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Sex, drugs and estradiol: Why cannabis affects women differently

Cannabis use is riding high on a decade-long wave of decriminalization, legalization and unregulated synthetic substitutes. As society examines the impact, an interesting disparity has become apparent: the risks are different in females than in males.

A new review of animal studies says that sex differences in response to cannabis are not just socio-cultural, but biological too. Published in Frontiers in Behavioral Neuroscience, it examines the influence of sex hormones like testosterone, estradiol (estrogen) and progesterone on the endocannabinoid system: networks of brain cells which communicate using the same family of chemicals found in cannabis, called ‘cannabinoids’.

Animal studies

“It has been pretty hard to get laboratory animals to self-administer cannabinoids like human cannabis users,” says study co-author Dr Liana Fattore, Senior Researcher at the National Research Council of Italy and President of the Mediterranean Society of Neuroscience. “However, animal studies on the effects of sex hormones and anabolic steroids on cannabinoid self-administration behavior have contributed a lot to our current understanding of sex differences in response to cannabis.”

So how does cannabis affect men and women differently? Besides genetic background and hormonal fluctuations, the paper highlights a number of important sex differences.

Men are up to four times more likely to try cannabis — and use higher doses, more frequently.

“Male sex steroids increase risk-taking behavior and suppress the brain’s reward system, which could explain why males are more likely to try drugs, including cannabis” explains Fattore. “This is true for both natural male sex steroids like testosterone and synthetic steroids like nandrolone.”

But despite lower average cannabis use, women go from first hit to habit faster than men. In fact, men and women differ not only in the prevalence and frequency of cannabis use, pattern and reasons of use, but also in the vulnerability to develop cannabis use disorder.

“Females seem to be more vulnerable, at a neurochemical level, in developing addiction to cannabis,” explains Fattore.

“Studies in rats show that the female hormone estradiol affects control of movement, social behavior and filtering of sensory input to the brain — all targets of drug taking — via modulation of the endocannabinoid system, whose feedback in turn influences estradiol production.

“Specifically, female rats have different levels of endocannabinoids and more sensitive receptors than males in key brain areas related to these functions, with significant changes along the menstrual cycle.

“As a result, the interactions between the endocannabinoid system and the brain level of dopamine — the neurotransmitter of “pleasure” and “reward” — are sex-dependent.”

Human impact

The inconsistency of conditions in these studies greatly complicates interpretation of an already complex role of sex hormones in the endocannabinoid system and cannabinoid sensitivity.

“The effects varied according the specific cannabinoid studied, as well as the strain of animals tested and duration of hormone exposure,” admits Fattore. However, the human data so far are consistent with the idea that estradiol regulates the female response to cannabinoids. As in animals, human males and females are diverse in their genetic and hormonally driven behaviour and they process information differently, perceive emotions in different ways and are differently vulnerable to develop drug addiction.

“Blood levels of enzymes which break down cannabinoids fluctuate across the human menstrual cycle, and imaging studies show that brain levels of cannabinoid receptors increase with aging in females — mirroring in each case changes in estradiol levels.”

Fattore believes that deepening our understanding of the interactions between cannabinoids and sex steroids is crucial in assessing the impact of increasing cannabis use, and tackling the fallout.

“Gender-tailored detoxification treatments and relapse prevention strategies for patients with cannabis addiction are increasingly requested. Optimizing personalized evidence-based prevention and treatment protocols demands further research on the source of sex disparities in cannabis response.”

Sex differences in cannabis use are beginning to be explained with the aid of brain studies in animals and humans.

Female Forward: Periods, Hormones and THC

Hormones are powerful chemicals that are constantly fluctuating and influencing the ways in which our bodies respond to our environments. Sex hormones, and in particular those produced in the ovaries, have been shown to play prominent roles in regulating cognitive and behavioural functioning of cisgender women.*

There are two studies that examine the relationship between cannabis and the menstrual cycle, both of which were done in the 1980s. Neither study satisfies the ‘gold standard’ of scientific inquiry: a randomized double-blind placebo study, large sample groups and few limiting and/or confounding factors.

