Before We Get Started
On to Part II
What Are Flavonoids?
Flavonoids are chemicals that are based on the simple skeleton structure of “Flavan”. The structure is provided below. The term “Flavonoid” is based on the Latin term Flavus which means “Yellow”. Many of the colors exhibited by flavonoids are white, yellow, red, blue, purple and even black. Flavonoids can be divided into primarily seven (7) different groups: Flavans, Flavanols, Flavanones, Flavanonols, Flavones, Flavonols, and anthocyanidins. For the sake of simplicity, when we refer to these chemicals in the broadest of categories, we will use the term “Flavonoid(s)”. Flavonoids belong to a larger family of chemicals called polyphenols. Polyphenol is a common name for compounds that contain a phenyl or benzene ring with an alcohol or -OH, oxygen hydrogen, group. But wait, you may remember that the structure of CBD has two hydroxy, -OH groups, attached to its phenyl ring. Why is CBD called a cannabinoid and not a Flavonoid? See the structures below to compare CBD with a polyphenol, Flavan, and a flavonoid.
Flavonoids are defined by a special structural feature starting with the benzopyran ring, numbered 1 through 8 in the Flavan structure above, with a phenyl group attached at the number two or three position of the benzopyran ring. For all the pertinent flavonoids in cannabis, we will find the phenyl ring attached at the two position of the benzopyran ring. The phenyl ring is number 1’, one-prime, through 5’, five-prime. While CBD has a similar arrangement of hydroxy groups on its phenyl ring, like that in Apigenin, CBD does not contain the benzopyran ring, and therefore; it is not a Flavonoid. There are over 8000 polyphenols known and nearly 4,000 of these are flavonoids. There are about 25 major flavonoids found in cannabis. Cannabis flavonoids can only be found only in the buds, leaves, and stalk of the plant, but not in the seeds or roots. For us, the importance of flavonoids are their potential health benefits. A pyran ring is a cyclic six-member ring containing 5 carbons on one oxygen. Benzene is a cyclic six-member ring with 6 carbons. Benzopyran is represented as a ringed structure such that there are a total of 9 carbons and one oxygen in what is termed a “Fused Ring”. See the structure below.
In flavonoids, this 10-atom, fused structure of benzene and pyran, is called a “Benzopyran”. The numbering starts at the oxygen and goes clockwise around the structure, as shown in the example of Flavan. In Part II, we will be discussing those flavonoids that are in the categories of Flavones, Glycosylated Flavones, Flavonols, and Anthocyanidins. Notice these flavonoid terms, except for anthocyanidins, start with the prefix “Flavo-.” The term flavo- is used when the benzopyran ring contains a carbon-carbon double bond between the positions 2 and 3. When the double bond is absent, then the prefix will be “Flava-, as seen in the Part I discussion. The naming suffixes, -one and -nol, gives use a clue as to what is substituted on the pyran portion of the benzopyran ring, besides the phenyl group at the 2 position. The term “-nol” refers to a hydroxy group. The term “-one” refers to a carbon-oxygen double bond group. You will find in many flavonoids hydroxy groups attached to the fused benzene ring of the benzopyran group and the phenyl group attached at carbon number 2. The attached hydroxy groups are considered to be functional substitutions that do not impact the base name of the flavonoid. See the basic structures for the different categories of Flavonoids below.
Let’s look at the flavonoids found in cannabis and see what their potential health benefits are.
Cannflavin A, B, C and Isocannflavin B
Cannflavin A has a geranyl side group attached at the number 6 position; whereas, Cannflavin B has a dimethylallyl group at position 6. Cannflavin C has the geranyl group at the 8 position; whereas, Isocannflavin B has the dimethylallyl group at position 8 in the structure above. The pattern for numbering is given in Cannflavin A structure above and follows the rules for that found in Flavan, previously shown. Again, if you are just listening to this article, please come back to the American Green website and watch this article so that you can see the structures provided and how they are related. To continue, these Cannflavins are flavonoids that are produced exclusively in cannabis, hence the name “Cannflavins”. They primarily react or inhibit the inflammation pathways of prostaglandin; and therefore, they have analgesic/pain reducing effects about 5 times stronger than that of Aspirin or Tylenol on an equal weight basis of administration. Most of the research regarding analgesia has been centered on Cannflavin A. The mechanism for this analgesic effect is thought to be related to the cannflavin’s antioxidative properties. Cannabinoids and terpenes are also strong antioxidants and have analgesic effects. Therefore, the entourage effect of all three can exert an even stronger action for pain reduction, i.e., greater than the 5-fold reduction by Cannflavin A alone. But pain reduction is not the only health benefit to be derived from these cannflavins. The cannflavins have also been shown to be effective against cancers. Isocannflavin B has been the primary target of these studies, although, all the cannflavins exhibit anticancer properties. Isocannflavin B has been shown in animal models to be highly effective in combating pancreatic cancer, either by itself or in combination with radiation treatment. While the combined treatment of Isocannflavin B and radiation provides the best results, this cannflavin administered independently shows better outcomes compared to radiation alone. Refer to the work by Michele Moreau et al., July 2019 in the journal of Frontiers in Oncology, Vol. 9, p. 660. Pancreatic cancer is a difficult form of cancer to treat and the current survival rate is about 8%. To be called a cure, the patient needs to be free of cancer for a minimum of 5 years. Below is the biosynthetic scheme for the synthesis of Cannflavins starting from the amino acid Phenylalanine.
