Cannabis is mostly associated with phytocannabinoids such as the psychotropic tetrahydrocannabinol (THC). Research shows that other constituents – terpenes and flavonoids – influence the therapeutic effect, which is called the entourage effect. Although the coloured flavonoids are widespread in the plant kingdom, little is known about their medicinal effects. Here we explain what these plant substances are and shed light on their potential.
Ingredients of the cannabis plant
The cannabis plant contains more than 500 different components. The best known are the phytocannabinoids, of which the plant has over 100. The best researched are the intoxicating tetrahydrocannabinol (THC) and the non-psychotropic cannabidiol (CBD). In addition, cannabis contains various non-cannabinoid plant substances such as phenols, terpenes, flavonoids and alkaloids. As of May 2021, 323 substances have been identified in cannabis, twelve of which have been newly discovered since 2017. So far, 23 different flavonoids with different chemical structures have been isolated from Cannabis sativa .
What are flavonoids?
Flavonoids are secondary plant constituents from the class of polyphenols that are widely distributed in the plant kingdom. They make up colour, smell and taste . Research currently knows of 8,000 flavonoids . The name “flavonoids” is derived from “flavus”, the Latin word for “yellow”. In the past, people used extracts of flavonoid-rich plants to dye wool .
Plants use flavonoids to defend themselves against pathogens, as attractants for pollinating insects and for protection against ultraviolet radiation (UV radiation) [2,3]. Due to the protective function, flavonoid biosynthesis is therefore not only dependent on plant genetics but is also subject to environmental influences such as temperature, solar radiation, precipitation and humidity .
Flavonoids can be divided into six classes :
Effects of flavonoids
Flavonoids not only benefit the plant, but also have nutritional and medicinal effects. Plant foods such as vegetables, fruits, grains and dried legumes are rich in flavonoids . Observational studies showed that regular consumption of these foods can prevent diseases such as diabetes, cancer, osteoporosis, cardiovascular and neurodegenerative diseases . Flavonoids were first discovered in 1936 by Nobel Prize winner Szent-Györgyi Nagyrápolt. He discovered that plant extracts from lemons and red peppers strengthen the capillary walls of blood vessels and initially named the substance class vitamin P .
The effects of flavonoids include :
- Anticarcinogen (cancer-inhibiting)
- Antithrombotic (anticoagulant)
- Antidiabetic (diabetes inhibiting)
- Antiparasitic 
- Antiviral [5,7]
- Promotes wound healing 
- Anxiolytic (anxiety-relieving) 
- Antioedematous 
Flavonoids can help with a variety of different diseases and conditions, including inflammation, cancer, eye disease and neurodegenerative diseases. Some flavonoids can be effective in viral hepatitis, cancer, malaria, autoimmune diseases and inflammatory diseases by inhibiting kinase, an enzyme. By inhibiting kinase, they have an immunosuppressive effect and, as a so-called radiosensitizer, increase the sensitivity of tumour tissue to radiation therapy .
Flavonoids in the cannabis plant
Flavonoids are found in most tissues of the cannabis plant, such as the seedling, leaves, flowers and fruits. No flavonoids are found in the roots and seeds. The flavonoid profile of the flowering bracts varies in the course of development. As with other plants, the flavonoid content of Cannabis sativa depends on environmental factors .
Italian scientists discovered a link between growing conditions and flavonoid formation in 2020: The research team grew genetically identical cannabis plants at different altitudes – mountains and lowlands – and analysed the concentrations of phytocannabinoids, terpenes and flavonoids. It was found that cannabis plants from the mountains contain more cannflavin A, B and C. In contrast, samples grown in the lowlands contained more apigenin .
Most of the flavonoids known so far have been isolated from “non-stressed” cannabis plants, i.e. cannabis plants grown under ideal conditions. Therefore, it is assumed that there are still unknown flavonoids that are only produced by the cannabis plant under certain stress conditions. Some flavonoids are specifically found in certain chemical varieties, so-called chemovars. For example, cannaflavin C is found in THC-rich cannabis varieties .
Some flavonoids in cannabis are :
- Cannflavin A
- Cannflavin B
List of phenolic substances in Cannabis sativa [2,11]:
Cannflavins – characteristic flavonoids in cannabis
Cannflavins are chemically prenyl flavonoids. They are characteristic for cannabis, but also occur in some other plants. Cannflavin A, B and C are distinguished . The modification of the flavonoid skeleton by prenylation and methoxylation makes cannflavins more fat-soluble than other flavonoids. Since the cell membranes are a lipid barrier, cannflavins are more easily taken up into the cells. Interaction with membrane-bound enzymes and receptors is also facilitated .
