Women’s Brains on Alcohol: Insight into the Science of Sex-Based Risks

Alcohol use disorder is a chronic disease that used to disproportionately affect men. But for the first time in history, women are catching up.

Today, women in the United States are drinking and engaging in harmful alcohol use at rates on par with their male counterparts. Historically, research on alcohol use disorder—characterized by an impaired ability to control alcohol use despite negative consequenses—has focused on men. But as alcohol use disorder in women is on the rise, researchers are finding that men and women are motivated to drink for different reasons—and women face greater health risks.

Now, the Yale Program on Sex Differences in Alcohol Disorder is exploring the neurobiological drivers of drinking behavior and alcohol use disorder in women. This work is helping inform the development of novel therapeutics which are responsive to known sex differences in alcohol use disorder—a particularly important advance since available FDA-approved treatments are based on research involving primarily (or often exclusively) men.

“Alcohol use disorder is incredibly heterogenous,” says Sherry McKee, PhD, professor of psychiatry at Yale School of Medicine (YSM) and director of the Yale program. “Not every medication is going to work for every person. And one of the key pieces that’s been missing in our research is a focus on sex and gender.”

Last year, the Centers for Disease Control and Prevention identified a disturbing trend—between 2016 and 2021, rates of alcohol-related deaths increased by 35% in women (and 27% in men). Some researchers hypothesize that changes in social norms may be one of the drivers of increased drinking in women. “Women are now earning more, delaying marriage, and delaying childbirth,” says McKee. “It’s thought that this might create more time and space for drinking.”

And, even among those who are married and starting families, alcohol companies have increasingly focused their marketing on women. Terms like “mommy juice” have grown in popularity, and gendered alcoholic drinks such as “Mom Water” have appeared on shelves in liquor stores. “We’ve seen that marketing toward moms has normalized ‘wine mom culture,’” says Kelly Cosgrove, PhD, professor of psychiatry, of neuroscience, and of radiology and biomedical imaging at YSM.

Research shows that the COVID-19 pandemic exacerbated the rise in drinking. One 2020 study found that the number of days in which women reported heavy alcohol use—at least four drinks within a couple of hours—rose by 41%. “It had to do with the amount of time that people were home and the stress that they were under,” explains Marina Picciotto, PhD, Charles B. G. Murphy Professor of Psychiatry at YSM.

The rise in alcohol use is especially concerning because women face greater drinking-related health risks at lower amounts of alcohol than men. “We refer to this as the risk-severity paradox,” says McKee.

Studies have found that women who drink are at a disproportionately greater risk for brain damage, cognitive deficits, various cancers such as breast cancer, cardiovascular issues, liver injury, and immune system dysfunction. Drinking is also associated with greater risk of mental health issues and suicide, physical and sexual assault, and pregnancy- and perinatal-related complications. Furthermore, alcohol can cause hormonal imbalances and menstrual irregularities.

The number of alcohol-related deaths is not only rising faster among women, but also driven by lesser amounts of alcohol. Men need to drink at least 3.2 drinks per day to be at increased risk of premature death, whereas women only need to consume 1.8. “Not even two drinks a day is putting a woman at significantly increased risk,” says McKee.

These disparities are reflected in the health care system. Emergency room visits related to alcohol use increased by 70% in women versus 58% in men between 2006 and 2014, and hospitalizations rose by 69% in women (compared to 43% in men) between 2000 and 2015.

Women experience greater health risks from drinking, in part, because they metabolize alcohol differently than men. Alcohol is not lipid-soluble. In other words, when we consume alcohol, it does not enter fat tissue—it only disperses into tissue that contains water. Women tend to have a lower percentage of body water and more fat tissue than men. Thus, they have less fluid to dilute the alcohol, leading to a higher blood alcohol concentration (BAC). Furthermore, the primary enzyme involved in the metabolism of alcohol—alcohol dehydrogenase—is as much as 40% less active in women.

As result, when a woman and a man of the same age and weight drink the same amount at the same rate, the woman will experience a greater BAC. “Let’s say they’re both 150 pounds and 48 years old, and they consume three drinks in two hours,” McKee says. “The man will be significantly under the legal drinking limit for driving, and the woman will be over the legal drinking limit—just because of this difference in how alcohol is metabolized.”

As alcohol-related harms continue to grow among women, they are also less likely to seek treatment than men. McKee believes that societal stigma surrounding alcohol consumption is the primary reason for this reluctance. But another obstacle is that medical providers do not consider the sex-related differences when diagnosing and treating alcohol use disorder. Women, for example, make up only about 13% of participants studied in research on withdrawal, according to a review in Frontiers in Psychiatry.

Medication trials for treating alcohol use disorder have also historically been conducted primarily on male cohorts. Only 1% of study participants involved in research on disulfiram—which, in 1948, became the first of the three FDA-approved medications for alcohol abuse —were women. Studies show that naltrexone, another FDA-approved medication, is more likely to have side effects in women such as nausea and sleep disturbances—making them less likely to stick with the treatment. Research has not revealed any sex differences related to acamprosate, the third FDA-approved medication.

The Yale Program on Sex Differences in Alcohol Disorder is investigating key differences between the underlying mechanisms of alcohol addiction in women compared to men. One of its missions is to create more effective therapeutics tailored to women. Emerging research, for example, shows that drivers of alcohol use differ between sexes. While men are more likely to drink to experience the positive aspects of alcohol, such as feelings of pleasure and connecting socially with others, women are more likely to drink to help manage stress. “So, we’re developing medications that target stress pathophysiology,” says McKee.

