our study suggests that the protein it acts on could be a new target for smoking cessation treatment,” said senior author Julie Blendy, PhD, a professor of Systems Pharmacology and Translational Therapeutics at Penn.

Cigarette smoking is the leading cause of preventable disease and death in the United States, with more people dying from nicotine addiction than any other preventable cause of death. Even though quitting smoking brings many health benefits, the abstinence rate remains low with current medications, likely because of an array of undesirable withdrawal symptoms.

Metformin has a variety of targets, one of which is a protein called AMPK. This study showed that the AMPK pathway in the hippocampus of the brain is activated following long-term use of nicotine. But, this heightened AMPK activity is rapidly reversed during nicotine withdrawal, which is associated with negative symptoms such as anxiety.

Increasing AMPK levels using metformin decreases anxiety following nicotine withdrawal in the mice. Anxiety was measured in two behavior tasks that are designed to trigger relevant behaviors and contrast the tendency for mice to explore or engage in social investigation against the anxiety-producing properties of novel objects in the cage (the marble burying test) or an open, brightly lit space (a novelty-induced decrease in eating test).

This study provides evidence of a direct effect of AMPK on nicotine withdrawal symptoms and suggests that activating AMPK in the brain could be a therapeutic target for smoking cessation. The authors say that the well-established safety profile of metformin for diabetes should hopefully encourage clinicians to translate these findings into clinical trials to improve sustained abstinence rates in ex-smokers.

As part of a collaborative effort, clinical researchers Rebecca Ashare, PhD, an assistant professor of Psychology in Psychiatry, and Robert Schnoll, PhD, an associate professor of Psychology in Psychiatry and director of the Center for Interdisciplinary Research on Nicotine Addiction, are studying the effects of metformin on smokers to see if it attenuates negative mood and cognitive deficits during withdrawal – symptoms known to be associated with the ability to quit. If the current trial suggests withdrawal symptoms can be reduced, a larger study would evaluate its effects on smoking cessation.

At present, little is known regarding the molecular targets of the AMPK pathway following chronic nicotine use withdrawal. In the future, studies are aimed at using novel molecular approaches to selectively delete AMPK in specific brain regions associated with nicotine dependence to better understand the functional role of this protein in addiction.

Julia K. Brynildsen, Bridgin G. Lee, Isaac J. Perron, Sunghee Jin, and Sangwon F. Kim are coauthors. This work was supported by the National Institutes of Health (T32-GM008076, R01 DA041180, DK084336) and a National Center for Advancing Translational Sciences Award (TL1TR000138). The clinical project is supported by a grant from the Commonwealth of Pennsylvania.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.

The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.

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Penn Medicine is an $11.1 billion enterprise powered by more than 49,000 talented faculty and staff.

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