The Entourage Effect

June 15, 2020

General

The term "entourage effect" has only been recently used and it describes modern scientific knowledge about the methods of action and the effect of phytocannabinoids on the endocannabinoid system.

In general terms, the entourage effect can be described as an interaction of plant compounds in the human body.

Special combinations of plant substances are more effective and produce greater activity to transmit crucial signals via receptors.

This can be explained through biology. The human body is made up of cells that not only form a basis for life, but also help in all our daily activities. For example, if we want to clench a fist, our cells transfer the signal from the brain to the muscles. This means the cells need to be able to send signals as well as receive and read them correctly. The receptors help with this.

In the endocannabinoid system, these messengers are the endocannabinoids (and also cannabinoids). The readable receptors are usually referred to as CB1 and CB2 receptors.

Many people are not very aware of the actual number of receptors in the ECS, the endocannabinoid system. Receptors such as GPR3, GPR5 or TRPV8 also make a critical contribution to the full functioning of over one hundred and twenty endocannabinoids. Their communication is complex.

What actually is the entourage effect?

The entourage effect describes these communication processes in our cell systems. Assuming that a single component lacks the sufficient power to generate certain stimuli and forward messages, it therefore needs a group. With this group effect (based on the French word: entourage) the desired receptors are put into action.

This process is unusual because in biochemistry, molecules known as ligands usually bind specifically to their receptors without the need for ‘entourage’.

The biochemist Prof. Dr. David Meiri, from the Faculty of Biology at the Technical University in Israel, has gained new insights into cannabis studies in cancer. His cell research has revealed that individual cannabinoids do not affect certain cancer cells, with no effect on their lifespan.^[1] If several components are combined, the desired effects are shown. This is possible because individual connections work as a team through the receptors and can develop enough strength to kill, for example, the cancer cells mentioned above. Their effectiveness will be strengthened.

This interaction between phytocannabinoids and terpenes and their common synergetic properties is called the entourage effect.

To fully understand the entourage effect, it is not only important to understand how cannabinoids work but also needs a basic understanding of what terpenes are and why they are far more important in cannabis plants than long believed.

What are terpenes?

Terpenes are a heterogeneous group of chemical compounds within natural organisms. They are insoluble in water, but soluble in fats.

Terpenes in the cannabis plant are the organic hydrocarbons that are responsible for the unique taste and intense smell of the flowers and plants. They are first produced in the sticky resin glands of the rather strange plant and can be likened to strongly scented oils, yielding a strong odour once developed. They co-exists with well-known cannabinoids such as THC, CBD or CBG.

Just like cannabinoids, at present, scientists can only estimate the exact number of terpenes within the cannabis plant. They now assume that it may have over two hundred different terpenes. However, the individual connections fluctuate. This also explains why different types of marijuana have different, often unique, scents. Terpenes are also responsible for the perception of consumers as to why a plant is soothing or brings on euphoric effects.

What are their tasks?

Like most cannabinoids, terpenes have other roles. This range extends from participating in the endocannabinoid system, decisive action within the growth process of the plant and therapeutic aromatherapy uses for human therapy. They are also said to have microbial properties, which could inhibit various infectious diseases or the spread of microorganisms.

In the meantime, research has progressed so far that many terpenes are listed according to their multifaceted actions. Five monoterpenes found in the cannabis plant are myrcene, linalool, lime terpinolene and pinene.

Myrcene

Myrcene is probably the most important and most well-known terpene from the cannabis plant. Strictly speaking, myrcene is actually a mono-terpene, i.e. with a simplified chemical structures that other, far more complex terpenes can build upon.

It is produced in the glandular heads of the flowers. Surprisingly, it is also found in other plants like hops, bay leaves, herbs such as cardamom, parsley, basil and thyme, as well as the mango. Its scent is most likely to be described as dominant, earthy and musky. The taste of the terpene is reminiscent of the intense sweet and peppery aroma of cloves.

Myrcene evaporates from a temperature of 166 - 168° C (330 - 334° F).

Its extensive therapeutic areas are most likely explained by the fact that scientific research for Myrcen, the best researched terpene, is already very advanced. Important insights have been gained from studies showing the terpene can have analgesic, anti-inflammatory and immune-boosting effects. These effects take place because myrcene attaches to receptors and from there, for example, it initiates the stimulation of pain-relieving substances. Mycren also crosses the brain-blood barrier.^[2] This helpful and selectively permeable barrier is used to control and regulate the harmful fluid exchange from the bloodstream and central nervous system.

Apparently, myrcene also has a sedative effect. This assumption is based on the observation that the terpene myrcene is found in particularly high concentrations in Indica plants, the cannabis strain which is also known to have a high concentration of CBD - the cannabinoid often used along with THC to alleviate the psychoactive effect on consumers and to provide more relaxation.

Linalool

Typical to all terpenes, linalool has its own aroma, which most people will have experienced as a lavender scent. This delightful scent is not only attractive to humans, but also to animals and insects. It can be described as fresh and tart at the same time. The cannabis plant also seems to contain linalool terpenes.

