Cannaba-what!?: Cannabinoids in their various forms — mainstream and uncommon

If I was to say the word “cannabinoid” to you, where would your mind go? Would you immediately wonder, “What? Is it just a fancy way to say weed?” or would you ask questions like, “As in the molecular components of Cannabis?” or “Are you referring to the specific endogenous cannabinoid ligands in our body?” If your first thoughts align with the latter, prepare for a nice refresher on cannabinoids. If your response was closer to the former, get ready for a crash course in how we characterize cannabinoids and how they can be used to treat various health conditions. 

“Cannabinoid” is a term that pertains to the wide array of molecular compounds that modulate cannabinoid receptors, which are present throughout our bodies’ central and peripheral nervous systems. These receptors are part of a larger system called the endocannabinoid system, which is an integral regulatory system in our body. In addition to cannabinoid receptor types 1 and 2 (CB₁ and CB₂, respectively), the endocannabinoid system is comprised of molecular transporters, endogenous cannabinoids, as well as enzymes that build and break down said cannabinoids. 

Cannabinoids can come from different places and, depending on their origin, are characterized and placed into one of three categories: endogenous cannabinoids, phytocannabinoids, and synthetic cannabinoids. Endogenous cannabinoids represent a class of cannabinoids that originate from the body, so these are compounds that we produce naturally. The term “phytocannabinoid” refers to cannabinoid compounds that are naturally produced by the Cannabis plant. In contrast, the class of synthetic cannabinoids consists of cannabinoid compounds that have been synthesized in a lab setting and, therefore, are not naturally-occurring, like its endogenous and phyto- cousins. 

Another term that one might come across when exploring the world of cannabinoids is “exogenous cannabinoids.” If this is getting too jargony, have no fear! “Exogenous cannabinoids” is simply an umbrella term that represents all cannabinoids not originating from within the body (i.e., phytocannabinoids and synthetic cannabinoids).

Now that you are familiar with the basic characterization of these compounds, let’s dive in and talk about both mainstream and lesser-known phytocannabinoids. The first two compounds we will discuss are delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), as they have become quite popular in the mainstream media over the last few decades. These two compounds are the most abundant phytocannabinoids found in the Cannabis plant, and they each interact with our endocannabinoid system’s CB₁ and CB₂ receptors. THC and CBD’s activity via CB₁ receptors has historically tied them both to the “high”-inducing effects of marijuana. It is important to note, however, that we have since learned that THC is a euphoria-inducing compound, whereas CBD is not.

THC’s euphoria-inducing effects are primarily due to its ability to bind and subsequently activate CB₁ receptors at their orthosteric binding site. Many cellular receptors possess two classes of ligand binding sites: an orthosteric site and an allosteric site. The former is the primary site in which most ligands bind, and the latter is a separate secondary site in which non-orthosteric ligands can bind to alter the biological properties of an orthosteric ligand. In addition to causing a “high,” THC binding at the orthosteric site of CB₁ receptors has also been heavily implicated in the psychiatric and addictive effects of marijuana. 

CBD also interacts with the CB₁ receptor; however, it has recently been reported to inhibit CB₁ activity via the receptor’s secondary allosteric site. Thus, CBD can attenuate CB₁ activity by reducing the effect of a ligand that binds to the orthosteric site of CB₁. In addition to the cannabinoid receptors, studies have reported that CBD has additional molecular targets, such as opioid receptors and different enzymes involved in the cytochrome P450 pathway and anandamide (AEA) metabolism (to name a select few). These modulatory characteristics of CBD have made it a highly compelling molecule, and its inhibitory signaling properties (i.e., within the cytochrome P450 pathway) have led to its approval by the FDA for therapeutic use in cases of childhood epilepsy. Although CBD has exciting implications and many claim that it is a cure-all medicinal, our understanding of CBD’s full signaling capacity is still very much in its infancy and requires further investigation.

Now that we’ve discussed the two big players in cannabinoid research, it is time to move on to exploring a few lesser-known phytocannabinoids, like cannabigerolic acid (CBGA), cannabigerol (CBG), tetrahydrocannabivarin (THCV), and cannabidiolic acid (CBDA). Starting with CBG, this compound stems from another lesser-studied cannabinoid called CBGA. As a Cannabis plant ages, CBGA is converted to CBG, CBD, and even THC, which has led to CBGA being referred to as the “mother cannabinoid.” CBGA conversions predominantly occur in favor of CBD and THC, which explains why CBG is of limited abundance in mature Cannabis plants. Similar to CBD, CBG does not have euphoria-inducing qualities, but has been shown to possess a handful of therapeutic benefits that could be useful for treating conditions such as pain, glaucoma, and even cancer. 

Another lesser-known cannabinoid is THCV. Although it bears a similar name to THC, THCV has its own distinct characteristics. Compared to THC, this compound is found at significantly lesser quantities within the Cannabis plant. THCV modulates CB₁ and CB₂ receptors, but it does so at a high potency (much higher than THC). It should also be mentioned that THCV inhibits CB₁ signaling, which means it could play a role in mitigating the negative side effects of THC; however, further research on the specific role of the compound is needed to confirm this. 

Moving on to the final stop on this cannabinoid joy-ride, we will talk about CBDA. This acidic version of CBD is readily converted to CBD when exposed to low levels of heat. This instability has made early scientific exploration of CBDA quite difficult; yet, because of the work of very motivated scientists, a technique has recently been developed to stabilize the compound so that it can be studied. Recent work suggests that CBDA attenuates nausea and anxiety via serotonin receptors. It may also be an effective antidote for relieving pain (check out the ScIU post about CBDA and pain entitled, “A better, stronger cannabinoid for pain relief?” to learn more!).

The therapeutic promise of these lesser-known phytocannabinoids is incredibly exciting; however, it should go without saying that, like all potential therapeutics, these compounds require more research to ensure they can be used safely and effectively. Because these minor phytocannabinoids are just starting to be studied, we do not have extensive knowledge of whether they could have a negative impact on one’s health in the long run. When drugs are developed to be used as potential therapeutics, it is important that we understand both the short- and long-term implications of the drug before it can be accepted as a form of treatment. The importance of being aware of the long-term effects of a drug was particularly evident in the early 2000’s, when an anti-obesity drug was removed from the European market. Rimonabant (or Acomplia, as it was commercially known) had shown great promise in both pre-clinical and clinical trials in reducing weight, preventing weight gain, and improving both the lipidomic and glycaemic profiles of participants. It was not until the CB₁ antagonist (inhibitor) was approved and had been on the European market for ~2 years, however, that people began to notice the drug’s severe side effects. One of its most concerning side effects was an increased risk for adverse psychiatric events, like suicidal ideation. This led to Rimonabant’s subsequent suspension from the European market and contributed to its failure in gaining FDA approval in the United States. So, while the lesser-known phytocannabinoids like CBGA, CBG, THCV, and CBDA all hold exciting therapeutic promise, it is important that we continue to investigate their capabilities. 

As you can see, cannabinoids are a diverse set of compounds with an array of origins, names, and functions! I hope this information has left your brain buzzing to find out more about these fascinating molecules and that you can provide your neighbor with fun nuggets of knowledge the next time someone asks what cannabinoids are!

 

Edited by JiHae Koo and Ben Greulich