Why Sex Differences Matter in Addiction Research

Why Sex Differences Matter in Addiction Research

Women face unique addiction risks tied to hormones, metabolism and brain function. Learn how sex-based research is reshaping treatment approaches.
By Julian Nowogrodzki

Rates of substance use disorders among women are rising worldwide. Yet, much of what we know about addiction—its prevention, treatment and underlying physiology—is based on research conducted primarily in men and male animals.

In 1990, men were about five times more likely than women to have an alcohol use disorder. Today, that gap has narrowed significantly: Men are now only twice as likely. The COVID-19 pandemic accelerated this shift, driving notable changes in women’s drinking behaviors. In the early months of the pandemic, women reported increased binge drinking and drinking earlier in the day. This pattern of increased binge drinking among women has persisted, according to a 2025 study in JAMA. Women’s drinking habits have not returned to pre-pandemic levels. 

However, the research landscape is beginning to shift. In 2014, the National Institutes of Health (NIH) began requiring researchers to include both sexes in NIH-funded animal studies. Since then, new findings have started to uncover differences in sex-based physiological responses to substance use, which could lead to more effective treatment and prevention strategies. This is crucial because female hormones and differences in their metabolism and body size affect how substances are absorbed, processed and affect key organ systems.

This research is essential to raising awareness that women are at risk of both addiction and physiological damage at lower levels than men, says Patricia Molina, MD, PhD, FAPS, head of the Department of Physiology, senior associate dean for research, co-director of the Alcohol and Drug Abuse Center of Excellence at Louisiana State University Health Sciences Center and 88th president of APS.

Basic Differences

Understanding physiological differences between men and women is important because women experience bodily harm at lower doses of alcohol than men do. Sex-based differences in metabolism, body composition, size and hormone levels all influence how substances affect the body. For example, women’s body size is on average smaller than men’s, and a certain amount of alcohol will raise blood alcohol to a higher—and therefore more toxic—level in a smaller body than a larger body. 

Even given the same body size, women and men metabolize alcohol differently. Women have lower levels of the enzyme alcohol dehydrogenase in their digestive systems, meaning that they cannot process alcohol as quickly as men.

“If I have a drink and a man my same size has a drink, by the time our blood alcohol levels are measured, his levels will be lower than mine because I am not able to process as much alcohol,” Molina says. “For women, the negative health consequences—for example fatty liver disease—occur at much lower levels of alcohol consumption.”

On the other hand, women metabolize nicotine faster than men. Men seem to be more sensitive to the effects of nicotine that make it addictive. Women struggle more to quit smoking, and nicotine patches and gum do not work as well in women, perhaps in part because of these physiological differences. 

In many substance use disorders, women progress to addiction or negative health consequences (for example, liver disease) faster than men do. This “telescoping effect” holds true even in non-substance-based addictions such as gambling, says Wendy Lynch, PhD, a professor of psychiatry and neurobehavioral sciences at the University of Virginia. 

Hormones

In addition to these basic physiological factors, hormonal differences play a role in how women react to substance use and experience cravings. Estradiol—the primary type of estrogen during the reproductive years—and progesterone both affect addiction. 

Estradiol is a huge driver of sex differences around addiction, Lynch says. In rats, estradiol increases vulnerability to addiction and adverse health effects. When researchers block or remove estradiol in rats, they are less likely to become addicted to substances, including fentanyl. When they replace estradiol in these rats, they replace the vulnerability to addiction, Lynch says.

Estradiol seems to act similarly in humans to increase motivation for drug use. In the human menstrual cycle, estradiol is highest during the follicular phase (between the first day of menses and ovulation), while progesterone is highest during the luteal phase (between ovulation and the next menses). Women report liking drugs such as amphetamines more during the phase of their menstrual cycle when estradiol is high, says Jill Becker, PhD, a professor of psychology at the University of Michigan and the Michigan Neuroscience Institute. Women who use cocaine have reported that they felt more “high” during the phase when estradiol is high than during the phase when progesterone is high. 

In both animals and humans, progesterone decreases risk of addiction. “If you give a person—male or female—progesterone, you can reduce positive reinforcing effects and craving,” Lynch says. Pregnancy is also a period of especially high progesterone, and lab animals show reduced cravings for drugs during pregnancy or pseudopregnancy. 