Chrysoeriol is found in cannabis and other plants such as Rooibos. Rooibos is generally made into a tea from its leaves. Chrysoeriol aids in blood circulation by defending against narrowing and hardening of the arteries. Chrysoeriol inhibits enzymes that contribute to these cardiovascular diseases. Regular consumption of Chrysoeriol has been linked to reduced blood pressure and a lower total cholesterol count.
Apigenin may induce muscle relaxation and sedation depending on the dose. It is also known for a number of other benefits such as being a strong antioxidant, having anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognitive-enhancing activities with a potential use in the treatment/prevention of Alzheimer’s Disease. Apigenin has demonstrated the ability to inhibit formation of β-amyloid-plaque which is responsible for the disease of Alzheimer’s. Apigenin is a very potent anti-cancer compound as well. It beneficially protects against a wide variety of cancers with high selectivity for cancer cells as opposed to non-cancerous cells. It also has a very high safety threshold. It has been suggested that an effective dose of Apigenin can be obtained through the consumption of vegetables and fruit. Apigenin, unfortunately, is unstable when isolated in pure form. It is, fortunately, stable in foods or other extracts.
Luteolin is an effective inhibitor of different hyaluronidases, enzymes which degrades hyaluronic acid. Hyaluronic acid, a heteropolysaccharide, is one the polymers that accounts for the toughness and flexibility of cartilage and tendon in and around our joints. Luteolin exhibits anti-spasmolytic effects, reduction of muscle spasms. Luteolin significantly inhibited both acetylcholine- and histamine-induced contraction of smooth muscle in the guinea pig model. Luteolin shows strong anti-histamine properties making it a good candidate for the reduction of allergenic responses. Luteolin displays anti-leishmaniasis activity. Leishmaniasis is a vector-borne disease that is transmitted by sand flies. Luteolin displays strong antinociceptic pain, pain which originates from peripheral nerves. The antioxidant potential of Luteolin is measured to be twice as strong as that of vitamin E and is significantly more potent than the synthetic antioxidant butylated hydroxytoluene (BHT), which is generally used in foods and medicines that require preservation from oxygen. Luteolin has strong scavenging properties for superoxide radicals. Luteolin is a potent physical quencher of singlet oxygen which causes single strand break in DNA. Chromosomal aberrations such as this are probably one of the causative factors in the formation of cancer. A study assessed the antioxidant potencies of several dietary flavonoids compared with vitamin C. When ranked in order of potency, luteolin was more effective than vitamin C and seven other flavonoids in reducing DNA oxidative damage. Luteolin has been shown to prevent LDL, Low-density lipoprotein, cholesterol oxidation; an effect that may reduce the risk of atherosclerosis.
Butin has similar properties to that of the other flavones. It has recently been investigated to possess significant cytoprotective properties on oxidatively, stress-induced mitochondria-dependent apoptosis (cell death).
Regulation of melanogenesis has been the focus of treatment for hyperpigmentary skin disorders. Hesperetin is thought to be a valuable photoprotective substance due to its capacity to increase melanin production in human melanocyte cultures. Hesperetin has also been reported to provide other health benefits such as antioxidative, anti-inflammatory and anticarcinogenic effects.
Additional Flavones and Their Associated Glycosylated Flavones
Glucose is the typical sugar found in glycosylated compounds. The glycosylation typically occurs at the 6 or 8 position of the benzopyran ring for various flavonoids. Numbering is shown on the Vitexin structure above. Glycosylation helps is the distribution and uptake of the unmodified flavonoids. Glycosylation can occur with any of the flavonoids discussed here and those in Part I.
One of the bioactive compounds, obtained from medicinal plants such as cannabis, is Orientin and is often used in various bioactivity studies due to its extensive beneficial properties. Orientin is Luteolin glycosylated at the number 8 position. Orientin exhibits many health benefits which include antioxidative, antiaging, antiviral, antibacterial, anti-inflammatory, vasodilatation, cardioprotective, radiation protective, neuroprotective, antidepressant activity, antiadipogenesis, and antinociceptive effects.
