From CBD to Cytochrome.

The liberal use of the term “CBD”, cannabidiol, has been thefoot in the door for cannabis medicine and the industry that underpins it. We have seen a social media craze of whacky and wonderful products that have been combined with CBD.

Society has undergone a remarkable cannabis transition in a little as 3 years. It feels like almost yesterday thatpeople were terrified to even follow cannabis-related social media pages forfear of professional backlash. Fast forward as little as 3 years and even grandparents are now indulging in cannabis products.

Cannabis has generated a great deal of business attention,but this excitement has been accompanied by a great deal of confusion. This new wave of health supplements has made its way into high streets across the UK and Europe. Dousing scores of people in CBD through a plethora of products and formulations. Although cannabis is an ancient servant to humanity, society remains highly na?ve to cannabis products, their safety, and their use.

Much of the cannabis industry we see today is based aroundjust two of the 1000+ phytochemicals that reside in cannabis: cannabidiol(CBD); and tetrahydrocannabinol (THC). All progress thus far has been madethrough a primary focus on these two phytocannabinoids, just a tiny fraction ofthe plant’s potential. CBD is just the tip of the iceberg.

Figure1. The Cannabis industry iceberg.

THC and CBD have exciting therapeutic and recreational properties,but this is by no means the extent of cannabis. Before humans even knew of the existence of THC and CBD, cannabis still played a historic role in thedevelopment of our modern world. Beyond the tides of surface-level mainstream informationand marketing language, there is a wealth of cannabis potential that has so fargone unexplored.

The cannabis debate can be reduced to two fundamentals: cannabis and people. The two encompass all of the complex intertwining relationships in between. However, the vast majority of this has gone overlooked. A great deal of conversation focuses on cannabis as a substance and particularly, CBD. As a result, there has been little to no exploration of thehuman element, i.e., the endocannabinoid system (ECS), a biological network ofendogenous neurotransmitters that bind to cannabinoid receptors. This would besomewhat comparable to us having discovered blood but not fully understandingthe cardiovascular system or launching an insulin industry whilst being unawareof the pancreas.?

A great deal of white and static noise fills the mainstream cannabis ‘conversation’. The public has been vulnerable to rogue claims around cannabis, whether regarding its products or the surrounding market. Patients in particular are susceptible to overzealous marketing. Medical advertisements are known to contain inaccurate information, designed primarily to be more promotional than educational (Sansgiry, Sharp and Sansgiry, 1999). Imagine the scale of this divergence from fact in less regulated markets such as cannabis, crypto, and psychedelics.

News and media stories have been statistically shown to include inadequate information on the benefits, risks,and costs of drugs. This extends to neglecting to mention the financial ties between research groups and pharmaceutical manufacturers (Moynihan et al.,2000). Furthermore, we should also consider that those reporting on research may lack the relevant academic or clinical experience or fail to declare conflicts ofinterest (Wang, Grey and Bolland, 2017). It is therefore important that consumers and industry operators are well versed in separating reliable knowledge from fictitious claims. If unchecked, these claims have the potential to augment and not only negatively impact the progress of the industry but the health of our population. Unreliable claims about the benefits and harms of cannabis are widespread.

One of the biggest risks at current is the use of over-the-counter CBD products by patients. Though cannabis products are extremely safe, certain sections of the population that are prescription medications may have unintended side effects.

One particularly powerful group of enzymes, known as cytochrome P450 (CYP450), play a key role in processing cannabis compounds. There are >300,000 protein have been sequenced from the CYP450 enzyme family which is comprised of over 50 enzymes, these are predominantly found in the liver (Lynch and Neff, 2007; Nelson, 2018). This enzyme group is responsible for the activation, degradation, andchemical alteration of roughly 75% of all drugs used in medicine (Guengerich, 2008). A large number of cannabinoids interact and operate through this CYP450, as do many other conventional drugs (Zendulka et al.,2016).

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Figure 2. Percentages represent the relative participationof individual CYP isoforms in metabolism. CYP isoforms are represented asindividual X-ray structures (?rejber et al.,2018).

Interestingly, prescription medication users are typically told toavoid grapefruit. The reason for this is that the furanocoumarin (flavonoid)compounds in grapefruit can affect this CYP450 group, inhibiting or modifyingtheir activity, and potentially provoking toxic effects (Fuhr, 1998).

