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The mysterious entourage effect

The cannabis plant contains more than 1,400 unique chemicals. Scientists have identified more than 100 cannabinoids, 200 terpenes, many flavonoids and several phenolic compounds. Many of these compounds have effects on the human body, and some may be fundamentally beneficial - such as CBD. A number of studies suggest that not only cannabinoids but also other substances in cannabis naturally interact with each other. They develop each other's potential and reinforce each other's effects. This theory of synergistic cooperation is called the entourage effect. How exactly does it work?


The phenomenon where several substances act together to produce an effect that they could not achieve alone is known as the entourage effect. Such a companion effect is therefore more than the net sum of the effects that the substances can have individually. It is the interaction of the compounds that enhances the resulting effect. More specifically, when substances work in synergy (interdependently), the effect of one compound may be more pronounced while the effect of another may be weakened.

One compound, for example CBD, can become more effective when combined with another (for example THC). But the reverse is also true - one substance can weaken some of the effects of another. For example, there is talk that CBD can counteract some of the unwanted side effects of THC, such as memory lapses or anxiety. Sometimes an inactive compound can even become active when combined with other compounds.

The entourage effect is essentially the combined effect of compounds acting in synergy. It is thought to arise from interactions between individual cannabinoids as well as between cannabinoids and terpenes.

The analogy of a pianist playing the piano serves well to illustrate this. While music played only by a pianist can be beautiful on its own, when accompanied by a singer, the music takes on a new dimension. Although, if the singer is bad and sings too loudly, the pianist would probably play better alone. So the effect of accompaniment doesn't automatically translate into a better experience. But I think we can all agree that listening to a professional orchestra playing in rhythm accompanied by a choir or a professional singer makes for a perfect musical experience.

1. How the interaction between CBD and THC works
2. Where did the escort effect come from?
3. More recent studies and their findings
4. Let's not forget the terpenes
5. We need more research

How the interaction between CBD and THC works

Of the large group of plant cannabinoids found in cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC) are undoubtedly not only the most popular but also the best studied. These, as well as other cannabinoids, interact when used with the endocannabinoid system in our body, which is responsible for many important bodily processes, especially the maintenance of internal balance.

It is their ability to bind to endocannabinoid receptors in the brain and throughout the central nervous system that gives rise to the potential therapeutic effects of not only CBD and THC, but also other cannabinoid compounds. But what does it look like when cannabinoids work together? 

The human endocannabinoid system is designed to couple with endogenous cannabinoids produced by the body. However, the compounds contained in cannabis can bind with these receptors just as effectively. A number of studies suggest that taking CBD and THC together, plus other organic compounds (terpenes and terpenoids) in cannabis, is more effective than taking CBD or THC alone.  Terpenes are essential oils with a characteristic smell and taste. Thus, the entourage effect theory, promoted by many, argues that the properties of individual cannabis products are often determined by the relative concentration of specific terpenes and their combination with cannabinoids and other substances.

All CBD products from the so-called full spectrum extract take advantage of this magical mix of substances, which are likely to act synergistically. This includes both hemp and coconut CBD oils from Hemnia. They contain the full spectrum of substances naturally occurring in hemp: in addition to CBD, there are other cannabinoids - CBG (cannabigerol), CBN (cannabinol), CBC (cannabichromene), THCA (tetrahydrocannabinolic acid) and the legally permitted amount of THC (tetrahydrocannabinol - always up to 0.3 %), as well as a mixture of natural terpenes.

Many people who work closely with cannabis believe that the entourage effect can greatly enhance the therapeutic utility of both CBD and THC, either by amplifying their known effects or by expanding their potential therapeutic uses.

Where did the escort effect come from?

The theory of the entourage effect was first formulated in 1998 by Raphael Mechoulam, a chemist at the Hebrew University of Jerusalem - an innovator and leading pioneer in cannabis research. Mechoulam and his colleagues studied the molecule 2-arachidonoylglycerol (2-AG), which binds to the cannabinoid receptors CB1 and CB2 in our bodies. They showed that in the spleen, brain and intestines of mice, 2-AG is usually found together with two other compounds (2-linoleoylglycerol and 2-palmitoylglycerol). Although these two molecules alone failed to bind to CB1 and CB2, they improved the ability of 2-AG to bind to receptors and enhanced some effects - such as pain relief - in the animals.

