The gender gap in Cannabis metabolism
Photo by Tim Mossholder on Unsplash
Early in April, I attended the Cannabis Innovation Summit organized by the Toronto Cannabis and Cannabinoid Research Consortium (TC3), where researchers from universities, hospitals, government and industry shared their findings and expressed the importance of strengthening research focused in cannabis products and the endocannabinoid system.
Many interesting topics were discussed, such as the effect of endocannabinoids in the motor ganglia of patients with Parkinson’s disease, and an intriguing discussion regarding the impact of cannabis use in brain development. Did you know that there is not enough evidence to determine that cannabis consumption will not have an impact in brain development in young adults under 29 years old? There is still too much to learn!
One of the arguments repeated by several scientists was that there is not enough high-quality scientific literature to support analytical methodologies, including cannabinoid extraction techniques, purification and analysis. In fact, some of the panelists shared stories where products labeled as CBD oil where in fact close to 100% THC.
Another concern shared by several panelists is how little we know about the effect of each of the components in the cannabis plant, reminding us that each substance, be it a cannabinoid or terpene, may act as an active pharmaceutical ingredient. When we think about it that way, consuming oils with several terpenes and cannabinoids is somewhat like taking several pills without fully knowing what they do.
These basic issues in quality control could pose a huge impediment in the development of the cannabis industry in Canada, and the lack of scientific evidence around the molecular mechanisms in which cannabinoids interact with the endocannabinoid system (and perhaps other receptors and pathways) is a big challenge to responsibly consume cannabis products.
It is not my intention to be alarming or sound fatalist here; it is a matter of making educated decisions to make the most of these compounds. This brings me to an interesting fact I learned in this summit: the molecular mechanisms of the endocannabinoid system are not the same between females and males. Even though behavioral responses in adults that consume cannabis are similar, the mechanisms that take place at a molecular level are not the same amongst female and male consumers. I find this fascinating and so I decided to dig deeper to get a better idea on what the literature says about the differences in mechanistic effects of cannabinoids amongst females and males.
If you are not familiar with the endocannabinoid system, I suggest you read this first.
Photo by holdentrils on Pixabay
The following program contains material that might be too nerdy. Reader discretion is advised.
Endocanbinoid receptors and reproduction
When I think about biochemical differences between females and males I immediately think of the reproductive system. The balance of sex hormones, such as testosterone, estrogen and progesterone, is quite different between both sexes, and obviously there is a huge difference between sperms and eggs. That is why I was so interested to learn about the effect the endocannabinoid system has in reproduction.
A mini-review authored by Italian researchers highlights the important role of the endocannabinoid system in reproduction, particularly related to sperm production and functions, providing examples of studies in both humans and other animals. For example, studies show that THC and the endocannabinoid AEA (anandamide) inhibit acrosome reaction (necessary to fertilize the egg) on sea urchin sperm, which was also observed on boar using the AEA analog methanandamide. Similarly, AEA inhibits sperm motility in humans and frogs (maybe there is a connection between princes and frogs after all…)
These effects result from the binding of the mentioned molecules to the CB1 receptor. For a moment I thought that activation of this receptor has a negative effect on sperm, but studies working with mutant mice lacking the CB1 receptor (Cnr1 null mutant) show that in the absence of this receptor these rodents have poor chromatin quality; in other words, the DNA in their sperm is not packed properly. So it is likely that CB1 plays an important role in formation of sperms, and there seems to be a delicate balance between the time of activation by the endocannabinoid AEA and the positive or negative effects in sperm production and function.
There is also evidence showing that the endocannabinoid system and sex hormones like testosterone, estrogen and progesterone, regulate each other. The mini-review mentions a couple of studies that demonstrate a correlation between cannabis consumption and a decrease in testosterone levels in the plasma of men, which also correlates to an inhibitory effect on sexual behavior. Similarly, a study in mice showed that production of the enzyme that degrades AEA (FAAH; fatty acid amide hydrolase), is controlled by the sex hormones estrogen and progesterone during pregnancy, suggesting that high amounts of AEA are required to modify the endometrium during pregnancy.
