Cannabinoids, Terpenoids, the Entourage Effect, and the Endocannabinoid System (ECS)
The frontier of cannabis science is actually not as new as one might think. After all, it has been grown for thousands of years, and even the Chinese emperor Shen-Nung (2700 BCE) recorded the herb’s medical versatility and experimented with the plant himself. Throughout the centuries the Greeks, the Assyrians, the people of Africa, India, China, South America, and even doctors in the UK and the United States prescribed and used cannabis for medicinal purposes until the prohibition of marihuana came about in 1937, a few years after which “hemp oil” and “cannabis oil” were removed from western pharmacopeia.
Now, despite prohibition and the inevitable War on Drugs that was brought about in 1971, various medical institutions, doctors, scientists, and researchers throughout the world continued to study and learn more about the cannabis plant. Some of these studies are actually available in our Medical Research Library for review. Notable discoveries and their credit go to Dr Raphael Mechoulam and his team out of Israel for isolating and “discovering” THC; the researchers out of St. Louis University led by Dr Allyn Howlett and William Devane for discovering and mapping out the Endocannabinoid System in the early 1990s, Dr Donald Abrams and scientists in the San Francisco bay area for helping to provide cannabis to HIV/AIDS patients in SF and for helping pass the first medical marijuana law Proposition 215 in 1996; and much of the work done by Dr Geoffrey Guy and GW Pharmaceuticals out of the UK over the past two decades for their cannabinoid research with epilepsy, autoimmune disorders such as multiple sclerosis, autism spectrum disorder, cancer, and more. There are definitely countless more doctors, scientists, researchers, and even activists and medical patients who deserve credit and thanks for their brave groundbreaking work with cannabis despite the social stigmas and legal challenges.
With that said, cannabis science has come a long way. Between the tens of thousands of scientific and medical research papers out there, our technological ability to analyze the cannabis plant and its many chemical constituents with cutting edge lab equipment, and the clinical trials that are beginning in legal states and countries, we are collectively learning more and more about this amazing plant than we could have ever imagined. Without writing an entire book about cannabis science (and there are several out there already), this article will simplify and discuss three major subjects in this category - The Chemical Constituents of Cannabis - Cannabinoids and Terpenoids, the Entourage Effect, and the Endocannabinoid System.
The Chemical Constituents of Cannabis
Phytocannabinoids (Phyto = plant)
Phytocannabinoids are a diverse and powerful set of organic compounds naturally produced by the cannabis plant. This term is often shortened to ‘cannabinoids’ and there are more than 100 that have been discovered. The most commonly known ones are Delta-9-Tetrahydrocannabinol (Δ9-THC), Cannabidiol (CBD), and Cannabinol (CBN). Some of these compounds are psychoactive and consuming them either smoked or eaten oftentimes leads to what is commonly called, “getting high.” These compounds are produced and contained in the crystal trichomes of the flowers or bud made by the plant. Although Δ9-THC is the most well known cannabinoid for psychoactivity as it is abundantly produced by a multitude of cannabis strains, a majority of the cannabinoids are actually not psychoactive in nature.
What makes these compounds truly fascinating is not how high they can get you, but rather their powerful and versatile therapeutic potential - they can treat multiple symptoms across multiple ailments and diseases and they do this without risking serious lasting harm or a lethal overdose to an individual. How are these cannabinoids so powerful for therapeutic purposes? And how is it that they can treat so many varied ailments and symptoms? This will be explained in detail in the last section below, the Endocannabinoid System. It may be a little hard to believe now, but upon learning about and understanding how this system actually works, you will get a sense of why this scientific field is so groundbreaking and exciting.
The top 6 most abundant and studied cannabinoids are: Tetrahydrocannabinol (THC or Delta-9-THC) , Cannabidiol (CBD), Cannabinol (CBN), Tetrahydrocannabidivarin (THCV), Cannabichromine (CBC), and Cannabigerolic Acid (CBGA). It is also important to note that cannabinoids also come in raw, heated (also chemically known as decarboxylated), and aged states. This is important as the raw counterparts of cannabinoids, Tetrahydrocannabinolic Acid (THCA) for example, do not cause psychoactivity in individuals eating them - this has important implications for consuming raw cannabis for medical benefit as patients may find juicing the flowers of the plant to be a viable way of incorporating cannabis into their treatment and diets.
