After decades of researching gender differences in the effects of drugs, Rebecca Craft has found that females using marijuana are likelier than men to become dependent on the drug and suffer more severe withdrawals.

At the same time, females seem to be more sensitive to the drug’s pain-relieving qualities.

Craft, a Washington State University psychology professor who studies the effects of psychoactive drugs on rats, has reported these findings most recently in journals such as Life Sciences and Drug and Alcohol Dependence. Her work, funded in part by the National Institute on Drug Abuse, focuses on the medical side of cannabinoids, the class of drugs found in marijuana.

“We shifted to cannabinoids just in the last few years, in part because of the expanding medical use of marijuana in this country, and really in many places in the world,” Craft says in her Johnson Tower office. “There’s been a big shift in the last 20 years in people’s interest in it. And of course being in one of the two states where voters recommended legal recreational use of marijuana, there’s even more onus on researchers in Washington state to try to discover more about the effects of marijuana, and if there are any differences in effect between males and females.”

Medical cannabis has been legal within the United States since 1996, when California voters approved its use. Since then, 19 other states and Washington, D.C. have joined the ranks, and 13 more have pending legislation to legalize its use. As Craft points out, a major shift in how medical researchers viewed marijuana came in 1988 when an “endogenous” cannabinoid system was discovered in the human nervous system. This means there are specific docking sites, or receptors, that bind THC, the primary psychoactive chemical in cannabis, within all of us, and that our bodies already create chemicals very similar to those found in marijuana.

The medical use of cannabis goes back centuries, and was first recorded as therapeutic 2,000 years ago in the Chinese pharmacopoeia commonly called Treatise on Medicine, which also described ephedrine.

“But about a hundred years ago in this country, we went through this purge and it became evil weed,” says Craft. “And we’ve been gradually tiptoeing our way back to, ‘OK, maybe there are some medical uses here.’”

Among other things, cannabinoids have an ability to affect our perception of pain. This is of particular note since research has shown that women suffer a lot more pain throughout their lives than men, both in frequency and intensity—even if we disregard the experience of childbirth. Craft hopes to find another way to alleviate chronic pain using cannabiniods, which have potentially fewer side effects than drugs already approved by the federal government, such as opium derivatives like oxycodone and morphine.

The difference between male and female response to cannabinoids may not be as shocking as it seems. In fact, we just don’t know the sexual differences in drug responses because most biomedical research is done on men. A 2006 study in the Journal of Women’s Health showed that women made up fewer than a quarter of patients enrolled in 46 examined trials that took place two years earlier. A 2008 study published in the Journal of the American College of Cardiology found that women comprised between 10 percent and 47 percent of the subject pools in 19 separate heart related trials, even though more women than men die from heart disease every year.

This paucity of women subjects in drug trials comes well after the National Institutes of Health suggested in 1993 that clinical trials start to include women, or give a good reason not to. There’s still no federal, state, or local mandate requiring even animal research to include female subjects. Craft, for one, thinks this is bad science.

While it’s true that we’re all human and the potency of a drug varies from person to person, it’s a desire for simplicity that prevents clinical trials from including women. The reason? Men don’t have a menstrual cycle and its concurrent swings in hormonal levels. In this way, men are a stable bunch of guinea pigs. Women, on the other hand, harbor complexity.

“But we need to understand that complexity,” says Craft, pointing out that we know very little about the interactions between drugs and hormones. She’s trying to remedy that with her work.

“One thing we do routinely is manipulate hormones and follow females across their cycle and see if their drug sensitivities change,” she says. “And they do. Very frequently. What we’re finding with THC is you get a very clear spike in drug sensitivity right when the females are ovulating. Right when their hormones have peaked and are coming down.”

Regardless, the simple truth in cannabinoid research is there’s just not enough of it. Years of political warfare over the drug, and its relative benignity compared to harder drugs such as opioids, methamphetamine, and alcohol, have left a lack of studies from which to draw results. Craft says there have been “maybe a dozen clinical trials for marijuana and synthetics for serious clinical pain.” There’s only been one study looking into the difference between men and women in cannabinoid pain relief, and it wasn’t a full-fledged clinical trial.

All of this is to say that Craft has faced challenges furthering her research. “Maybe if we continue to show that female rats are more sensitive than males to a range of these cannabinoid drugs on a range of measures, like pain and other things, then folks who conduct clinical trials in people will pay attention to gender as an important variable,” she says. “But it hasn’t happened yet.”