The Entourage Effect of pCBs & terpenes
What is the Entourage Effect?
Anyone who starts to learn and become interested in medical cannabis products and CBD products has heard the term ”Entourage Effect”. In the past, the subject was considered one that is dealt with only by medical cannabis consumers, but not so today, when the CBD industry breaches the boundaries of audiences and markets and when the concept is not only theoretical but is expressed in a wide range of products and the nature of the entire industry.
When discussing the entourage effect, it is important to remember two things:
1. Most prescription drugs available today are based on one molecule and one target protein.
2. There are currently two FDA-approved drugs based on the two main molecules in cannabis, the phytocannabinoids – THC and CBD. The first is called ”Marinol” and is based on THC and the second is “Epidiolex”, which is based on pure CBD. The oral spray “Sativex” contains CBD & THC in a 1:1 ratio between them.
The cannabis plant,on the other hand, (on its two varieties – marijuana and hemp) contains more than 500 different compounds.
Scientific truth or hypothesis only?
The “Entourage Effect” is a hypothesis first proposed in the early 2000s, based on the idea that a whole plant should be more effective than taking an isolated molecule based on just one of the plant’s active compounds. The hypothesis has been developed extensively since it was first introduced. Today, some scientists believe that different types of cannabis plant compounds or the combination of different molecules from the plant (phytocannabinoids, terpenes, and flavonoids) can be more effective for specific conditions and symptoms - as well as the type of intoxication they can induce based on their chemical profiles. In 1999, researchers Prof. Shimon Ben-Shabat and Prof. Raphael Mechoulam noted for the first time that the cannabis plant may be preferable to different drugs thanks to the influence of entourage compounds. This hypothesis was based on their observations when they studied the endocannabinoid system. They observed that some naturally produced endocannabinoids (eCBs) in the body are more effective when mixed with other inactive compounds – the endogenous fatty acid glycerol esters.
Endocannabinoids are fatty acids that are naturally produced in the human body “On Demand” and affect us by binding to eCBs receptors across membranes of the different brain & immune cells. The two known and important eCBs are anandamide (AEA) and 2-AG. The role of the Endocannabinoid System (ECS) in the body is to restore its systems to balance (Homeostasis) and for this, it produces eCBs from cell membranes when necessary ’ON DEMAND’. Phytocannabinoids (pCBs) are cannabinoids found in the cannabis plant (marijuana & hemp) that can mimic the action of the eCBs or influence their action.
Interestingly, THC’s affinity for eCBs receptors is higher compared to the affinity of AEA or 2-AG to these receptors.
Is the entourage effect a synergy?
According to Prof. Mechoulam and Prof. Ben Shabat, “natural products are biologically active… often accompanied by chemically related, although biologically inactive ingredients… investigations of the effect of the active ingredient in the presence of its ‘entourage’ compounds may lead to different results from those observed with the active ingredient only.”
Prof. Shimon Ben-Shabat and Prof. Raphael Mechoulam the pioneering researchers concluded that “this type of synergy may play a role in the prevailing (but not experimental) view that in some cases, whole plants are better medicines than purified isolated natural products.”
A few years later, researcher Dr Elizabeth Williamson provided evidence of the idea that ”a whole or partially purified extract of a plant offers benefits over one single ingredient”. One of the examples used in that study was the ability of CBD to weaken some of the side effects of THC. Dr Williamson concluded that. ”this synergistic effect would be very important if cannabis became a medicine by reducing the sometimes unwanted psychotropic side effects.”
Does the Entourage Effect only exist in medical cannabis products?
Of course not. The two main types of cannabis are the marijuana plant from which medical cannabis products are produced and the Hemp plant from which CBD is produced. Both types have the same molecular composition in different concentrations! It is quite possible that when the term “Entourage Effect” was coined in scientific research, it meant a very high concentration of THC about other cannabinoids including CBD, while in CBD products the psychoactive molecule THC Is only a small part of an Entourage.