The first study was on self-reported cannabis use during the menstrual cycle. The sample size was small with only 28 women included. Further, the nature of the study design did not account for the different ways in which women consume cannabis.

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The study found that there were no significant relationships between THC and sex hormones in women. However, based on the potency of THC used, take these results with a grain of salt.

Instead, let’s examine the specific effects THC has shown to have on ovarian hormones and vice versa.

Like Hormones, Tolerance Can Fluctuate

Women generally have higher tolerances for THC compared to men, for a few reasons.

Consider the chemical properties of THC. It is lipophilic, meaning that when it crosses paths with fat cells, it will attach itself to them. You may have heard that THC can stay in your system for weeks to months beyond abstinence—this is why.

For evolutionary purposes, women have higher fat percentages than men, resulting in higher amounts of THC going to fat cells rather than the bloodstream when ingested by women versus men. The result? Not as much THC circulates to get to your brain for that ‘high’ effect to take hold.

Another reason women have a higher tolerance to THC is ovarian hormones. However, which ovarian hormone we are talking about matters. The amount of tolerance you experience depends on which phase of your menstrual cycle you’re in.

The Estrogen (Estrus) Phase

A menstrual cycle is typically 28 days long. The two weeks is called the estrus phase, or how I like to call it, the ‘sexy’ phase: it builds up until you release your egg and ovulate. Those two blissful weeks where acne and pimples lay to rest and B.O. remains a non-issue is evolutionarily, on purpose.

During this phase your ovaries are producing estrogen, the ‘come hither’ hormone— it’s meant to find you a mate, among other things. It heightens your sexual prowess, which includes your sensitivity. Greater awareness generally indicates an animal-like ‘on the hunt’ state.

Studies using rat models have shown that during the estrus phase, females were more sensitive to THC compared to the diestrus phase, the last two weeks of your cycle. Studies conducted on humans examining the effects of caffeine, alcohol, and stimulants found similar results: during the estrus phase, women felt they were more sensitive to the effects of these substances.

During the diestrus phase (ie. after ovulation), sensitivity to cannabis decreases, along with everything else. Progesterone becomes your ovaries’ best friend and you are left feeling cranky, tired, and agitated when these levels are high.

The Progesterone (Diestrus) Phase

The dynamics between THC and female sex hormones can vary. So far, estrogen and THC seem to have a cordial relationship where they build each other up—but what about progesterone?

Poor progesterone, nobody likes them. No surprise there: it’s developed a bad reputation for the culprit of PMS. In fact, mood swings, tender/sore breasts, fatigue and acne are due to declining levels of Progesterone. Progesterone in high levels actually keeps the female body stable.

Luckily, studies conducted on rhesus monkeys (at least we’re in the primate category!) show that THC reduced the amount of progesterone produced in the diestrus phase. This was not a direct inhibition, which means it ‘modulated’ the production of progesterone—a safer version than simply arresting its production directly.

It’s no wonder that many women are turning to cannabis products during PMS and menses: it helps to level out the effects of progesterone and satisfy a physiological need for cannabinoids.

What I mean by ‘physiological need’ is that studies have shown that CB1 receptor increases in the hypothalamus during the diestrus phase. This means that your body is in demand for cannabinoids—whether you are producing them yourself or ingesting them through cannabis.

Additional studies are needed on the subject of female sex hormones and cannabis. Hormones are highly complex: there are layers to which they affect cognitive functioning (short-term and long-term), physiological changes (CB-1 receptor fluctuation), and their role in the female reproductive system.

However, some things are beginning to be clear. The estrus phase can cause a heightened state of awareness, which tends towards greater sensitivity towards mind-altering substances. The diestrus phase produces progesterone and increases CB1 receptors in the hypothalamus—both of these changes can be helped by a spoonful of THC in the diet.

That being said, consume in moderation and consult your physician if you experience severe symptoms associated with PMS.

*This article uses the terms women, females, men, and males in reference to biological sex.

How does THC influence female biology? We examined hormonal fluctuations and their reactions to cannabinoids in the body. ]]>