Isoorientin has similar properties to Orientin and is glycosylated at the number 6 position of Luteolin.
Vitexin is Apigenin glycosylated at the number 8 position. Vitexin is an active component found in many traditional Chinese medicines and more recently in cannabis. Vitexin has received increased attention due to its wide range of pharmacological effects, including, but not limited to, antioxidative, anticancer, anti-inflammatory, antihyperalgesic, and neuroprotective effects.
Isovitexin, is Apigenin that is glycosylated at the number 6 position and is an isomer of Vitexin. Generally, Vitexin and Isovitexin are purified together since they are difficult to isolate individually. Both Vitexin and Isovitexin exhibit diverse biological activities as mentioned above.
Flavonol differs from flavanol because there is a carbon-carbon double bond between the number 2 and 3 positions, in addition to a hydroxy group at the 3 position.
Kaempferol is a flavonol that has demonstrated abilities to reduce the risk of chronic diseases such as cancer. Kaempferol, having strong antioxidative properties, aids in the body’s antioxidant defense against free radicals. Kaempferol has been shown to modulate apoptosis (cancer cell death), angiogenesis (creation of new blood vessels), reduction of inflammation, and inhibition of cancer metastasis. The antioxidant effects have been shown to reduce the risk of developing cardiovascular disease. Kaempferol is useful in the treatment for symptoms of depression, like other cannabinoids.
Quercetin has similar properties to that of Kaempferol with regards to antioxidative properties and its potential health benefits. Quercetin is found in almost all vascular plants, including cannabis, providing anti-inflammatory, antimutagenic, antiviral, antifungal, neuroprotective, and, of course, antioxidative effects.
Galangin is found in cannabis, honey, and ginger. Galangin has antiviral, antimicrobial, and anticancer properties, without side effects. Galangin has been shown to have significant antihyperlipidaemic and antidiabetic properties. However, the underlying mechanism-of-action remains to be understood accurately. Galangin has been shown to be a strong antioxidant. It also has immunoprotective, cardioprotective and tumor-fighting properties.
Anthocyanidins are ionized forms of the flavonoids. A double bound exists between the oxygen at the number 1 position and the carbon at the number 2 position. There is also a carbon-carbon double bond between the positions 3 and 4. Typically, a protonated, plus charge, on an oxygen is not very stable. However, because of the arrangement of double bonds throughout the benzopyran ring, a resonance structure called aromaticity occurs, which provides stability to the protonation of oxygen in the benzopyran ring. Most anthocyanidins are isolated as chloride salts making them fairly water soluble.
Capensindin is found in cannabis and other plant materials, such as red grapes and dark colored berries such as raspberries, blueberries, and blackcurrants. Modern research has revealed that dietary consumption of flavonoids-rich foods significantly improves cognitive capabilities, inhibit or delay the senescence process, reduces loss in the ability for cell division due to age, and related neurodegenerative disorders including Alzheimer’s Disease (AD). The protective capacity that Anthocyanidins have has been shown to be mediated through the inhibition of cholinesterases including acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), β-secretase (BACE1), free radicals and modulation of signaling pathways. BACE1, a β-secretase, is recognized to be the enzyme responsible for the buildup of β-amyloid plaque in the brain which causes Alzheimer’s Disease. A more detailed discussion of flavonoids and Alzheimer’s Disease is discussed in Part I. Flavonoids such as Capensinidin interact with various signaling protein pathways providing beneficial neuroprotective effects. Moreover, they enhance vascular blood flow and instigate neurogenesis particularly in the hippocampus. Flavonoids also hamper the progression of symptoms for neurodegenerative diseases by inhibiting neuronal cell death induced by neurotoxic substances such as free radicals and β-amyloid proteins (Aβ). All these protective mechanisms contribute to the maintenance in the number and functionality of neurons and their synaptic connectivity in the brain. Thus, flavonoids like Capensinidin can thwart the progression of age-related disorders and can be a potential source for the design and development of new drugs effective in cognitive disorders.
Hirsutidin has similar properties as Capensinidin. In addition to that given above, another factor that promotes β-amyloid plaque buildup are proteins called “Tau” proteins. Several studies describe the effects of anthocyanidins against the formation of highly phosphorylated tau proteins, a pathological hallmark of Alzheimer’s Disease. Anthocyanidins have been reported to avert heparin-mediated tau formation. In other studies, using grape seed proanthocyanidin extract (GSPE), tau neuropathology was significantly reduced in animal models for Alzheimer’s Disease via inhibition of tau peptide aggregations. Hyperphosphorylation of tau proteins by several kinases is a major contributor for cognitive dysfunctions. Flavonoids such as Hirsutidin inhibit the activities of these kinases and thus aids in the prevention or slows the progression of Alzheimer’s Disease.
