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For thousands of years, humans have used cannabis for religious and medicinal purposes around the globe. Scientists debate on its specific ancient origins, but modern technology is beginning to unravel the mystery behind humanity’s close relationship with this special herb. To better understand these finding, let us first begin with the plant itself.

What’s In Cannabis?

Cannabis is a flowering herbal plant that possess over 400 compounds including cannabinoids, terpenes, and flavonoids. Cannabinoids are the molecular compounds found within cannabis, with the two primaries being tetrahydrocannabinol (“THC”) and cannabidiol (“CBD”). There are at least 120 cannabinoids, but we have only identified a handful of these unique compounds and know even less about their individual and synergistic therapeutic capabilities. It is worth noting that while the industry uses the term “strains” to differentiate between plants, this is a misnomer as botanicals do not have “strains”— only viruses and bacteria do. Plants have chemovars, or chemical varieties. These chemovars are what account for the difference in effect.

The major cannabinoids, THC and CBD, were first discovered in the 1940s by American chemist, Roger Adams. Later in the 1960s, Dr. Raphael Mechoulam and his team were the first to isolate and synthesizes these compounds in the lab (prior to the launch of Nixon’s War on Drugs). While research is still nascent because of these policies, we have observed that these two compounds appear to have a modulating relationship (Chung H, 2019) (Russo & Geoffrey, A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol, 2006). In other words, one balances out the other. However, commercial demand for THC or CBD only has led to a selective breeding which minimizes the quantity of these two cannabinoids in any given plant. There are other notable benefits of these compounds in isolation, but they also appear to be vital in the modulation of other therapeutic constituents, such as terpenes (Russo E. , 2011). 

As mentioned, there are only a handful of minor cannabinoids that have been identified. They are referred to as the “minors” because they lack prevalence in the plant. Today, the market has mostly demanded high THC or CBD varieties, which has led to a lack in diversity between cannabinoids for commercial products. It does not mean that their therapeutic potential is any less than the majors. We simply have not had enough time (or legality) to research and evaluate the multitude of potential effects. Furthermore, we believe the minors will play a greater role in the years to come. Until that time, the major cannabinoids will be the primary focus in the determination of therapeutic potential.

The demand for high THC or CBD narrows the cannabinoid assortment found in today’s commercial markets. The chemical variety amongst cannabis products is largely due to their terpene profiles (Casano, 2011). The indica/sativa/hybrid “effects” classification model is not based on these profiles and are largely inaccurate and unreliable. Since the cannabinoid diversity is limited to primarily THC and CBD, we can focus on the terpene profiles to deduce the expected effect (LaVigne, Hecksel, Keresztes, & Streicher, 2020).

Terpenes are the drivers behind the smell and help modulate effect. For example, when your nose detects that zesty tang of a lemon or orange, that is the terpene limonene. Because terpenes are so abundant in plants, they have been studied for decades for different use cases from essential oils to homeopathy herbal blends. Like cannabinoids, they possess their own therapeutic properties (Lewis, Russo, & Smith, 2018). Cannabis is also one of the richest natural sources of terpenes allowing us to dive deeper into their use cases.

Flavonoids are responsible for the taste of the flower. These compounds may also hold unique therapeutic properties, but more research is needed before determining their effects. For the purposes of our discussion, we will only evaluate the relationship between terpenes and cannabinoids but do not rule out their potential.

The Endocannabinoid System (“ECS”)

In 1992, Dr. Mechoulam led a team of researchers who discovered the first endocannabinoid (from Greek “endo” meaning “from within”), cannabinoids naturally produced in the body (Mechoulam, et al., 1992). The team aptly named the molecule anandamide after the Sanskrit word meaning “bliss”. Shortly after, a second endocannabinoid, 2-AG, was also discovered. The detection and synthesis of these compounds proved cannabinoids were naturally produced by the body. Later investigations would reveal an entire cell-signaling system previously unknown to humanity, the endocannabinoid system (or ECS). Incredibly, we have now come to realize that all vertebrates have an ECS. This fact means that the ECS is older than homo sapiens.

The ECS is best described as an internal homeostatic regulatory system comprised of three elements:

(1) Receptor sites with psychoactive CB1 (nervous system), non-psychoactive CB2 (immune system), and sensory receptor TRPV1, as well as subtype serotonin 1A and 2A receptors (Marco EM, 2004)

(2) Enzymes which break down cannabinoids

(3) Endocannabinoids (anandamide and 2-AG) directly interact with the ECS at the various receptor sites. Endocannabinoids are produced by the body for a variety of functions, including important metabolic processes to stress reduction. The fatty acid amide hydrolase, or FAAH enzyme, breaks down the endocannabinoid after the agent has reacted with the receptor site(Pacher, Bátkai, & Kunos, 2006). This cycle of creation and destruction is what enables the body to maintain homeostasis.

In 2004, the concept of an endocannabinoid deficiency was proposed, but currently lacks clinical criteria for diagnosis. Dr. Ethan Russo is a board-certified neurologist, psychopharmacology researcher, and author. Russo is one of the world’s leading experts on cannabis pharmacology. He and a growing number of physicians believe many modern illnesses are mischaracterized endocannabinoid deficiencies (Smith SC, 2014) (Russo E. , 2016). However, given the recency of the ECS’s discovery, many researchers and healthcare professionals have been apprehensive to adopt the proposal. Insurance companies are even slower to adapt, currently hindering progress in research and diagnostics.

