Cannabis and its mechanism of action – a complex plant
It contains over 400 molecules and compounds – cannabinoids , terpenes , flavonoids, and other phytochemicals. Various research findings show that these chemicals have great medical potential and have different effects on the brain and body. They interact synergistically, thus creating and enhancing the overall therapeutic benefit.
The effects of all these ingredients and their interaction are called the entourage effect. Each cannabis strain has a unique profile of plant compounds. As a result, some strains have a focusing and stimulating effect, while others are calming and relaxing.
You can think of the entourage effect and the molecules involved like a cast of actors in a theater production. THC and CBD are the main actors. The other cannabinoids and terpenes play supporting roles. But you also need people in the background such as costume designers, light and sound or make-up artists. This task is carried out by the flavonoids and the remaining plant substances. Only if everyone involved works together will the play be a success.
Entourage effect – many research findings
A research study conducted at the University of London in 1981 already provided evidence for the entourage effect. Using a test, researchers J.W. Fairbairn and Joan T. Pickens were able to demonstrate that full-spectrum extracts from the cannabis plant elicit 330% more activity than THC alone. They hypothesized that cannabis contains "synergists" and "inhibitors" that serve to enhance therapeutic effects and inhibit potentially negative psychoactive reactions.
The hypothesis that the compounds in cannabis produce a better effect when combined than when isolated, was first confirmed and published in a 1998 scientific study by the Hebrew University of Jerusalem . World-leading cannabis researchers Shimon Ben-Shabat and Raphael Mechoulam found that the synergistic relationship between these compounds is largely responsible for the therapeutic effects of cannabis. In this study, the researchers investigated 2-AG, one of the two most important endocannabinoids . When they administered 2-AG to mice in addition to two related cannabis compounds, the positive effects—such as pain reduction—were stronger.
, in 2009 Hildebert Wagner and Gudrun Ulrich-Merzen from Ludwig Maximilian University in Munich published a paper entitled: "Synergy Research: Approaching a New Generation of Phytopharmaceuticals". In it, they discussed and outlined the following fundamental mechanisms of the entourage effect:
- Compounds derived from the whole plant can affect multiple targets in the body.
- The interaction of all plant substances improves the bioavailability, absorption and solubility rate of the active ingredients.
- The synergy of the whole plant helps overcome bacterial defense mechanisms.
- The plant's compounds and their interaction help minimize adverse side effects of active ingredients.
The entourage effect has also been demonstrated in other research studies. In 2010, British researchers showed that an extract containing THC and CBD led to greater pain reduction in cancer patients than THC alone. Brazilian researchers also demonstrated the entourage effect in 2018. They compared a full-spectrum CBD extract with a CBD isolate in the treatment of epilepsy. The full-spectrum extract was more effective. Furthermore, the subjects required lower doses and experienced fewer side effects than those who took the isolate.
The cannabinoids THC and CBD – an important discovery – but only the tip of the iceberg
Cannabis preparations have been used by practitioners in folk medicine for millennia. Back then, however, no one was interested in the plant's molecular composition. What mattered was its effect, and that convinced our ancestors. This changed in the mid-20th century with the discovery of the remarkable cannabinoids – tetrahydrocannabinol (THC) and cannabidiol (CBD).
This sparked the researchers' interest in the plant's mechanisms. Cannabis research began, uncovering many interesting compounds, the entourage effect, and, in 1992, the endocannabinoid system (ECS) . This system is the reason why cannabis has an effect on the human body. It essentially regulates all the fundamental functions and patterns our body performs, such as appetite, memory, inflammation, immune function, neuroprotection, pain, reproduction, sleep, mood, metabolism, and digestion. There is justified hope that targeted interventions in the body's own endocannabinoid metabolism will open up new therapeutic possibilities.
Today, science knows that there are certainly more than 113 cannabinoids . New ones are still being discovered. Some researchers even speak of 144 or more. Among those that have been studied for some time are THCA and CBDA, the acidic forms of the cannabinoids THC and CBD. They are said to have, among other things, anti-inflammatory properties. Then there is cannabigerolic acid (CBGA) – the precursor molecule from which other cannabinoids are synthesized, or cannabinol (CBN), a mildly psychoactive cannabinoid. It is found in "old" cannabis and has a sleep-inducing effect. There is tetrahydrocannabivarin (THCV). This is a homolog of THC. Research shows that THCV suppresses appetite. THC, on the other hand, is known to stimulate appetite. And there is cannabidivarin (CBDV). It has an anticonvulsant effect during seizures. These are just a few examples and the effects of cannabinoids.