Cyanidin has properties similar to Capensinidin and Hirsutidin. Anthocyanidins are responsible for the deep color, mainly red, orange, blue and even black, of many plants and fruits. Cyanidin and its glycosides are very strong antioxidants and are active at pharmacological concentrations. The antioxidant activity is stronger than that of vitamin E, vitamin C and resveratrol. Cyanidin quickly neutralizes reactive oxygen species such as hydrogen peroxide, reactive oxygen and hydroxyl radical. A study in Japan by Takanori Tsua et al indicated that cyanidin may have benefits for the prevention of obesity and diabetes. Cyanidin reduces blood glucose level and improves insulin sensitivity due to the reduction of retinol binding protein 4 expression in type 2 diabetic mice. Many studies have demonstrated the anti-toxic effect of cyanidin, mainly against mycotoxins. Plants rich in anthocyanidins may help to control inflammation. Cyanidin, from Black Cherries, help alleviate arthritis and gout flair-ups in animal models, including human, and reduces the serum level of malonaldehyde, which is a biomarker to measure the level of oxidative stress. There are numerous studies demonstrating the anti-cancer activities of cyanidin. The anti-cancer and anti-mutagenic properties of Cyanidin is directly linked to its antioxidative properties. In vivo and in vitro studies link cyanidin to a reduced risk of leukemia, lung cancer, colon cancer, skin cancer and prostate cancer. In vitro refers to studies performed in cell cultures and test tubes, but not directly on human or animal models. In vivo refers to examining the efficacy of substances by direct administration to humans or animal models, like the people who volunteered to be guinea pigs for the Covid-19 vaccine trials. Cyanidin induces cancer cell apoptosis, reduces oxidative damage to DNA, inhibits cell growth and decreases cancer cell proliferation. Endothelial dysfunction causes the development of atherosclerosis, which can result in heart health problems, including stroke and heart attacks. Cyanidin increases the levels of endothelial nitric oxide synthase and heme oxygenase in a dose-dependent manner and inhibits the formation of reactive oxygen species induced by platelet-derived growth factor, a protein which has been linked to the development of atherosclerosis.
As indicated in the beginning of each discussion on cannabis flavonoids, Parts I and II, we see that there are several different types of flavonoids present in the plant. Flavonoids can act as protectorates of the plant based on colors that warn various predators of the dangers of chewing on their stalks, leaves, and buds. Remember, we discussed that some of the flavonoids produce rather irritating, acrid flavors. On the other hand, some of these flavonoids act as colorful billboards to attract insects and birds, not to eat the plant, but rather, to aid in pollination and seed dispersal. While there are many benefits for the plant, there are also many benefits for us to enjoy too. Many of the flavonoids we are discussing can be isolated in pure form and many are sold as nutritional supplements. While they are not gathered from cannabis at this time, the chemicals supplied are the same chemicals found in full and broad-spectrum cannabis isolates. While each of these flavonoids does show considerable activity, their effects can be enhanced through the entourage effect when full and broad-spectrum cannabis isolates are taken. Just a note of clarification, full-spectrum isolates refer to extracts of marijuana including terpenes and cannabinoids, such as THC, besides the flavonoids. Only in states allowing recreational or medical cannabis can you obtain full-spectrum products. Broad-spectrum isolates come from Hemp and can be obtains in all 50 states. The same is true for CBD isolates obtained from Hemp. Cannabinoids, terpenes and flavonoids all share some interesting capabilities, for instance their antioxidative properties. Since they share similar properties, the increase in the effect from one item is multiplied when taking a full or broad-spectrum isolate which contains cannabinoids, terpenes, and flavonoids. Remember the entourage effect does not help only one item, e.g., cannabinoids, but enhances the benefits from all items together, including flavonoids. If you are taking an isolate of CBD, you may want to think of adding not only terpenes to your dosing regimen, but also flavonoids of your choice to help bolster the effects from all three. The research regarding flavonoids is still somewhat in its infancy. We can expect to hear new and exciting findings for our health from cannabis flavonoids in the future.
What Are Flavonoids?
The term “Flavonoid” is based on the Latin term Flavus which means “Yellow”.
Many of the colors exhibited by flavonoids are white, yellow, red, blue, purple and even black.
Can Flavonoids Be Divided Into Groups?
How Many Flavonoids Are Found In Cannabis?
These cannabis flavonoids can only be found in the buds, leaves, and stalk of the plant, but not in the seeds or roots.