The gender gap in Cannabis metabolism

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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. 

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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. 

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 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. 

The Cannabis Industry: how high can it go?

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With the recent legalization of recreational cannabis consumption in Canada, I felt it would be appropriate to bring back the conversation about the perhaps not-so-obvious potential in the cannabis industry.  

Let’s start by introducing the stars of this emerging industry: the plants themselves. There has been a huge debate about the taxonomic organization of the Cannabis genus. You have likely heard about Cannabis sativa and Cannabis indica, the two alleged ‘species’ of the genus, and there is a third variant rarely heard of called Cannabis ruderalis. However, some believe that there is only Cannabis sativa, and that indica and ruderalis are strains as opposed to separate species.  

Taxonomic accuracy aside, one classification has been generally accepted, and that is the distinction between marijuana and hemp. Marijuana is mostly exploited for its richness in cannabinoids, including significant amounts of the psychoactive THC, whereas hemp is popular for the production of CBD and other non-psychoactive cannabinoids, phytochemicals, and a vast diversity of industrial products. Leading to legalization we were exposed to amazing studies implicating the many health benefits the cannabis plants offer. But what else can we do with these plants?  

Here are a few examples of products derived from a cannabis plant that you might not have known of before.   

Foods and cosmetics 

OK, this one might not come as a surprise… most of you might already be familiar with hemp products in the cereals section at the grocery store. Amongst the popular hemp foods we can find are granola products, vegan protein powders, and gluten-free flour.  Hemp seeds are rich in healthy fats (including omega-3 and omega-6 fats), proteins, fibers, vitamin E and iron. And let’s not forget the incredible potential in cannabis essential oils, which can be a great source of powerful phytochemicals such as policosanols and phenolic compounds.   

Similarly, the oils and nutrients in these plants are popular ingredients in cosmetic products. Whether you are looking for a nice lip balm, shampoo or moisturizing cream, the hemp plant has you covered! 

Clothing 

It’s hard to imagine a world where cotton is not the leading crop in the textile industry, but up until the 18th-century flax and hemp where the top players in this industry, and I believe hemp fibers are about to make a strong come-back! 

More and more evidence piles up in support of hemp cultivation as a more sustainable alternative than cotton. From the physiological perspective, the hemp plant has a higher photosynthetic efficiency than the cotton plant, and it requires far less water to grow. Substituting cotton fibers for hemp fibers would not decrease the quality of the final product. A study showed that using hemp fabrics, instead of cotton fabrics or synthetic fibers, for furnishing applications is a viable alternative and I can’t see why this shouldn’t be the case for other textiles. And let’s not forget that our knowledge in plant genomics and biotechnology increases by the day, and it is likely we could improve the quality of these fibers through breeding of new hemp variants.  

Construction 

When I found out that hemp is used in the construction world, I was certainly surprised. It might not be news to some of you, but I got really excited reading about this, and I had to share it here.  

The fibers present in the stalk of the hemp plant can be used for the formation of bio-based composites. In general terms, there are two types of fibers in the stalk: woody fibers are lignified fibers found in the core of the stalk, whereas blast fibers are found in the cortex, which can be peeled off the stalk.  

A popular composite made with woody fibers is the hemp-lime composite, or as the cool kids call it, hempcrete. Hempcrete is usually less dense than cement, making it unable to support the same forces than cement, and it has outstanding thermal properties that make it ideal for insulation, even on external walls. However, high-density hemp-based composites can also resist physical and mechanical stress similar to cement, as demonstrated by researchers from the University of Bologna. 

Hemp blast fibers, however, are usually used as an alternative to glass fibers. Blast fibers can be infused with epoxy resins following standard methods in the composite industry, significantly increasing the strength of the hemp-based composite, and providing a new generation of materials for applications in the construction and automotive industries. These new hemp-based composites are an excellent alternative to petroleum plastics, as they are stronger and lighter than polypropylene, a popular plastic in the automotive industry.  

Bioenergy

Amongst the fibers present in the cannabis plant, you can find cellulose and hemicellulose, polysaccharides present in the cell walls of plants. Through a series of treatments, these polysaccharides can be extracted from the cannabis plant to be broken down to fermentable sugars. The woody core of hemp is composed of ≈ 40% cellulose and ≈ 35% hemicellulose, and the agricultural yield of the plant is between 2 – 18 tons per hectare. This gives a bioethanol yield of more than 80 gal/ton.  

It is also possible to simultaneously obtain several sources of energy from the cannabis plant. A recent study showed that simultaneous production of 50 gal/ton of bioethanol and 115 kg/ton of succinic acid (an important chemical to synthesize polymers and used as a food additive). Similarly, another study demonstrated that co-production of bioethanol and biomethane from the whole hemp plant is feasible, yielding over 40 gal/ton of bioethanol and 175 m3/ton of biomethane (a.k.a. renewable natural gas), generating over 10 GJ of energy per ton of hemp. To put this into perspective, all the natural gas required by an average house in Canada for a year could be produced in a single hectare, while also producing bioethanol and other products from the seeds and flowers.

Insecticides and antimicrobials

Cannabis tissues have been attributed to having antimicrobial properties for some time now. A recent study has concluded that cannabis essential oil may be a good green alternative for botanical pesticides as it proved to be quite toxic to aphids, flies and leafworm larvae, although ladybugs and earthworms proved a bit more resistant. Nonetheless, this opens the possibility of using cannabis essential oils as insecticides in organic agriculture after cannabinoids have been purified.  

Of course, if we are discussing antimicrobials, we have to talk about nanoparticles. Recently, scientists successfully developed silver and gold nanoparticles with antimicrobial properties, inhibiting the growth of bacteria like Pseudomonas aeruginosa and Escherichia coli. These nanoparticles were developed using an aqueous extract from hemp stems and showed excellent physical and chemical stability.  

Adsorbents 

From time to time we hear about toxic spills in natural environments on the news, or we read about heavy metals contaminating our lakes and groundwater. These are important problems we need to tackle, and the cannabis industry may be a great contributor to solve this.  

Several products are already being developed for water remediation. For example, a hemp-based felt with a thickness of 5 mm, and a composition of 75% cellulose, 15% hemicellulose, 3% lignin, and 5% pectins, was able to remove 75-80% of metals from water, including Cd, Cu, Zn, Co, Fe, Ni, Cr, Al, and Mn.  

The capacity of these fibers to adsorb heavy metals from water is very exciting, but I am actually equally as excited about the possibility to desorb metals. It has been shown that zinc ions can be recovered from contaminated sites, by adsorbing the ions onto hemp fibers and then desorbing them for recovery and reutilization. Researchers are investigating the extent to which these fibers can be used, in hopes to establish a guideline to maximize adsorption-desorption cycles.  

To me, this is particularly exciting! It looks like a promising tool to recover metals that play crucial roles in our society, such as phosphorous in agriculture and zinc in batteries and electronics.  

Here you can find an interesting review on hemp-based materials for the adsorption of metals.   

I hope you enjoyed the brief summary of non-cannabinoid products available from the cannabis plant. Now, you might say ‘well all these examples talk about hemp.’ Yes, hemp has been a valued industrial crop for quite a while now, and keep in mind, marijuana plants have been in our industry for a shorter time, so it is possible many of the products we get from hemp could also be produced from marijuana.  

With the increasing demand of cannabinoids in Canada, the cannabis industry needs to increase cultivation capacity… Why not explore all the products we can get from these plants?