What are flavonoids?

The Cannabis Sativa plant produces hundreds of chemical compounds, but only two of them have dominated the medical cannabis scene up until now: THC and CBD. They are the most abundant compounds, which makes them the most commercially viable and easiest to study.

Research studies on the possible medical applications of these cannabinoids continue to demonstrate their effectiveness in reducing inflammation. But THC and CBD are not the only compounds with anti-inflammatory properties. In fact, it is likely that they are not the most potent analgesics found in cannabis. This could well be the place of a different family of compounds called flavonoids.

What are flavonoids and what do they do?

Like terpenes, flavonoids are a type of secondary metabolites, also known as natural products, that influence our perception of cannabis through our senses. We often attribute marijuana's characteristic flavours and aromas to terpenes; however, flavonoids also provide qualities that bestow the distinguishing differences between marijuana's countless strains. In fact, cannabis owes its smell and taste to the synergistic properties of both terpenes and flavonoids.

Flavonoids are chemical substances found in all plants, and not only in cannabis. They are responsible for pigmentation in fruits and vegetables. There exist around 6,000 flavonoids in total, and about 20 of them are unique to cannabis (known as cannflavins). The main function of cannflavins is to add colour to marijuana's leaves and flowers in order to protect them from ultraviolet radiation and to attract insects for pollination purposes.

Generally speaking, flavonoids provide any color other than green. For instance, the flavonoid responsible for those beautiful purple tones in some marijuana plants is anthocyanin, which is also present in fruits of the forest and is responsible for purple, red, and blue hues.

Medical properties of flavonoids

Flavonoids have been proven to hold powerful antioxidant properties. This is the reason why some nutritionists state that we should choose food, particularly fruits and vegetables, for their colour. Moreover, when a plant is identified as a 'superfood', this is partly due to its flavonoid concentration.

Quercetin is the most common and abundant flavonoid in the human diet. It is found in broccoli, onions and tomatoes, and showcases antifungal and antioxidant properties. Catechin is also common; it can be found in green tea and cocoa, and assists to maintain cardiovascular health.

Flavonoids are known for their antioxidant power but also provide other benefits to human health. In 1979, two flavonoids specific to Cannabis Sativa were discovered: cannflavin A and cannflavin B; and they immediately captured the interest of scientists.

In a 1985 research study, scientists discovered that cannflavins A and B's anti-inflammatory properties were approximately thirty times more effective than aspirin's, one of the most common analgesics.

Almost three decades later, in 2014, scientists published another study validating cannflavins A and B's efficiency; they also discovered that these work to block the production of two chemical compounds that encourage inflammation in animal cell models. In short, cannflavins A and B stop inflammation at a cellular level.

Nonetheless, despite these important findings, hardly anyone paid attention to how Cannabis Sativa synthetizes these non-psychoactive cannflavins. Identifying the therapeutic properties of flavonoids is only half of the equation; the other half is how to produce medical drugs with them. The fact that flavonoid concentrations are so low only makes this process even more difficult.

Cannabis genome as a solution

Cannflavins are present in 0.014% of the plant's fresh weight; therefore, in order to benefit from them, they would need to be ingested in massive quantities. Scientists at the University of Guelph in Ontario, Canada, believe that they have found a way to use genome mining to extract the genes that create cannflavins, in order to then metabolically design them without having to grow the plant.

With this purpose in mind, it is possible to study the Cannabis Sativa genome, which, like many other sequenced genomes, is available to the public. The genome can subsequently be used to bring genes to life using biochemical methods and to then reassemble the molecules of interest, in this case those of cannflavins A and B.

Drugs based on these two compounds could theoretically transform the way in which we treat pain, as "what's interesting about these molecules is that they actually stop inflammation at the source… And most natural products don't have the toxicity that's associated with over-the-counter pain relief drugs", states Tariq Akhatar, assistant professor at the University of Guelph and coauthor of this study.

Exactly. Cannabis-based drugs do not target opioid receptors like many analgesics that are currently prescribed. This means that they are not likely to cause addiction or an overdose. Moreover, they are not considered NSAIDs (Nonsteroidal anti-inflammatory drugs), like aspirin or ibuprofen, which can cause dangerous complications in pregnant women or patients who take anticoagulant drugs such as heparin.

The health industry is facing the challenge of finding alternative pain-relief drugs without the risks of many opioid-containing drugs, which have already provoked a health crisis in the U.S. As far as we know, cannflavins do not produce any secondary effects as they treat the inflammation at the source. And, according to the available research, they do it in a safer and more effective way than aspirin.

Flavonoids and the 'entourage effect'

But this is not the only thing about flavonoids that is being studied. They are also believed to boost or slow down the effect of cannabinoids, like CBD and THC, in the endocannabinoid system. In fact, flavonoids are non-psychoactive; their effect is similar to that of cannabidiol, so they could help reduce the high produced by cannabis.

This is known as the 'entourage effect', a term introduced by the chemist Raphael Mechoulam in 1998 that refers to the effect of other cannabis compounds, such as terpenes and flavonoids, and how, for instance, they can eliminate the anxiety derived from tetrahydrocannabinol's psychoactivity.

Finding the technology to study the synergy between the different compounds found in cannabis, as well as to study methods for harvesting and synthesizing them, could radically transform the medical sector. Therefore, it is vital that cannabis is legalized so that further research can be carried out for a better understanding of the role of flavonoids in human health.

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References:

- Biosynthesis of cannflavins A and B from Cannabis Sativa. Kevin A. Rea, José A. Casaretto, M. Sameer Al-Abdul-Wahid, Arjun Sukumarana, Jennifer Geddes, Tariq Akhtar. Phytochemistry 2019.

- Cannflavins from hemp sprouts, a novel cannabinoid-free hemp food product, target microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase. Oliver Werza, Julia Seegers, Anja Maria Schaible, Christina Weinigel, Dagmar Barzc, Andreas Koeberle. PharmaNutrition 2014.

- Flavonoid variation in Cannabis L. M. N. Clark, B. A. Bohm. Botanical Journal of the Linnean Society, 1979