Terpenoids are a diverse class of organic compounds naturally produced by a vast majority of plants and flowers, including cannabis. Terpenoids are responsible for producing the various aromas and smells most plants produce and they also possess medicinally valuable characteristics. Traditionally terpenoids have many uses - they can be found in cleaners, sprays, perfumes, and they are still used in aromatherapy. In the cannabis world, you will often hear of stoners and wooks (avid fans of the cannabis culture) constantly talk enthusiastically about terps and the amazing flavors that translate into the flowers and concentrates they enjoy vaping.
Surprisingly, in addition to simply adding fruity kushy tastes (and more) to the smoking and vaping experience, scientists have found that these terpenoids actually work synergistically with the cannabinoid compounds the plant produces to create the therapeutic effects. These terpenoids also help explain why cannabis provides a wide variety of psychoactive effects and varied experiences as well.
Upon understanding this and when looking at numerous lab tests for the various strains of cannabis, it becomes evident that the mixture and multitude of terpenoids alongside the psychoactive compounds in each strain - Δ9-THC and THCV for example - are what dictate the type of “high” a certain strain will produce, not whether they are Indica or Sativa. Essentially, terpenoids modulate and help to further drive the type of therapeutic effects of the various cannabinoids, as well as dictate or provide the varied psychoactive effects possible when consuming the plant.
Oftentimes, the words Terpenoid and Terpenes are used interchangeably but there is a slight difference between the two - Terpenes are a hydrocarbon, meaning that the only elements that make up the chemical structure of these compounds are hydrogen and carbon. Terpenoids on the other hand have been altered from their original natural state by oxidation (such as when drying and curing) or have been chemically modified or tampered with (such as when BHO or Rosin is manufactured or even when individual terpenoids are extracted and isolated through fractional distillation).
There are a multitude of terpenoids that scientists have identified - more than 200 when it comes to just cannabis (and not all terpenoids produced by the plant have been fully studied). One common example of a terpenoid would be α-Pinene, a known mood enhancer with anti-bacterial, anti-fungal, anti-inflammatory, and bronchodilating properties; this is a compound naturally produced in pine needles and in several strains of cannabis. Another common example would be Myrcene, a compound prevalent in mangoes and lemongrass and also produced in many cannabis strains, which has been known to have analgesic, anti-cancerous, anti-inflammatory, anti-insomnia, and anti-spasmotic properties!
A short list of some of the most common terpenes found in cannabis includes: Alpha Pinene, Beta Caryophyllene, Camphor, Citronellol, Eucalyptol, Geraniol, Humulene, Limonene, Linalool, Myrcene, Ocimene, Nerolidol, Phytol, Terpineol, Terpinolene, and Valencene.
The Entourage Effect
Now that we have covered the chemical constituents of the cannabis plant - cannabinoids, terpenoids- we can discuss a powerful concept when it comes to cannabis science: the Entourage Effect which describes the ability for these particular compounds to work in concert with each other in order to provide a more powerful, more potentiated therapeutic effect. That is, when consuming an assortment of these compounds, an individual will find a more well rounded and more effective therapy than if he/she were to consume an individual cannabinoid such as THC or CBD alone.
One way to illustrate and give an example of this is to observe the Analgesic (pain relief) properties of the cannabis plant: the cannabinoids CBGA, THC, CBD, CBC, CBN, and the terpenoids, Borneol and Myrcene all share the same therapeutic characteristic of being pain relieving compounds. When consuming these compounds together, than if one were to consume them individually, it can be observed that each of the compounds “contribute” to the overall therapy being received by the individual. In other words, say THC, CBD, and CBN were combined into a medicine such as a pill or a tincture, a patient would be receiving 3 compounds that can help to remedy his or her pain than if he were to simply take a THC pill such as Marinol; the 1, 2, 3 punch of the former is obviously superior to the isolate.
