Gender hormone differences affect marijuana use

Men and women tend to use cannabis differently, according to a recent review article published in Frontiers in Behavioral Neuroscience, which explains that men have been found to use larger amounts of cannabis more frequently than women. Female users, however, are more likely to form unhealthy habits; studies found that women progress faster to problematic cannabis use, show more severe withdrawal symptoms, and are more likely to relapse. Researchers are still unsure about the relative contribution of biological (sex) and socio-cultural (gender) factors on these differences, but emerging evidence from animal studies suggests that hormones play an important role in cannabinoid sensitivity.

As more and more countries and U.S. states legalize medical and recreational marijuana, the drug's use is increasing. While many see weed as completely benign, scientists believe that about 10 percent of cannabis users will develop an addiction, called cannabis use disorder (CUD). CUD is characterized by high consumption levels and continued use, problems controlling use, cravings, withdrawal, and negative effects on personal, social, and work-related life.

What are cannabinoids?
The term cannabinoid describes a class of molecules that are found in cannabis, including the one non-biologists might be quite familiar with: tetrahydrocannabinol (THC). A group of similar molecules responsible for intercellular signaling in our bodies, as well as their receptors and several enzymes involved in their synthesis and degradation, are named after the plant in which the class was originally identified; they are collectively known as the endogenous (something that originates from within an organism), cannabinoid system or just the endocannabinoid system. The exogenous (from outside an organism) cannabinoids found in marijuana interact with our bodies’ naturally occurring signals by mimicking our endogenous ones.

Biological sex differences
Studies suggest that there is a high genetic contribution to cannabis use and addiction. Variation in certain genes which tell our bodies how to make the cannabinoid receptors affect how sensitive we are to the drug’s effects. However, scientists have not yet found the genetic variants that are most highly associated with cannabis use. Brain imaging studies have shown that the endocannabinoid system is sexually dimorphic: its makeup depends on biological sex, particularly sex hormones. This difference in cannabinoid sensitivity between men and women provides a biological basis for the differences in cannabis use and addiction between males and females.

Animal studies
As it turns out, rats are not particularly likely to light a joint or hit a bong without human intervention. Researchers have only recently been able to perform animal studies on the effects of sex hormones on cannabinoid self-administration. This research was limited, as the paper’s authors point out, by the challenges of modeling human cannabis use on lab animals. Reliable protocols of animal cannabinoid self-administration were only development in the late 90’s and early 2000’s.

Animal studies have since helped to support the theory of hormonal influence. In one study on self-administration of cannabinoids in rats, scientists removed some females’ ovaries. They found that the female rats whose ovaries had been removed were significantly less likely to seek out cannabinoids, indicating that ovarian hormones are important factors in cannabinoid self-administration. One issue with this kind of study is that researchers cannot identify which specific sex hormone is most important in modulating cannabinoid intake, highlighting the need for studies that combine the removal of hormone-producing gonads with specific hormone replacement.

While some of the differences between the endocannabinoid system in men and women’s brains’ might be permanent, cannabinoid sensitivity overall is not fixed. The density of a certain type of cannabinoid receptor in the brain (CB1R) is dependent on hormonal fluctuations. Levels of sex hormones such as estradiol will change throughout the menstrual cycle and are age-dependent. The level of enzymes which break down cannabinoids fluctuate throughout the cycle, and brain levels of cannabinoid receptors increase with aging in females.

While scientists are increasingly studying the differences in cannabinoid action between the sexes in animals, the authors note that controlled human studies are still limited.