Cannabis and its mechanism of action – a complex plant
It contains over 400 molecules and compounds – cannabinoids , terpenes , flavonoids and other phytochemicals. Various research results show that these chemicals have great medical potential and have different effects on the brain and body. They interact synergistically to create and enhance the overall therapeutic benefit.
The effects of all these ingredients and their interaction is called the entourage effect. Each cannabis strain has an individual phytochemical profile. As a result, some strains have a focusing and stimulating effect, while others have a calming and relaxing effect.
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 – lots of research evidence
A research study conducted at the University of London in 1981 provided evidence of the entourage effect. Using a test, researchers JW Fairbairn and Joan T. Pickens were able to demonstrate that full extracts from the cannabis plant trigger 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.
This assumption, that the compounds contained in cannabis together produce a better effect than their isolated molecules alone, was confirmed and published in 1998 in a scientific study at the Hebrew University of Jerusalem The world's 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, researchers examined 2-AG, one of the two main endocannabinoids . When they gave the mice 2-AG alongside two related cannabis compounds, the positive effects - such as pain reduction - were greater.
Building on this, in 2009 Hildebert Wagner and Gudrun Ulrich-Merzen from the Ludwig Maximilians University in Munich prepared a paper entitled: “Synergy research: approaching a new generation of phytopharmaceuticals”. In it, they discussed and outlined the following basic 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 proven in other research studies. In 2010, British researchers were able to show that an extract containing THC and CBD leads to greater pain reduction in cancer patients than THC alone. Brazilian researchers also entourage effect in 2018. They compared full CBD extract with CBD isolate in the treatment of epilepsy. The full extract was more effective. In addition, the test subjects required lower doses and had fewer side effects than the test subjects who took the isolate.
The cannabinoids THC and CBD – an important discovery – but just the tip of the iceberg
Cannabis preparations have been used by doctors in folk medicine for thousands of years. At that time, no one was interested in the molecular composition of the plant. What was important was the effect and it convinced our ancestors. That changed in the middle of the 20th century. The remarkable cannabinoids – tetrahydrocannabinol (THC) and cannabidiol (CBD) – were discovered.
This made the researchers interested in the plant's mechanisms. Cannabis research began and discovered many interesting ingredients, the entourage effect and in 1992 the endocannabinoid system (ECS) . This system is the reason cannabis works in the human body. It essentially regulates all the basic functions and patterns our body needs to perform. For example, appetite, memory, inflammation, immune function, neuroprotection, pain, reproduction, sleep, mood, metabolism and digestion. There is legitimate hope that targeted interventions in the body's endocannabinoid metabolism will open up new therapeutic perspectives.
Today, science knows that there are certainly more than 113 cannabinoids . New ones are still being discovered. You can also find researchers who talk about 144 and more. Those that have been researched for some time include THCA and CBDA, the acid form of the cannabinoids THC and CBD. They are said to have, among other things, anti-inflammatory properties. Then there is cannabigerolic acid (CBGA) – the starting 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 homologue of THC. Research shows that THCV suppresses appetite. THC, on the other hand, is known to stimulate the appetite. And there is cannabidivarin (CBDV). It has an antispasmodic effect during seizures. These are a few examples and spectrums of effects of cannabinoids.
More intensive research is needed to decipher the mechanisms of all cannabinoids on the body. But that might not be all that relevant. The entourage effect proves that the combination of all plant substances is particularly important. The specific effect of the individual cannabinoids is primarily of interest to science in order to better understand the plant. It is desirable for patients to be provided with many cannabis varieties with different plant substance profiles.
in Israel and there is also a website in the USA that helps you find which types of cannabis are suitable for your own illness. This is a useful help for sick people and the doctors who prescribe it to them. These patient experiences could also provide researchers with interesting approaches for further experiments and advance cannabis research. Science will still need decades to truly understand the complex plant and all its components if it devotes attention to each individual molecule.
The terpenes – important assistants
Around 140 of the chemical components in cannabis belong to the group of organic hydrocarbons – the so-called terpenes . They are nanoparticle-sized, aromatic molecules and define the scent of the cannabis plant. But they also occur 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 found in black pepper.
Nature uses terpenes as a repellent 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 muscle ion channels, neurotransmitter receptors, G protein-coupled receptors and enzymes.
Studies have shown that limonene, for example, has an anti-anxiety 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.” Which in German means something like: “Taming THC: possible cannabis synergy and phytocannabinoid-terpenoid entourage effects”. In his research series, he examined how the cannabis entourage effect affects mammals.
In his experiments, Russo found that terpenes have a wide range of medicinal effects. But he also discovered that they can change how cannabinoids interact with their respective receptors. This influences and changes their effect. A notable example is the terpene myrcene. It can cross the blood-brain barrier, making it easier for cannabinoids to penetrate the brain. This makes them more effective.
In his work, Russo paid particular attention to these phytocannabinoid-terpenoid interactions. In his opinion, these synergies could create interesting approaches for the treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal diseases and bacterial infections. His scientific work showed that non-cannabinoid plant components are a possible antidote to the intoxicating effects of THC. They can also increase the therapeutic benefit.
He also recommended further investigating the entourage effect in future experiments and thereby improving cannabis medicines. He saw the proven interaction of phytocannabinoids and terpenes as an opportunity to produce an extensive 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 are flavonoids. This subgroup is called cannflavins. They were in 1986 by Marilyn Barrett at the University of London . The scientist found 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 and other cannabinoids. In addition, around 20 other flavonoids were found, such as luteolin, kaempferol and quercetin. All flavonoids contained can influence the taste, color and scent of cannabis flowers and they also have an influence on the effect 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 treatment without the risk of addiction, such as with opiates. Cannflavins target pain with a different approach, namely by reducing inflammation. The problem with these molecules is that they are present in cannabis in very small quantities and cannot yet be produced on a large scale.
There is also evidence that flavonoids could help treat cancer. A paper published in December 2018 shows that they promote apotosis - the death of cancer cells. Additionally, a 2019 study found that cannabis flavonoid derivatives provide promising results in the treatment of pancreatic cancer.
But flavonoids can also be helpful to protect the skin from the sun, pigmentation disorders and skin aging. In the future, it is hoped that they can be used successfully for skin diseases. This is the conclusion of a research paper published in February 2018. Flavonoids are absorbed very efficiently through the skin. This makes them suitable for topical application. The flavonoids contribute all of these interesting therapeutic properties to the entourage effect.