Given that many of the cannabinoids, terpenoids, and flavonoids share numerous therapeutic properties, the theory behind the Entourage Effect opens up many possibilities in the realm of treatment and healing. In the next page is a chart listing most of the therapeutic possibilities with cannabis and the respective cannabinoids and terpenoids which coincide with the stated therapy. This particular concept was popularized and discussed by multiple cannabis scientists and doctors, and Dr. Ethan B Russo and Dr. John McPartland explain how “cannabis is inherently polypharmaceutical and that synergy arises from interactions between the plant’s multiple components.” In his paper, Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects, Dr Ethan Russo goes into great detail to describe and elucidate the various particular interactions with specific cannabinoids to their respective “entourage terpenoids.” The previously mentioned organization Fundacion Canna out of Spain also expands into this concept and theory - they list and discuss how particular flavonoids add to this rounded therapy.
Overcoming the Bell Shaped Response in Cannabinoid Consumption
The previous concept of the Entourage Effect is actually further observed when looking at CBD exclusive medicines (medical preparations that only contain CBD and no other cannabinoids, terpenoids, or flavonoids). As discussed in the paper, Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol by Ruth Gallily et al., it is stated, “Cannabidiol (CBD), a major constituent of Cannabis, has been shown to be a powerful anti-inflammatory and anti-anxiety drug, without exerting a psychotropic effect. However, when given either intraperitoneally or orally as a purified product, a bell-shaped dose response was observed, which limits its clinical use. In other words, consuming CBD by itself provides the user a plateaued effect, and even diminishing returns after exceeding high doses of CBD. This means that you cannot simply take more and more CBD for better therapy; one will notice significant diminishing effects.
Whole Plant Therapy
The paper does go on to investigate what happens when utilizing whole plant extract - a complete assortment of the other cannabinoids and terpenoids produced in the plant. The study found that there was a clear correlation between the shared effects of the various compounds produced in the plant and that increasing the dosage of the medicine showed that this is how to overcome the diminished effect of individual cannabinoid consumption. In fact, many cannabis scientists today support the stance that whole plant therapy is far superior to isolated cannabinoid therapy, which the Entourage Effect explains.
The Endocannabinoid System (ECS)
The Endocannabinoid System (ECS) represents a fascinating new field in the realm of biology and physiology. Although it was only discovered in the early 1990s, and limited research and scientific efforts into it’s mapping and study are desiring more worldwide attention, it is nevertheless a scientific and medical wonder for several blaring reasons:
Scientists and doctors are now discovering that this system and its set of receptors alongside the compounds it produces, are actually bigger than our own immune system - in fact the immune system is encompassed within the ECS!
In observing system, the ECS is amazingly largely involved with managing the following functions within our bodies: Memory and Learning; Brain Plasticity; Neuronal Development, Stress and Emotions, Thermogenesis, Addiction, Nociception (our ability to sense pain), Energy Balance, Appetite Regulation, Digestion, Metabolism, Motility, and Fertility.
Scientists and doctors are also now discovering that particular deficiencies within this system could be related to a large number of ailments, diseases, and their respective symptoms. Conversely, upregulating and caring for this system can actually help to correct several difficult to treat sickness.
So what is the Endocannabinoid System?
This amazing and complex system is comprised of several components within your body. Involved are a set of receptors, classified as CB1 receptors (which are located throughout your Brain, Lungs, Gastrointestinal tract, your Reproductive system, your Muscles, and your Cardiovascular system, as well as the respective cells themselves contained in each of these), and CB2 receptors (which are located in your Bones, Spleen, and throughout the surface of your skin, and consequently the respective cells found in each of these). Both CB1 and CB2 receptors can also be found throughout your Immune System, your Liver, Pancreas, within your Bone Marrow, and again all of the cells associated with these organs/systems. It is also exciting to know that this system has not been fully mapped, and that scientists theorize that a 3rd set of receptors, CB3 may exist. Sounds like a lot, but it’s true.
Endogenous cannabinoid receptors are located throughout your entire body, and these receptors, when functioning normally, help to promote and maintain what is known as homeostasis - an optimally functioning natural system, that is disease free.
Now, imagine that within your body, you are constantly producing several special compounds, 2 of the major and most important ones being - Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG). These compounds, known as endocannabinoids bond to the above mentioned receptors and are the flowing fuel of keeping this system going. Note that these particular cannabinoids are called “endo” to signify that they are produced from within. Also note that the production of these compounds within your body can take a hit and be diminished due to a number of external reasons - physical and psychological stress, physical trauma, lack of proper diet and nutrition, lack of proper exercise and health maintenance are just a few of the possible causes that lead to a deficiency in these essential compounds. More on this will be covered shortly.