How does the entourage effect work?
Although some researchers have contributed to the entourage effect theory when referring to cannabis, the most related scientist to do it extensively is Dr Ethan Russo.
In his 2011 article “Taming THC: Potential Cannabis Synergy and Phytocannabinoid-terpenoid entourage effects”, Dr Russo thoroughly presented the previous works on cannabinoid synergy, and mainly coined the term “Entourage Effect”, defining its mechanism. To explain how the entourage effect works, Dr Russo cited a 2009 study from Germany: Approaching a new generation of phytopharmaceuticals, which defined the behaviour of synergy in plant compounds in general, not only in cannabis. He described four main mechanisms, three of which are particularly relevant to cannabis:
1. Multiple target proteins improve the effect of CBD:
Most often, drugs work on one target protein in our bodies, creating a specific effect. Multi-goal impact means that plant compounds can work on many targets simultaneously.
In cannabis, a popular example will be the interaction of THC & CBD with a large number of target proteins – A. Ion channels: TRPV1, TRPV2, TRPV3, TRPA1, TRPM8, B. Orphan receptors: GPR12, GPR18, GPR55, C. Endocannabinoid System receptors CB1, CB2 , and many other receptors, some of which are nuclear receptors that are transcription factors such as PPARγ. This multi-goal can enhance the effects of THC, but as mentioned above, it is not only THC. There are other cannabinoids, terpenes, and perhaps even flavonoids that can also activate a large number of targets, thus improving the effects of purified THC or CBD. One of the earliest published examples of the increased effects of THC when synergistically given with other plant compounds was the comparison of pure THC with full spectrum in the treatment of muscle over-contraction. Another study stated:”With equal doses of THC, whole-plant extraction is considered more effective as an anti-convulsive than the THC alone”.
2. Molecular movement improves the effect
The two main branches of pharmacology are pharmacodynamics [PD] (how drugs affect your body) and pharmacokinetics [PK] (how your body affects medications and metabolises them and the movement of drugs within the body).
While the multiple effects of cannabis are first related to pharmacodynamics, the effects that improve the movement of cannabinoids in our bodies are related to pharmacokinetics. The effect that improves certain health aspects is caused by the interaction of molecules on a variety of protein targets in the human body.
The effects that improve the movement of the pCBs as a whole are the way a group of molecules moves in the human body more efficiently than if one of them is moving alone. A prominent example of a molecular movement that improves therapeutic influence is demonstrated in that CBD inhibits the FAAH enzyme that metabolises & degrades the eCB anandamide (AEA), thereby increasing its concentration in the blood and brain.
The cannabinoids – Cannabichromene (CBC) and cannabigerol (CBG) inhibit the reuptake of anandamide (AEA), thereby increasing its action in synapses. Another example of effects that improve pCB molecular movement in the body is also demonstrated by the monoterpenes limonene, myrcene, and pinene.
These terpenes are biologically active and can cause relaxation of the airways in the lungs. When taken as separate molecules it does not cause a large physical reaction (at least not in low doses), but when inhaled, these terpenes together with pCBs, the absorption of the cannabinoids through the lungs can be improved by the presence of these airway expanding terpenes.
3. Reducing the side effects
Reducing the side effects ”can be reached when an ingredient contained in a herbal extract ’neutralises’ or destroys a toxic component, and therefore produces better efficacy compared to a drug in which a single isolated ingredient.”
Several cannabis side effects are related to THC and some cannabis compounds may help in dealing with these side effects. The best and most popular is CBD oil.
a large and growing amount of studies was recently collected that support CBD’s ability to weaken side effects of THC, especially impaired short-term memory: Does Cannabis Composition Matter? Differential Effects of Delta-9-tetrahydrocannabinol and Cannabidiol on Human Cognition
Cannabidiol as a Potential Treatment for Anxiety Disorders, and psychomimetic effects (such as paranoia and social withdrawal): Clinical and Preclinical Evidence for Functional Interactions of Cannabidiol and Δ9-Tetrahydrocannabinol
Terpenes and cannabinoids share the Entourage Effect
In the above-mentioned paper, Dr Ethan Russo also added a new study direction: “Perhaps it is not just the interaction of CBD, but also compounds such as other cannabinoids such as CBG. CBC, terpenes, and flavonoids play a role in the entourage effect”. Terpenes are aromatic molecules responsible for smell and taste in most plants, but they also have medicinal activity and can affect the human body in many ways.