More intensive research is needed to decipher the mechanisms by which all cannabinoids affect the body. However, this may not be so relevant. The entourage effect demonstrates that the combination of all plant compounds is what truly matters. The specific effects of individual cannabinoids are primarily of interest to science, enabling a better understanding of the plant. For patients, it is desirable to have access to a wide variety of cannabis strains with diverse compound profiles.
In Israel, a database is being developed, and in the USA , there is also a website that helps users find suitable cannabis strains for their specific condition. This is a valuable resource for patients and the doctors who prescribe it. These patient experiences could also provide researchers with interesting starting points for further experiments and advance cannabis research. It will take science decades to truly understand this complex plant with all its components if it studies every single molecule.
Terpenes – important assistants
Around 140 of the chemical components in cannabis belong to the group of organic hydrocarbons – the so-called terpenes . These are nanoparticle-sized, aromatic molecules that define the scent of the cannabis plant. They are also found in other aromatic plants, as well as in fruits and vegetables. Limonene, for example, is found in citrus fruits. Pinene is responsible for the intense scent of pine trees. Linalool is found in lavender, and beta-caryophyllene is also present in black pepper.
Nature uses terpenes as a defense mechanism against insects. In humans, however, interesting medical mechanisms of action have been discovered. At concentrations of 0.05%, terpenes are considered "of pharmacological interest" and interact with cell membranes, neuronal and muscular ion channels, neurotransmitter receptors, G-protein-coupled receptors, and enzymes.
Studies have shown that limonene, for example, has an anxiolytic effect. Pinene can be used as an antibiotic. Linalool is an anesthetic and anticonvulsant. Beta-caryophyllene has a strong anti-inflammatory effect, and then there is the relaxing myrcene, to name a few.
Interesting synergies – the phytocannabinoid-terpenoid interactions
Cannabis researcher and neurologist Ethan Russo – now Director of Research and Development at the International Cannabis and Cannabinoids Institute – published an article in the British Journal of Pharmacology in 2011. The title was: "Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects." In his research, he investigated how the cannabis entourage effect impacts mammals.
Russo discovered in his experiments that terpenes have a wide range of medicinal effects. He also found that they can alter how cannabinoids interact with their respective receptors, thereby influencing and modifying their effects. A notable example is the terpene myrcene. It can cross the blood-brain barrier, thus facilitating the entry of cannabinoids into the brain and making them more effective.
In his work, Russo focused particularly on these phytocannabinoid-terpenoid interactions. He believed these synergies could offer promising approaches for treating pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal infections, and bacterial infections. His research demonstrated that non-cannabinoid plant components can act as a potential antidote to the intoxicating effects of THC and may even enhance therapeutic benefits.
He also recommended further investigation of the entourage effect in future experiments to improve cannabis medicines. He saw the proven interplay of phytocannabinoids and terpenes as offering the potential to create a wide range of new therapeutic products from this venerable medicinal plant.
Interesting components – the promising flavonoids
Another chemical component found in cannabis that contributes to the entourage effect is flavonoids. This subgroup is called cannflavins. They were in 1986 by Marilyn Barrett at the University of London . She identified two specific cannabis flavonoids – cannflavin A and cannflavin B. In 2008, cannflavin C was also identified. Chemically speaking, these are prenylflavonoids and are not related to THC or other cannabinoids. In addition, about 20 other flavonoids have been found, such as luteolin, kaempferol, and quercetin. All of these flavonoids can influence the taste, color, and aroma of cannabis flowers, and they also affect the effects that different cannabis strains have on humans.
One of the greatest therapeutic benefits of cannflavins is their excellent anti-inflammatory properties. Current research shows that cannflavin A and cannflavin B are 30 times more anti-inflammatory than aspirin. Researchers at the University of Guelph in Canada published this discovery in July 2019. This opens up the possibility of natural pain management without the risk of addiction, such as with opiates. Cannflavins target pain with a different approach: by reducing inflammation. The problem with these molecules is that they are present in very small quantities in cannabis and cannot yet be produced on a large scale.
There is also evidence that flavonoids could help in the treatment of cancer. A study published in December 2018 shows that they promote apolysis – the death of cancer cells. Furthermore, a 2019 study found that cannabis flavonoid derivatives yield promising results in the treatment of pancreatic cancer.
Flavonoids can also be helpful in protecting the skin from the sun, pigmentation disorders, and skin aging. In the future, there are hopes for their successful use in treating skin diseases. This is the conclusion of a research paper published in February 2018. Flavonoids are absorbed very efficiently through the skin, making them suitable for topical application. All these interesting therapeutic properties contribute to the entourage effect.