The theory of the entourage effect posits that the compounds in cannabis affect a wide range of processes in the body and, most importantly, that they work better together than in isolation. Ethan Russo, a neuroscientist and former director of research and development at the International Institute for Cannabis and Cannabinoids in Prague, has taken this concept and extended it to other chemicals in cannabis. Perhaps no one in the field has made more of an effort to prove the existence of an additive effect than Russo, who has devoted decades of scientific work and a search of the scientific literature in an effort to find traces of it.

When Mechoulam published his work, Russo realized that its results could support his idea that THC was not the only component of cannabis with potential pharmacological uses. For decades, he had heard anecdotes about strains of cannabis that affected people in different ways - one might be good for pain relief, while another could improve sleep. Russo came up with the thesis that cannabis contained compounds other than THC that could explain these differences. After learning about terpenes, known as essential oils, which can be extracted from plants (such as lavender and peppermint) and which supposedly have medicinal effects, he hypothesized that these compounds might be able to enhance the effects of THC.

Russo also came up with the claim that CBD could act to enhance the therapeutic effects of THC. As evidence, he cites a 2010 clinical study of the painkiller Sativex, which contained a fairly balanced mixture of THC and CBD extracted from cannabis. Sativex is used to treat neuropathic pain in people with multiple sclerosis. The drug was developed by GW Pharmaceuticals, a British company for which Russo served as chief medical advisor from 2003-14.

The controlled study involved 177 people suffering from cancer pain and compared three approaches: one group of participants was given a placebo, another was given a high-THC drug and a third group was given Sativex. Participants were asked to rate the level of pain they were suffering during the two-week study and at the end to confirm how much, if any, their pain had been reduced. A reduction in pain of 30% or more was considered clinically significant. Almost a third less pain was reported by about 40% of those treated with Sativex - almost twice as many as those receiving placebo or THC alone. This difference was observed even though the THC content of each product was the same, which could only mean that CBD somehow enhanced the analgesic effect of THC.


More recent studies and their findings

The 2019 study, mentioned in S. Ratliff's article on the Cannabis tech website, tested six common terpenes alone and in combination. The researchers found that the effects of THC on the cannabinoid receptors CB1 and CB2 were not altered by the addition of the terpenes. However, this does not mean that the effect of the accompaniment does not exist. It may well be that the terpenes are interacting with THC elsewhere in the brain or body, or in a different way than what this study focused on.

One 2018 meta-analysis that Russo cites in support of the existence of an additive effect revealed that when trying to reduce the incidence of seizures in epilepsy patients, pure CBD extracts (isolates) proved to be much less effective than those extracts that contained a mixture of cannabinoids including terpenes (broad- or full-spectrum extracts). The research involved 670 people with treatment-resistant epilepsy who were given either CBD isolates or just CBD-rich hemp extracts that contained a broader spectrum of substances (contained in cannabis). At 71%, those taking these extracts reported experiencing seizures less frequently. This was only 46% of those receiving the CBD isolate. However, those who experienced at least a 50% reduction in seizure frequency were evenly represented in both groups.


Let's not forget the terpenes

Russo has gathered evidence suggesting that terpenes and terpenoids (aromatic compounds) have the potential to alleviate psychosis as well as memory problems that can be triggered by high-dose THC use. And these compounds could also enhance the more positive properties of THC. Studies suggest that the terpene myrcene may improve sleep in people with chronic pain and that limonene may help relieve anxiety. Russo is thus a proponent of the idea that using terpenes alongside CBD and THC offers the opportunity to more effectively "tweak" medications to suit patients' individual needs.

For example, as Adie Wilson-Poe, a neuroscientist at the Legacy Research Institute and director of Smart Cannabis, based in Portland, Oregon, writes, some terpenes have been shown to have antioxidant and analgesic properties. However, he admits that no research has yet focused on finding suitable combinations of molecules for different disease symptoms.


We need more research

Like most of what we know so far about the therapeutic potential of cannabis, the entourage effect is still a relatively well-founded theory. However, not all research has found solid evidence to support it. Both proponents and doubters agree that more research, including double-blind clinical trials, is needed to confirm with absolute certainty that the entourage effect exists. And if it does, we are still left to understand exactly how it works.

Although that day has not yet arrived, further research is coming up with fairly convincing evidence. Beyond that, there is indeed a wealth of anecdotal evidence - from users whose experiences with medical cannabis vary depending on the chemical composition of the products they have consumed. The debate thus often takes the form of a battle between the scientific method and the personal experiences of users.

We firmly believe that the active ingredients in cannabis can indeed work together to produce beneficial effects. It may just be happening in a way that is difficult to determine by current methods. Time will tell.


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