One of the unique things about cannabis plants is the variance in the terpenes (there are almost 200 different terpenes in cannabis). According to Dr. Russo, the high concentration of terpenes in certain chemovars may determine their effects. These terpenes may affect whether a specific “strain” will be soothing [Myrcene] or stimulating [Pinen] and whether it will be better for situations and symptoms such as pain, inflammation, anxiety, epilepsy, or depression & PTSD. Some examples of the potential synergy of cannabinoids, terpenes, or terpenoids proposed include:
• THC + Pinene = Expands bronchial airways in the lungs
• THC + Limonene + Linalool + Pinene = Alzheimer’s disease treatment
• THC + Linalool + Myrcene = Muscle relaxant
• CBD + Limonene + Linalool = Anxiolytic
• CBD + Linalool = Anti-convulsant
• CBD + Limonene = Potentiates the immune system
• CBD + Pinene = Anti-inflammatory
• THC + CBD + Linalool = Pain relief.
Although there is evidence of cannabinoid synergy (mainly THC & CBD as well as CBG & CBD), the terpenoid-cannabinoid synergy, however, is supported only by little evidence so far. But this may be due to a lack of research on the subject.
Is the Entourage Effect present in CBD products that have less than 0.3%THC?
Of course, it does, CBD products contain the full spectrum of ingredients found in the cannabis plant (hemp): 125 Phytocannabinoids (the main of which is CBD) and the concentration of the psychomimetic molecule THC does not exceed 0.3%), Hundreds of terpenes, and dozens of flavonoids. The low concentration of THC allows these products to be sold legally in countries where CBD is approved by the health authorities because this minimal amount of THC is not in any way dangerous and does not cause intoxication. The Entourage Effect, on the other hand, and the synergistic action of the molecules will indeed exist although it is possible that at a lower intensity. Our experience shows that the entourage effect in the full spectrum has a better effect on depression and stress than purified CBD products.
CBD and individual customer tailoring
Some people prefer pure CBD to any other product. Some people react badly to theTHC molecule. Even if it is present in a very small amount, some suffer from symptoms that the pure molecule will take better care of. For example, people with anxiety report that pure CBD products are preferable to their tastes to CBD products with a full spectrum.
From our accumulated experience:
Full Spectrum products are suitable: For strengthening the immune system, balancing blood pressure, treating depression, balancing appetite, and lowering stress.
Pure CBD products are suitable for anxiety, migraines, and cluster headaches, muscle, and bone & back pain, as well as ADHD.
Our daily experience of accompanying and guiding thousands of consumers who experience self-medication using CBD oil and sharing users’ experiences [Online Questionnaires] helps us understand in-depth the differences between the different products and their suitability to the customer (personalised medicine).
Soon, CBD products will become more diverse through different (and higher) concentrations of minor cannabinoids that are currently present in full-spectrum products only in very low concentrations. For example, products that have a high concentration of the molecule CBG (Cannabigerol), CBN (Cannabinol), or CBC (Cannabichromene) in combination with CBD. The market is already available in this area, and in this respect, people’s reports can already be seen on certain features characteristic of these products and their medical benefits.
What does the entourage effect mean for consumers?
One of the main consequences of the entourage effect on consumers will be the way they choose cannabis products.