However, a study looking at AEA levels of pregnant women explores this topic further. Levels of AEA in the bloodstream of pregnant women decreased 50% from the first to the second trimester, and remained unchanged from the second to the third trimester. Interestingly, levels of AEA increased 370% during labor (compared to the third trimester levels), and there was a direct relationship between AEA levels and the duration of contractions, suggesting that this endocannabinoid plays a role in preparing the body for birth. The authors recommend that “…the current exploration of the use of exocannabinoids for pain relief in labor be delayed”, as in vitro stimulation of the CB1 and CB2 receptors resulted in the relaxation of myometrial strips (involved in contractions), and a correlation between high levels of AEA and miscarriages has been reported.
Although the relationship between the endocannabinoid system and reproductive mechanisms is not completely elucidated, these studies suggest an important interaction between the two, highlighting the importance of timing and concentration in which these cannabinoids interact with the endocannabinoid system.
Differences in brain development
One of the topics that I consider fundamental for the responsible consumption of cannabis is the potential effect cannabinoids can have in brain development. However, I never considered that this would be different between young females and males.
A study published in Neuropsychopharmacology looked at the effects of chronic THC consumption in adolescent rats. The authors exposed adolescent rats to THC and observed their behavior in adulthood as well as changes in the development of the cannabinoid receptors. Interestingly, CB1 receptor levels in the brains of adult female rats exposed to THC decreased in the amygdala (a part of the brain responsible for processing emotions), ventral tegmental area, and nucleus accumbens (both involved in reward mechanisms), whereas the decrease in CB1 receptor levels in male rats was observed only in the amygdala and hippocampal formation (part of the brain associated with memory). There were also differences in the behavioral effects, as female rats exhibited alterations in the emotional circuit, leading to depressive behaviours, whereas changes in the behavior of male rats were reflected as an altered sensitivity to rewarding stimuli.
A similar study showed that activation the CB2 receptor plays an important role in cell proliferation of the medial amygdala, which modulates behavioral sex differences at several ages. The authors suggested that activation of the CB2 receptor reduces cell proliferation in the medial amygdala; in other words, when the endocannabinoid 2-AG binds to the CB2 receptor, CB2 is activated and stops cell proliferation in the medial amygdala of neonatal female rats. The endocannabinoid 2-AG is found in about 40% higher amounts in neonatal male rats, and the enzyme responsible for the degradation of the endocannabinoid 2-AG (MAGL; monoacylglycerol lipase), is found in about 50% higher amounts in female young rats than male. To put it simply, male rats have much higher amounts of 2-AG, while female rats purposefully degrade this endocannabinoid. This increase in 2-AG availability in male rats suggests that “CB2 signaling is maximally activated”, which may explain why young males have lower cell proliferation than females. To further support this theory, newborn female rats were exposed to a cannabinoid receptor agonist that mimics the effects of 2-AG, and the authors observed “masculinization of juvenile behavior”. The effects on brain development after exposing newborn rats to high amounts of THC were so big that it caused very apparent changes in behavior… but only in females.
Based on these studies, stimulating the endocannabinoids system could have different effects in several areas of the brain of females compared to males, and even changes in behavior have been observed. So, when exploring the possibility of using cannabinoids to treat a medical condition, would it be as efficient amongst both sexes? Or rather, would it be safe for both?
Addressing the gender gap in the molecular mechanisms of cannabinoids
Even though the CB1 and CB2 receptors are found through out the brains in both sexes, activation of these receptors by either endo- or exocannabinoids impacts different areas of the brain amongst females and males. The studies discussed in this article are just a few examples of differences in the effects cannabinoids can have on brain development of both sexes, and how different the changes in behavior can be.
The cannabis plant has shown to produce promising active pharmacological ingredients to treat many diseases, which I personally find very encouraging, but evidence like the very few studies mentioned in this article should not be ignored. Gvien that the lack of effects in one sex could be masking the effects on the other sex when analyzing the data, any treatment targeting the endocannabinoid system should be carefully investigated to assess potential differences in responses amongst female and male patients.
Going back to the lack of information on the individual cannabis substances mentioned at the beginning of this article… If we want to fully understand how to make the most of these substances, researchers should consider the sex of their subjects as an important parameter for their observations. As the few studies discussed here suggest: there is no gender equality in the molecular mechanisms involved with cannabinoids.