This may be explained by key sex differences in the brain that emerge during adolescence, particularly differences in the interactions of three key neural systems—the prefrontal cortex, striatum, and amygdala. The prefrontal cortex is responsible for executive functions such as impulse control and decision-making. The striatum drives pleasure-seeking behaviors and processes rewards, and becomes activated when individuals engage in risk-taking scenarios. The amygdala is associated with our emotional responses, especially those related to fear.

Brain imaging studies have shown that men have greater activation in the striatum, which makes them more likely to engage in risky behaviors. The prefrontal cortex of women, on the other hand, develops earlier than in men—acting as a brake on impulsivity. However, women also show greater reactivity of the amygdala, which makes them more susceptible to anxiety or other mood disorders. This may explain why women, unlike men, do not seek alcohol for the thrill of drinking, but rather to cope with negative emotions, McKee says.

These findings may also explain why women who suffered major stressors in early childhood, such as abuse or neglect, might be especially vulnerable to developing alcohol use disorder. “The prefrontal cortex and the amygdala are key brain regions that interact with the experience of childhood adversity, childhood trauma, and stress,” says McKee. “Our working hypothesis is that these experiences will lead to the internalization of disorders such as anxiety and depression, which then lead to alcohol use. A lot of data suggest that this is a common pathway for alcohol use disorder in women.”

Yale School of Medicine researchers are now diving even deeper into understanding how differences in the brain may be uniquely driving alcohol use disorder in women. Cosgrove, for instance, is focused on the neuroimmune system. “Most of us are familiar with the peripheral immune system—it keeps us healthy,” she says. “But the brain has its own immune system, and we’ve been focused on that because it’s responsible for healthy brain function. It’s at the root of everything.”

Cosgrove’s team is using a radiotracer—a radioactive substance used in medical imaging—that binds to an important type of immune cell in the brain called microglia. Microglia play a crucial role in maintaining brain health, and their dysfunction is associated with a range of neurodegenerative disease such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.

Using positron emission tomography scans, the researchers are investigating whether there are differences between the microglia of men and women with alcohol use disorder. They are finding that women with alcohol use disorder have a greater deficit of microglia than their male counterparts.

The findings, Cosgrove says, are not surprising. The fact that women are more likely than men to suffer from autoimmune diseases such as multiple sclerosis points to differences underlying female immune processes. “Women have different immune systems inherently,” she says.

Because immune dysfunction and inflammation are intertwined, when part of the neuroimmune system malfunctions, it can lead to increased or chronic inflammation. Cosgrove’s research into neuroimmune sex differences could help explain why women are prone to alcohol-related harms such as alcohol-related liver disease. “These sex differences are likely driven by differences in inflammation,” says Cosgrove. “And we can think of different medications and treatments to target and treat this inflammation.”

Cosgrove’s team is also working to identify other differences in the neuroimmune system that might be easier to therapeutically target. “The target we have now, TSPO [a protein expressed by microglia], isn’t an easy target to make a medication for,” she says. “But there are likely other targets that could give us new ideas for medication development.”

Meanwhile, Picciotto is testing hypotheses raised by studies like Cosgrove’s in mice. By feeding a blocker of microglia to female mice, for example, her team is studying how this alters their likelihood to choose alcohol over water when under stress.

So far, they have found that reducing microglia by half does not significantly impact stress-induced alcohol consumption. In future studies, they plan to investigate whether a greater deficit of microglia will impact mice behavior.

Her team has shown, however, that reducing inflammation does alter alcohol-seeking behaviors. The researchers blocked signaling pathways known to promote inflammatory responses using a drug called apremilast. In humans, this drug treats conditions such as psoriatic arthritis and plaque psoriasis by reducing inflammation. They found that the drug reduced the likelihood of mice choosing alcohol over water.

In future studies, Picciotto hopes to identify specific subtypes of inflammatory responses that are important in the context of alcohol use disorder. “We’re interested in whether different circuits are engaged in response to stress-induced alcohol drinking in male and female mice,” she says. “And we’re going to continue to look at the consequences of these inflammatory responses on neural signaling.”

This January, former U.S. Surgeon General Vivek Murthy issued a report communicating to the public for the first time that alcohol is a significant cause of cancer—further highlighting the urgent need for effective therapies for alcohol use disorder. The ongoing research at the Yale Program on Sex Differences in Alcohol Disorder is paving the way for a new era of more personalized therapeutics for women. “We’re just at the beginning of really understanding what it is about the brain and body that differs between men and women who drink,” says Picciotto.

McKee hopes her program will help contribute to a healthier society overall. “Our goal is to improve the health of everyone,” she says. “We really need to be focused on a personalized medicine perspective—particularly in regard to addiction and alcohol.”

Women can develop alcohol use disorder no matter what stage of life they’re in. And there is no shame in seeking support, the researchers say. “We think about adolescents as being particularly susceptible to problematic drinking—and they certainly are—but women can be at risk of developing problematic drinking patterns across their lifespan,” says Picciotto. Research shows that alcohol use, for instance, is also on the rise among women ages 60 and older. “Stressful life events may increase a woman’s alcohol intake in ways that are surprising to them, and there are options for them to get help if they need to decrease their drinking during stressful times.”

For resources on finding quality, evidence-based care, women can visit the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcohol Treatment Navigator. The Yale Program on Sex Differences in Alcohol Disorder is also enrolling for medication trials.

The Yale Program for Sex Differences in Alcohol Use Disorder is supported by a SCORE grant (award U54AA027989) from the Office of Research on Women’s Health and the National Institute of Alcohol Abuse and Alcoholism at the National Institutes of Health, and by Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.