Rats don’t have a menstrual cycle similar to humans, but rhesus monkeys do, and their menstrual cycle influences their consumption of alcohol. Kathleen Grant, PhD, chief and professor of neuroscience at the Oregon National Primate Research Center at Oregon Health & Science University, has worked for decades with rhesus monkeys using an alcohol self-administration protocol. The monkeys in these experiments can self-administer alcohol or water several times throughout the day and night by interacting with a panel. This allows Grant’s team to study monkeys that choose to drink heavily, moderately or hardly at all, to glean what factors predict who is at risk for heavy drinking.

Female rhesus monkeys chose to drink more during the luteal phase and the most in the late luteal phase, when progesterone declines rapidly. Progesterone derivatives called neurosteroids are active at GABA receptors, which are an inhibitory force in the brain. During the luteal phase, progesterone rises gradually over seven to 10 days, and neurons probably adapt to this increasing inhibition, Grant says, similar to the way your eyes adjust when the lights gradually dim.

When progesterone plummets just before menses, the neurons may become over-reactive, the way that your eyes would be hyper-reactive if you were in a dim room and someone suddenly turned on the lights fully. One theory is that this shock could nudge people—and monkeys—toward drugs to cope. 

Some populations of women take supplemental estradiol, which would seem to offer valuable natural experiments that could further elucidate the role of estradiol in addiction. But published data on these populations are either nonexistent or in early days. For example, Lynch’s team is beginning a study of women who have had their ovaries surgically removed, which is a component of some hysterectomies and can also be done independently. After the estradiol-producing ovaries have been removed, some women choose to receive estradiol treatment and others do not. Lynch plans to compare these two groups.

Some transgender women also take estradiol as hormone replacement therapy, as do some perimenopausal and menopausal women. Lynch has not been able to get proposals funded to study menopausal women, she says, though this population is becoming more important to study.

“Usually drug use is much more prevalent in adolescent and young adult populations, but that’s not what we’re seeing now. There’s a lot of drug use going on in baby boomers,” Lynch says. “It’s definitely something that we need to look at.”

Brain Function

Sex-based differences in brain function also affect addiction. Researchers have observed subtle differences in how women’s and men’s brains—and the brains of female and male lab animals, including rats and rhesus monkeys—react to addictive substances such as alcohol, tobacco, cocaine, opioids and methamphetamine.

“If we want to come up with treatments for addiction,” Becker says, “the neural circuitry is the key to develop the next generation of drugs.” She believes that understanding sex differences will allow more effective and precise treatments. “What we currently have are sledgehammers.”

Different substances of abuse each act on a different part of the brain initially, says Scott Edwards, PhD, an associate professor of physiology and neuroscience at Louisiana State University Health Sciences Center. They bind to different receptors and have different targets. “But there’s this common ability to increase dopamine neurotransmission,” he says. “Because the brain is connected, they do have this final common result.” 

In both rats and rhesus monkeys, females and males have differences in the bed nucleus of the stria terminalis (BNST), a part of the amygdala involved in behavioral control. In rhesus monkeys, Grant’s team found that females’ BNST neurons are more excitable at baseline—without alcohol—than those of males. In addition, alcohol increased excitation in both sexes—but, in males only, alcohol also had a counterbalancing inhibitory effect. Females did not experience this inhibition, only the excitation, which might make them more vulnerable to alcohol-related brain changes.

Becker and others have also observed sex differences in the rat striatum, a part of the basal ganglia that is part of the brain’s reward system. One estradiol receptor in the brain is called GPER1. When Becker activates or blocks this estradiol receptor locally in the dorsal striatum of males, she sees an effect. By contrast, in female rats, activating the GPER1 receptor locally has no effect—it only has an effect if activated in the whole brain.

Becker’s working hypothesis is that estradiol needs to be active at GPER1 in more brain regions in females than in males. In an additional wrinkle, activating the estradiol receptor decreases how much males like cocaine, but it increases motivation for cocaine in females, Becker says. It’s not clear why estradiol has these opposite effects in males and females. 

Perception of pain is another area of sex differences. Female rats addicted to alcohol have a lot more pain when the alcohol is taken away than males do, Edwards says, “and that matches what we see in humans.” 

Becker is hopeful that research in rodents might encourage people to do research in humans. “People say it’s so expensive, but it is expensive to have people who are addicted and out on the street and can’t support themselves. For me, this is a no-lose situation.” 

This article was originally published in the September 2025 issue of The Physiologist Magazine. Copyright © 2025 by the American Physiological Society. Send questions or comments to tphysmag@physiology.org.