So, the Endocannabinoid System (ECS), by definition is represented by both the CB1 and CB2 receptors that have been mapped thus far, as well as the endocannabinoids that bind to them which are produced from within our own bodies.
Comparing Endocannabinoids to Phytocannabinoids
Now, here’s the miraculous and really cool part - THC, CBD, and the other phytocannabinoids found in the cannabis plant (remember that phyto means plant), actually mimic the endocannabinoids perfectly, and interact with the ECS and its complex set of receptors just like their “endo” counterparts AEA and 2-AG. More specifically, phytocannabinoids can be taken as a supplement in order to help upregulate this system in the case that our own bodies are not producing enough endocannabinoids to keep the ECS healthy and going.
This helps to explain why cannabis is actually so useful and effective at treating so many diseases and symptoms - the interactions that phytocannabinoids have with our own endocannabinoid system strongly indicate that they can help to correct issues related to Memory and Learning (potential for Alzheimer’s and brain disorders); Brain Plasticity (also potential for Alzheimer’s and brain disorders); Neuronal Development (again potential for Alzheimer’s and brain disorders), Stress and Emotions (mood disorders such as PTSD), Thermogenesis (the body’s ability to regulate its temperature potential for fever and a possible correlation to autoimmune diseases), Addiction (alcohol and opiate), Nociception (this relates to pain relief with strong potential for Fibromyalgia and other autoimmune diseases), Energy Balance (uplifting strains of cannabis can help with raising one’s vitality), Appetite Regulation (munchies for wastings syndrome, THCV for diet control), Digestion (helpful for sickness and nausea), Metabolism (munchies are great for eating disorders), Motility (refers to movement, which means this can significantly help in the realm of seizures and tremors associated with epilepsy and Parkinson’s respectively), and Fertility (check out the documentary [LEAF] The Health Benefits of Juicing Cannabis which covers Dr. William Courtney and a case study patient who juiced cannabis to relieve her lupus; her doctors had stated that she would be infertile, but with her treatment and consumption of cannabis, she was later able to have a child). All of the previous mentioned bodily functions or categories are regulated by the ECS.
Clinical Endocannabinoid Deficiency (CED)
Whether or not you have even heard of the Endocannabinoid System, you may not find it hard to believe that there is a term for what happens when the ECS takes a hit and is unable to adequately produce enough endocannabinoids to modulate and run the very said system; you can compare it to a car running out of gas, or an athlete tiring out - in either example, they may or may not be able to keep going if they’ve exhausted themselves. Research within the past 20 years suggest that the ECS being unable to upregulate itself may correlate to several of the more difficult to tackle ailments and diseases such as Multiple Sclerosis, Fibromyalgia, Parkinson’s Disease, Alzheimer’s, and even multiple forms of Cancer.
With all of that said, this system can be safely and healthily upregulated with cannabinoid compounds from the cannabis plant - phytocannabinoids (cannabinoids produced within a plant) and they can simply be consumed to correct deficiencies within this system. Sounds overly simple, and perhaps too good to be true. Some of the many scientific studies covering ALL of what was encompassed in this article can be found below in the references section. The door is obviously open for debate, and indeed it is encouraged. There is a serious need for the professionals of the medical and scientific worlds to become involved. Countless lives could be positively affected by the medical potential of cannabis - the world just needs to catch up with the science and studies surrounding this herb for several decades; in fact it’s been a part of the world’s history for thousands of years.
Understanding How Cannabinoids And Terpenoids Possess Medical Potential
Cannabis is a medicinal herb, plain and simple. Today we have the science and technology to study and understand it better; and to make utilizing it as a medicine an evolved boon to the world. There is great need worldwide for the scientific and medical communities to revisit this plant that has been cultivated and utilized in numerous ways for several thousands of years. With what we have learned over the past several decades identifies cannabis as a very powerful herb that could safely ease suffering in countless individuals across numerous ailments and conditions.
Cannabis Education and Research Director