If the cannabinoid & terpene profiles of cannabis plants determine their impact, we will need a system to catalogue and group these products. In an ideal world, after much research has been done on the entourage effect, it will be possible to group cannabis products for the most suitable use and treatments for situations and symptoms such as pain, sleep disorders, nausea, and headaches. They can be seen as products with relaxing combinations suitable for evening and towards sleep, as opposed to stimulating combinations for the morning, recreation, or work. The names of current “strains” or the terminology ”Indica” for the night and ”Sativa” for the day will not define their true effects. They refer only to morphological differences at best, and often completely ignore their chemical variant profiles [chemovar]. Moreover, all medical cannabis today is hybrid and complex.
Frequently Asked Questions [FAQs]
Does the “Entourage effect” also exist in CBD oil that is sourced from the hemp plant?
Of course, it does. The hemp plant is a cannabis subspecies that contains the same compounds as the marijuana plant. The concept of the ”Entourage effect” comes from the medical cannabis world, but today, when CBD products also have a full spectrum hemp oil of the ingredients in the plant, the concept also applies to them. It is important to remember that the entourage’s two main ” members” are the phytocannabinoids THC and CBD found in these plants at high concentrations relative to the other ingredients.
Does the“Entourage effect” also exist in hemp seed oil?
No, Hemp seed oil is sold in a food additive that contains no cannabinoids at all but other natural ingredients such as amino acids and omega fatty acids. The active ingredients found in cannabis, hemp, and marijuana, are derived from the resin produced in glandular trichomes [GTs] on stalks and leaves.
Does CBD oil also have terpenes and flavonoids?
Yes, Full Spectrum Oil is an initial extraction of all active ingredients found in the flower of the cannabis plant. There are 125 cannabinoids, dozens of flavonoids, and about 200 terpenes in this extract.
What is the difference between the entourage effect of medical cannabis versus the entourage effect of CBD products?
In the products of medical cannabis companies, the main cannabinoid is the molecule that has intoxicating properties and other compounds (including CBD) are found in a lower amount.
The presence of the molecule THC in large quantities causes side effects in some patients to the point of disrupting daily routines. In CBD products, the main molecule is CBD while the THC molecule is in the (minimum) quantity that does not exceed 0.3% w/w. In these products, there is an entourage effect without a psychoactive effect (intoxicating, “HIGH”) and the daily routine does not get interrupted. As you can see in the attached table, the molecular composition of both varieties [marijuana & hemp] is the same, but their relative concentrations are different.
Is there one entourage effect or does each product have its Entourage Effect?
In the medical cannabis world, for years producers have been looking for a way to improve certain strains of cannabis whose entourage effect is considered particularly effective. This is an almost impossible task when the main form of consumption is smoking-dried inflorescences. Today, using innovative technologies, all plant compounds can be isolated and diluted by any carrier oil in a consistent and measured manner according to a ”pre-order”.
How can we know the exact contents of the product ingredients?
As in any market also in the CBD market, it is, unfortunately, possible to find companies that mislead the public and market products whose product contents do not match the written and guaranteed labels on the packaging. We have become accustomed for years in the pharmaceutical and cosmetics industries to read the ingredients on the packaging knowing that the companies would not dare lie and risk losing their licence or getting sued. As the CBD industry began its path amid ”legal fog” over the legality of the molecule, authorities have not yet set regulatory rules for oversight.
So what can we do? Looking for a reliable CBD company.
CBD company stands firmly behind their products and this position is expressed with maximum transparency towards customers. A third-party lab testing page is the most important page on the CBD company’s website in which you are interested. There you will find the certainty that each batch that came out of the factory is checked by an independent body.
· Russo E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British journal of pharmacology, 163(7), 1344–1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x
· Wagner, H., & Ulrich-Merzenich, G. (2009). Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine: international journal of phytotherapy and phytopharmacology, 16(2-3), 97–110.
· Limonene-induced activation of A2A adenosine receptors reduces airway inflammation and reactivity in a mouse model of asthma
· A review of the relaxant effect of various medicinal plants on tracheal smooth muscle, their possible mechanism(s), and potency