Cannflavins could therefore have many therapeutic properties. So far, the strong anti-inflammatory properties have been investigated in preclinical studies. The relationship between the chemical structure of cannflavins and their anti-inflammatory, neuroprotective, anticarcinogenic, antiparasitic and antiviral effects has not yet been fully elucidated. Further research will reveal more about the structure activity relationships (SAR). Appropriate optimisation of the chemical structure could lead to more effective therapeutic options in the future. Likewise, the microbiological degradation products should be researched to understand the metabolism and biological effect of cannflavins in humans .
Effects of cannflavins :
- Anticarcinogen (cancer-inhibiting)
In 1981, researchers discovered for the first time that cannabinoid-free extracts from cannabis sativa have an anti-inflammatory effect. In mice, the extract affected the metabolism of prostaglandin E2 (PGE2). Further research showed that the formation of PGE2 triggered by the proinflammatory substance TPA is inhibited. In vitro studies showed that cannflavin A and B reduced pro-inflammatory prostaglandins and leukotrienes: The flavonoids blocked PGE2 synthase, the enzyme for prostaglandin formation, and 5-lipoxygenase, the enzyme for leukotriene biosynthesis.
Cannflavin A also had a strong anti-inflammatory effect in cultures of human rheumatoid cells: Cannflavin A inhibited PGE2 synthesis 30 times more strongly than acetylsalicylic acid (ASA), a non-steroidal anti-inflammatory drug. However, in contrast to ASA, cannflavin A only weakly inhibits the enzyme cyclooxygenase (COX): therefore, cannflavin A does not cause side effects such as gastric mucosal damage, which are typical for non-steroidal anti-inflammatory drugs . Further studies also showed an inhibition of PGE2 production for cannflavin B and thus an anti-inflammatory effect .
Flavonoids in cannabis also have antiviral effects. The results of a computer simulation, a so-called in silico study, published in 2020 showed that canflavone (isocannflavin B) could be effective in covid-19. The computer binding study showed that isocannflavin B inhibits viral entry and replication of SARS-CoV-2: canflavone attaches to the ACE2 receptor – the entry port of the coronavirus – thereby preventing it from entering the host cell.
In addition, the flavonoid inhibited two viral proteases that the virus needs to replicate in human lung cells. The studies showed that the phytoantivital flavonoids hesperidin, myricetin, linebacker and canflavone bind at least as strongly to ACE2 receptors as chloroquine, another compound studied in Covid-19 .
Computer studies show antiviral effects of cannflavins also in other viral infections: Cannflavin A has a high binding affinity to HIV-1 protease, a viral enzyme that mediates the infectious properties of the HI virus. Cannflavin A also binds to various proteins of the viral envelope of the dengue virus. So far, in silico studies indicate antiviral effects of cannflavins. However, studies in biological systems are necessary to investigate the bioactivity .
In preclinical studies, neuroprotective effects of cannflavin A were shown even at small concentrations: The nerve cells showed improved survival against beta-amyloid, a cytotoxic protein. Beta-amyloid can form plaques. Cannflavin A prevents plaque formation and thus protects nerve cells . Protein deposits of beta-amyloid play an important role in Alzheimer’s disease.
Preclinical studies in the “test tube” and in animal models show an anticarcinogenic effect of isocannflavin B, a synthetic isomer of cannflavin B. Isocannflavin B inhibits the proliferation, i.e. the growth, of oestrogen-dependent human breast cancer cells. In preclinical studies, isocannflavin B also showed good results in pancreatic cancer: the flavonoid delayed the growth of local tumours and metastases in pancreatic cancer and prolonged the survival of the mice. However, studies in humans on the anticarcinogenic effect of isocannaflavin B are still lacking .
In vitro and in silico studies show that cannflavin A and B could control parasites. Cannflavins A and B showed moderate antiparasitic activity in cultures of Leishmania donovani, the parasitic agents of leishmaniasis. Cannflavin A binds strongly to the enzyme Leishmania pteridine reductase. Cannflavin A also shows success against Trypanosoma brucei, the causative agent of Nana disease in domestic animals. So far, however, the mechanism of action of the antiparasitic effects is unknown and requires further research .
Flavonoids in metastatic pancreatic cancer
Pancreatic cancer is one of the most aggressive tumour diseases. With current therapies, only a 5-year survival rate of eight percent is achievable. This makes research into new therapies all the more important in order to improve patients’ chances of cure and quality of life. In a preclinical study published in 2019, an American research team showed that a non-psychotropic flavonoid derivative (referred to by the scientific team as FBL-03G) can help with pancreatic cancer. It is a synthetic isomer of cannflavin B, which occurs naturally in the cannabis plant.
- In vitro studies have shown that FBL-03G induces programmed cell death (apoptosis) of cell lines of human pancreatic cancer cells. The flavonoids thus cause more tumour cells to die in the “test tube”.
