In the first study to assess sex differences in sensitivities to THC, the key ingredient in cannabis, researchers have found that smoking the concentrated marijuana of today may be riskier for women - thanks to the hormone estrogen.

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The new study, conducted in rats, details how the hormone estrogen makes females more susceptible to effects of THC in marijuana.

The researchers, led by Prof. Rebecca Craft of Washington State University, publish their National Institute on Drug Abuse-funded study in the journal Drug and Alcohol Dependence.

Previous studies have shown that women are more prone to cannabis abuse and dependence than men. In women, cannabis withdrawal symptoms of irritability, sleep disruption and decreased food intake was shown to be more severe, and women also have a higher likelihood of relapsing when quitting the drug.

However, despite these differences in how marijuana affects males and females, most tetrahydrocannabinol (THC) tolerance studies have been conducted on males, due to their more stable hormones.

Prof. Craft says that in 1993, the National Institutes of Health issued a recommendation to include more women in studies - or to give good reasons as to why not to. Still, many scientists have avoided working with the hormone swings that come with the female biology.

But Prof. Craft has been studying drug sensitivities in females for quite some time, and in this latest study conducted in rats, she and her team "routinely manipulate hormones and follow females across their cycles to see if their drug sensitivities change along with their hormones. And they do... very frequently," she says.

Females developed significantly more tolerance to THC

The researchers focused on the pain-relieving effects of THC in both male and female rats and found that, after 10 days of treatment, females showed significantly greater tolerance to THC than the males.

Tolerance occurs when the subject's body gets used to THC so that larger and larger doses are needed to produce the same effects experienced with the first dose.

Because the researchers knew that females were more sensitive to THC, they adjusted their doses so they were 30% lower than those of the males. Still, the females developed more tolerance.

"What we're finding with THC is that you get a very clear spike in drug sensitivity right when the females are ovulating," says Prof. Craft, "right when their estrogen levels have peaked and are coming down." Because the females develop tolerance to THC more quickly, they have increased vulnerability to negative side effects such as anxiety, paranoia and addiction.

She adds that the dose they used "is the lowest dose anyone has ever used to induce tolerance."

Another finding from their study is that a low dose of THC did not disrupt the reproductive cycles of the female rats, which is a subject that has long been under debate and that needs more study.

Males more susceptible to the "munchie effect"

Marijuana contains over 60 compounds called cannabinoids. THC is the psychoactive ingredient that gives users the characteristic high. Cannabidiol and cannabinol occur in smaller concentrations and have medicinal properties.

All three of these compounds are in the most common species of marijuana, but Prof. Craft says selective breeding in modern-day recreational pot has resulted in concentrations of THC that are double or triple those from the 1960s and 1970s.

Prof. Craft further explains:

"Marijuana is very different than it was 40 years ago. It's much higher in THC and lower in cannabidiol, so a little bit goes a very long way.

We're more likely to see negative side effects today like anxiety, confusion, panic attacks, hallucinations or extreme paranoia. And women are at higher risk."

Interestingly, the "munchie effect," whereby marijuana use increases appetite, is the only THC reaction where males exhibit more sensitivity than females, she notes.

Because states like Washington and Colorado have recently legalized recreational marijuana use, the researchers say there is a greater responsibility to understand the differences in cannabis effects on males and females.

Prof. Craft and her team are now studying how the effects of cannabidiol can counter some of THC's negative side effects, so that they can understand how medical marijuana can help those with back or joint pain, cancer, Crohn's disease and other conditions.

"These people have pain that lasts for months or years," Prof. Craft says. "Tolerance develops differently and sometimes you get a lot less tolerance to a drug when people are in chronic pain."

Medical News Today recently reported on a study published in JAMA Internal Medicine that suggested states that legalize medical marijuana have fewer deaths from opioid painkillers.