Thanks to the recent wave of cannabis legalization across the US, there is a revitalized interest in better understanding the ECS and its therapeutic implications. As we better understand the role of the ECS, we can begin to unravel the mystery behind the effects of cannabis. What researchers have discovered is that phytocannabinoids (from Greek “phyto” meaning “of a plant”) bind with our ECS in the similar way that endocannabinoids do, although there are some differences (Di Marzo, 2016).  As a simplification, this interaction can be described as a “lock and key” mechanism — with the receptor being the “lock” and the cannabinoid acting as the “key”. Different phytocannabinoids perform a variety of functions and act upon a myriad of receptor sites. Essentially, these phytocannabinoids act as chemical messengers throughout our bodies as they bind and communicate via different receptors distributed throughout our entire body and nervous system.

The ECS is still heavily under-researched considering its purported all-encompassing function in the body. While few have studied this system in depth, their findings demonstrate just how important it is. As part of cell-signaling, the ECS is said to play a vital role in the regulation of mood, appetite, memory, reproduction, and fertility. The ECS’s essential function is to keep the mind and the body in a state of homeostasis, or balance.

How Does Cannabis Interact with the ECS?

Since Dr. Mechoulam’s discovery of anandamide in the 1990s, extensive research (within the capabilities of a prohibition environment) has been launched to better understand the pharmacological interactions between cannabis and the ECS. While the pharmacology of CBD is less understood, researchers have been able to “relatively establish” the pharmacology of its well-known counterpart, THC (Zagzoog, 2020). THC is believed to be a partial agonist on the CB1 and CB2 receptors. To be a “partial agonist” means to partly activate a receptor. When a receptor is activated, the cannabinoids can deliver their therapeutic effects.

Contrary to popular understanding, CBD does not appear to bind with neither CB2 nor CB1 receptor sites directly. Instead, new research suggests that CBD acts as what is referred to as an allosteric modulator (Chung H, 2019). An allosteric modulator indirectly regulates a receptor’s activity and the way it reacts to stimulus and other compounds. This research could explain why CBD and THC seem to have a relationship based on balancing each other out. Another way to interpret the data is to say that CBD regulates THC’s function in the body. THC seems to be the child that runs around turning on all the lights, while CBD is the parent that dictates which switches the child has access to. The takeaway is the two demonstrate a clear harmonious relationship which gives credence to the idea that all the compounds in cannabis share a similar relationship.

To quickly recap, an endocannabinoid is naturally occurring in the body while a phytocannabinoids is produced in the cannabis plant. Both terms can be simply referred to as cannabinoids. The ECS directly interacts with major and minor cannabinoids in a variety of ways depending on the presence of other bioactive compounds such as terpenes and flavonoids.

What is the Entourage Effect?

Cannabis is notorious for having a range of effects spanning from sedating to energizing. Aside from the cannabinoids, terpenes are the drivers behind the smell and the variety of different therapeutic effects.  During his multi-decade research into plant medicines, Russo observed the intelligent relationship between cannabinoids and terpenes. He discovered that while these chemical components carry medicinal properties in isolation, their therapeutic potential dramatically increased when they worked together (Russo E. , 2019). After this observation, he popularized the term, “The Entourage Effect”, which describes the relationship between cannabinoids and their smaller counterparts. For Russo and consumers alike, this theory best explained the wide variety of effects experienced after consumption.

Russo first published his theory in his widely cited article from 1998, Taming THC: Potential Cannabis Synergy and Phytocannabinoid-terpenoid Entourage Effects. At the time, his thoughts were relegated to mostly theory aside from observational data. As cannabis science has dramatically progressed, he believes we have enough evidence to support a clear synergistic relationship between the compounds in the cannabis plant. While the exact mechanism of interaction has not been found, Russo and others are confident of its existence.

The pharmacodynamics—the way a compound physiologically moves throughout the body—is largely unknown. What we are beginning to see evidence for is the suggestion that terpenes modulate the activity of cannabinoids (LaVigne J. H., 2021). Both compounds hold medicinal capabilities in isolation, but we see a dramatic increase in the efficacy when an interaction occurs. Terpenes do not directly act on the ECS by themselves but may be able to hit receptor sites they would otherwise be unable to in the absence of cannabinoids. In essence, the sum is greater than the individual parts.

Due to limited research, Russo’s claims remain controversial. U.S. skeptics have been mostly unsuccessful in recreating the Entourage Effect in the lab (Finlay DB, 2020). However, new research is beginning to emerge which validates the Entourage Effect. It is our postulation (and Russo’s) the scientific community is struggling to recreate nature. This fact does not invalidate its existence, but rather highlights the limits of man’s capabilities at any given time.

Russo’s research offers a foundational explanation as to why cannabis has been used for such a wide variety of health conditions. If the Entourage Effect is clinically proven (current prohibition blocks any human trials), it could dramatically alter our approach to health and wellness. Currently in the West, we approach medicine symptomatically and in isolation. The Entourage Effect could prove why a holistic approach is superior to current, conventional methods.

The cannabis plant and the ECS has existed longer than the human species has walked this Earth. Their co-evolution could be the linchpin to better understanding our relationship to nature and how we can achieve more vibrant and healthy lives. Join us on our quest to validate natural alternative medicines for the twenty-first century.


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