From Plant to Patient
Is it time for cannflavins to step out of CBD and THC’s shadow and into medicinal use?
There is no disputing that the Cannabis plant is a pharmacological treasure trove. Though CBD and THC dominate research (not to mention the public imagination), we would do well to remember there are an abundance of other metabolites – from phytocannabinoids and phenols to flavonoids and fatty acids – purported to have therapeutic properties, either alone or in conjunction with other compounds.
Take cannflavins, for example. First identified in 1980, cannflavins A (CFL-A), B (CFL-B), and C (CFL-C), as well as the CFL-B structural isomer isocannflavin B (IsoB), have been subject to promising preclinical research over the years. But, for reasons simple and complicated – one of which is that yield is often low, limiting the ability to produce enough compound for assessment in humans – they are yet to be translated to a medical setting.
To speed up the process, the Imperial Medical Cannabis Research Group performed a scoping review of all cannflavin articles on EMBASE, MEDLINE, Pubmed, CENTRAL, and Google Scholar databases. They identified 26 texts detailing the production, isolation, and potential translation of the compound into clinical use. The team hope that by identifying what we know so far – and, equally, what we don’t – we can better plan future research.
Q&A
We speak to Simon Erridge, Honorary Clinical Research Fellow in the Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, UK, about the study
Why has research into cannflavins been so limited since they were found in the ’80s?
There is a multitude of reasons, not least the sociopolitical challenges and barriers also faced in researching other compounds from the cannabis plant. Specific to cannflavins, however, is the fact that yield of dried cannabis plant for all cannflavins is very low [CFL-A (range: 0.000013–0.019%; study n= 7), CFL-B (range:0.00055–0.0064%; study n= 4), CFL-C (0.00014–0.00014%; study n=1)]. As a result, clinical translation through studying its clinical effects as an isolated compound seems unlikely.
Were you surprised by the extent of their anti-inflammatory properties?
To be honest, prior to conducting the review, we were already aware of cannflavins’ anti-inflammatory properties which, in some settings, have – if anything – been exaggerated.
What prompted our review was knowing that this group of compounds exists with potential therapeutic properties and wanting to understand why they have yet to be translated into the clinical setting. To do this, we examined the preclinical evidence for cannflavins not only in inflammation, but also in models of cancer, neurological, and infectious disease, to see what implications it may have clinically. This is in addition to assessing the published data on cultivation, extraction, and analysis.
Do we understand the mechanism behind this?
The mechanisms behind the anti-inflammatory activity of cannflavin-A and cannflavin-B are secondary to their inhibition of microsomal prostaglandin E synthase-1 (mPGES-1) and 5-lipooxygenase (5-LO).
mPGES-1 is an enzyme in the synthesis pathway of prostaglandin E2, a key prostanoid in proinflammatory processes, such as increasing vasodilation and vascular permeability to facilitate leukocyte infiltration – a hallmark of inflammation.
5-LO is an enzyme involved in the synthesis of leukotrienes, which are proinflammatory compounds implicated in a wide range of inflammatory diseases, most notably asthma and allergies.
You mention ideal growing conditions. What would these be?
Ideal growing conditions for cannflavin yield are areas of high solar radiation and cooler temperatures or artificial environments that recreate this. Obviously, not all seed varieties and potential chemovars were studied across this narrow range of literature, but the seed variety most associated with strong cannflavin yields is the Ermo variety.
However, a 2019 study by Rea and colleagues identified the biosynthetic pathway for cannflavin A and B formation, which may lead to bioengineering approaches that provide larger, more reliable yields.
What needs to happen for us to truly harness the therapeutic potential of cannflavins?
The way to truly harness the therapeutic potential of cannflavins is to demonstrate cannflavin production on a scale that is translatable into clinical research. Without this, scientists and funders will fail to see how cannflavins can become a finished pharmaceutical product. This will hopefully improve now that the synthetic pathway for cannflavins has been uncovered.
An alternative approach is to target areas of clinical translation that are less reliant on large-scale production. A good example of this, highlighted in our review, is the work by Moreau and colleagues at Harvard, who used smart radiotherapy biomaterials to deliver isocannflavin-B (the structural isomer of cannflavin-B) to pancreatic tumors in mouse models. Attaching isocannflavin-B to these materials helps target treatment to the cancer site, requiring less of the active compound. In these mouse models, isocannflavin-B attached to smart radiotherapy biomaterials reduced tumor size; adding radiotherapy also resulted in improved survival. Flavocure, who provided the isocannflavin-B for this study, has now planned phase I and II trials in human patients with pancreatic cancer.
What’s next for your research?
At the Imperial Medical Cannabis Research Group, our three main research themes are inflammation, cancer, and pain – which cannflavins encompass quite nicely. We are currently working on preclinical models of both pancreatic cancer and neuropathic pain using major phytocannabinoids; however, we welcome interested partners to get in touch. Let’s see how we can work together to move cannflavin research forward!
To get involved, please contact Simon at [email protected].
- S Erridge et al, Fitoterapia, 146, 104712 (2020). PMID: 32858172.