Linalool can also be found in many herbs. These include coriander, healthy ginger, basil, marjoram, thyme, saffron, cinnamon and many other spices. Since it is present in so many plants that are good for health and have a healing effect, of course, it is reasonable to assume that linalool could be useful in medical therapies. In fact, it is already used in today's medicine. Studies have shown it acts as an anti-inflammatory.^[3] In addition, it has antihyperalgesic and antinociceptive properties. This means that the terpene can influence crucial signal pathways in pain treatment and weakens the sensitivity to pain. Products with this effect that are medically recognised include analgesics.

Linalool also uses the binding points of receptors in our body for its pain-relieving effect. In this case, the A1 and A2A receptors at least partially play a role in this process as activity mediators.

Many websites claim that this terpene even has an antispasmodic effect. Contrary to this assumption, experts and scientists warn against consuming basil with linalool as the main ingredient in cases of epilepsy, but studies in mice show promising findings for an increased latency period in convulsions.^[4]

Thanks to various studies, we know that terpenes not only change the psychoactive effects of the cannabis plant, having a significant impact on the consumer’s feelings, but also build a bridge for new communication channels through our receptors.

The benefit of the entourage effect

To understand the successful benefits of the entourage effect, it is helpful to differentiate between entourage effect drugs and pure THC drugs or CBD drugs. The latter have earned a particular reputation due to their increasing use in severe oncological diseases such as cancer. Prescription drugs can help patients with nausea from stressful chemotherapy. Tumours can be reduced and a loss of appetite regained after illness. So, if individual cannabinoids already show such great potential, why is it necessary to have drugs that contain more than one phytocannabinoid?

Of course, there are also disadvantages of pure cannabinoid medications. For example, the effects of oral THC medication take a few hours to have an effect. The areas that can be affected are often limited and by no means cover all areas necessary for fully comprehensive recovery. For this reason, dealing with cancer only with these drugs is not an option.

The entourage effect for medical use

As we already know, scientists from an Israeli university have looked into the entourage effect on cancer cells. They found that the interaction between cannabinoids and terpenes is important for biochemical processes.

Other research has also looked at the numerous possibilities of terpenes and cannabis cannabinoid combinations and found that even a low dose of terpenes can have a decisive influence on the action of transformation products. In addition, they are believed to be strong enough to deliver such important therapeutic effects that they are essential for the entourage effect of cannabis-based medicine.^[5] So, the terpene myrcene can help with sleep disorders due to its sedative effect. In the right composition, it has a calming effect on those who take it and relaxes the muscles.

Other clinical cases and symptoms that can be covered by this phenomenon and benefit are:

- Inflammation

- Depression

- Epileptic seizures / epilepsy

- Cancer

- Mycoses and bacterial infections

- Muscle cramps and tension

- Anxiety and addiction

Interaction of individual cannabinoids

Without terpenes even in the picture, the interactions between individual cannabinoids is very interesting. Depending on the dosage, different phytocannabinoids can, for example, support, mitigate or even completely inhibit the effects of their relatives. An example of this phenomenon can be found in THC (tetrahydrocannabinol) and CBD (cannabidiol). New studies have shown that CBD has some (albeit extremely low) psychoactive effects. Plant cultivators are increasingly looking to grow female hemp plants with the lowest possible CBD levels to change THC intoxication for consumers. Although CBD has no direct action on the psychoactive properties of THC, the effect can be explained by binding to receptors. The theory is that CBD is able to revise the typical THC properties through the receptors and manipulate the psychoactive effect, which is passed on as a message via receptors in the endocannabinoid system.

CBGV and CBD behave in a similar way. Cannabidiol has many important properties that the medical field is interested in for various procedures. This little cannabinoid has an anxiolytic and relaxing mode of action. It also has anti-epileptic effects and can even act as an antioxidant. However, it often lacks the strength to effectively bind to receptors and take full effect from there. Its brother, CBGV (cannabigerovarin) helps with this. CBD comes from the molecular source CBG (cannabigerol), with CBGV as the starting chemical. CBGV makes it easier for CBD to bind to receptors in the ECS more easily and efficiently. This knowledge is also still relatively new, since CBGV is only found in extremely small quantities in many plants.

Further findings

The chemical structure of terpenes was first explained (after initial difficulties) in 1884. The German chemist and later Nobel Prize winner in chemistry, Otto Wallach, succeeded in identifying and clearly describing their compounds.

Today, science knows of over eight thousand terpenes and three thousand terpenoids. The difference in terpenoids is that they are not pure hydrocarbons, but represent atomic compounds.

All terpenes are based on the unsaturated hydrogen isoprene.

Almost all terpenes are volatile in steam, which is an advantage when extracted from the plant. They can be exploited by processes using steam distillation.

Although full research into the biological functioning of terpenes has unfortunately not yet been fully completed, we already know they can be used as an environmentally friendly insecticide and at the same time often have an antimicrobial effect. This behaviour fits the natural protective mechanism of the cannabis plant with a defence system that develops on the resin glands and, as trichomes, can ward off natural predators and external environmental influences.

These trichomes, found in a variety of plants, also provide a home for terpenes and cannabinoids.