- FBL-03G also proved successful in animal models of pancreatic tumours. For this purpose, the tumours were treated with different concentrations of the flavonoid in addition to radiotherapy. FBL-03G was injected directly into the tumour and implanted as a drug depot in the form of so-called “Smart Radiotherapy Biomaterials (SRB)” for a prolonged effect. The depot dissolves slowly, releasing the flavonoid. In order to investigate the effect on metastases, a second tumour site of the animals was not treated. Tumour size and survival rate of the mice were investigated. It was found that FBL-03G delayed the growth of both local tumours and metastases. Compared to the control group, which only received radiotherapy, the survival rate of the mice treated with FBL-03G increased significantly. The positive results of this study lay the foundation for further investigations .
Entourage effect with cannabis
The most important active substances in cannabis are the phytocannabinoids. In addition, a large number of other biologically active substances, especially terpenes and flavonoids, influence the pharmacological effect. Research has shown that full-spectrum extracts, i.e. preparations from the entire cannabis plant, have a better effect and are better tolerated than isolated cannabinoids such as THC or CBD. This phenomenon was discovered in 1998 by the Israeli professor of pharmaceutical chemistry, Raphael Mechoulam, and called the entourage effect . The inter-entourage effect refers to interactions between cannabinoids and non-cannabinoid plant substances such as flavonoids. Currently, however, flavonoid metabolism and the entourage effect of the cannabis plant have hardly been studied .
The entourage effect also comes into play in the external application of cannabis preparations. The cannabinoids THC and CBD bind to cannabinoid receptors found in the skin and thus have an anti-inflammatory effect. In addition, they have a blood circulation-promoting and wound-healing effect by dilating blood vessels. Flavonoids promote wound healing through their anti-inflammatory and antioxidant effect.
Preclinical studies showed: Quercetin promotes wound healing on skin cell cultures through increased levels of certain growth factors. The combination of the flavonoids diosmin and hesperidin inhibits the formation of vascular cell adhesion molecules (VCAM), endothelial intercellular adhesion molecule 1 (ICAM-1) and other adhesion molecules. Thus, the combination acts on the veins and has a positive effect on varicose veins.
A Canadian study published in 2021 showed that topical cannabis preparations with phytocannabinoids, the terpene beta-caryophyllene and the flavonoids quercetin, diosmin and hesperidin, in addition to treatment with compression stockings, can support the healing of leg ulcers. 14 patients with a total of 16 wounds were included in the study. After an average of one month (34 days), the wounds were completely closed in 11 people with 13 ulcers. The remaining three people had an advanced healing process but could not be followed up .
Cannabis sativa has also been used in dentistry for thousands of years and is mentioned in old pharmacopoeias of Asian, African and Indian medicine. The plant was used for toothache and possibly also for caries and inflammation of the gums (gingivitis).
The endocannabinoid system is also active in the mouth. The presence of CB1 receptors in the salivary glands explains dry mouth as a typical side effect of THC. The anti-inflammatory, analgesic, antioxidant, anticarcinogenic, antimicrobial and anxiety-relieving effects of cannabinoids, terpenes and flavonoids, among others, could be used therapeutically for inflammations in the oral cavity, oral cavity cancer and dental anxiety.
Cannflavin A and B might help with toothache because of their strong anti-inflammatory effects. Oral cavity carcinomas, which are characterised by an increased formation of oxygen radicals, could benefit from flavonols (e.g. quercetin, kaempferol), flavanones and anthocyanins. Synthetic antibiotics with their side effects and the risk of resistance development make natural dental hygiene products more and more interesting. There are already patents on cannabis-based preparations for dental hygiene and therapy of dental diseases .
Effects of other flavonoids and phenolic substances in cannabis
The flavonoid apigenin has an anti-anxiety effect and an anti-inflammatory effect by inhibiting TNF-alpha. In skin models, beta-sitosterol was shown to have an anti-oedematous effect and local anti-inflammatory effects: topical inflammation was reduced by 65 percent and chronic oedema (water retention) by 41 percent. In addition, there are other phenols in cannabis, but much less is known about them .
Other phenolic substances in cannabis are :
- Phenolic amides
For the therapeutic effect of cannabis, the entourage effect plays an essential role. The interaction of phytocannabinoids, terpenes and flavonoids could explain the wide range of medicinal effects. Scientific studies are increasingly showing positive evidence for medicinal cannabis in chronic pain and other conditions. However, how flavonoids contribute to medicinal effects is poorly understood. Computer models and studies on cell cultures and animals are optimistic. Clinical trials with patients will further investigate the therapeutic benefits of flavonoids. This research will reveal which ratios of active ingredients between cannabinoids, terpenes and flavonoids are beneficial for certain diseases. Thus, in time, science will realise how this millennia-old medicinal plant can act on pathological processes via its diverse substances. In the future, it may be possible to cultivate cannabis plants that are individually tailored to patients or specific diseases.
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