Cannabinoids have a strong metabolicrelationship with two other major cytochrome groups, the CYP3A4 and CYP2D6 enzymes, among several others (Yamaori et al.,2011; Stout and Cimino, 2014; Bouquié etal., 2018). These two enzymes metabolise many drugs, such as antidepressants, antihistamines, andanti-cancer drugs. CBD is an inhibitor of the CYP2C19 subfamily. Concomitant administration of CBD can significantly change serum levels of topiramate,rufinamide, clobazam, eslicarbazepine and zonisamide in patients withtreatment-resistant epilepsy (Gaston et al.,2017).?

CYP3A4 enzymes:?CYP3A4 is responsible for around half of cytochrome metabolism (Zanger and Schwab, 2013). CBD’s ability to inhibit the activity of this enzyme may increase serum concentrations of many drugs including macrolides,calcium channel blockers, benzodiazepines, cyclosporine, sildenafil,antihistamines, haloperidol, antiretrovirals and some statins (Arellano et al.,2017).Interestingly, other substances such as grapefruit juice can also interfere with CYP3A4’s activity (Bailey et al.,1998).

CYP2D6 enzymes: Thisgroup of enzymes metabolise many antidepressants, but are inhibited by CBD, THCand CBN. They may, therefore, increase serum concentrations of SSRIs, tricyclic-antidepressants, antipsychotics, beta-blockers and opioids (including codeineand oxycodone) (Yamaori et al.,2011).

Opioids such as codeine are also metabolised by CYP2D6, which has seen it become atarget for the treatment of codeine dependence (Romach et al.,2000).

Knowledge of these enzymatic interactions is certainly not mainstream. These seemingly insignificant caps in understanding have the potential to be incredibly costly for all involved. If education and awareness are not consciously established pillars to our industry, there may be large-scale implications in the near future that stem from these knowledge gaps. The endocannabinoid system remains a tremendous unknown in CBD and cannabis science and so it’s important to consider that we truly do not understand the implication of this new wave ofcannabinoid use and its impact on our physiology.

The downstream implications of our ignorance on the well-being of consumers are something to be seriously considered. As an industry, we have toeducate ourselves and our customers. Ensuring our staff is well informed can adequately preparing consumers for safe consumption. Education is certainly not just a defensive measure but a foundation that can drive your business forward. This industry is riddled with obstacles, and these hurdles are constantly evolving.

The growing reach of cannabis is apparent. The focus now needs to be on creating a sustainable path forward that preserves and strengthens this infant industry.

Awareness and education are key to supporting informed decisions at all levels of society. We must also understand that knowledge is an evolving entity, continually adapting and growing. This process is accelerated bymerging knowledge with diverse sources and overlapping understandings.

In our mission to inform the future of the cannabis industry, the GCS team has developed a series of educational tools to tackle some of these risks to our industry but also risks to our communities.

You can explore our range of educational products via the GCS website and see how you can strengthen our industry and your business.

??www.globalcannabinoidsolutions.com

References

Arellano, A. L. etal. (2017) ‘Neuropsychiatric and General Interactions of Natural andSynthetic Cannabinoids with Drugs of Abuse and Medicines’, CNS &Neurological Disorders - Drug Targets. Bentham Science Publishers Ltd.,16(5), pp. 554–566. doi: 10.2174/1871527316666170413104516.

Bailey, D. G. et al. (1998) ‘Grapefruit juice-drug interactions’, BritishJournal of Clinical Pharmacology. Blackwell Publishing Ltd, pp. 101–110.doi: 10.1046/j.1365-2125.1998.00764.x.

Bouquié, R. et al. (2018) ‘Cannabis and anticancer drugs: societalusage and expected pharmacological interactions – a review’, Fundamental andClinical Pharmacology. Blackwell Publishing Ltd, pp. 462–484. doi:10.1111/fcp.12373.

Fuhr, U. (1998) ‘Drug interactions with grapefruit juice: Extent, probablemechanism and clinical relevance’, Drug Safety. Springer, 18(4), pp.251–272. doi: 10.2165/00002018-199818040-00002.

Gaston, T. E. et al. (2017) ‘Interactions between cannabidiol andcommonly used antiepileptic drugs’, Epilepsia. Blackwell PublishingInc., 58(9), pp. 1586–1592. doi: 10.1111/epi.13852.

Guengerich, F. P. (2008) ‘Cytochrome P450 and chemical toxicology’, ChemicalResearch in Toxicology, pp. 70–83. doi: 10.1021/tx700079z.

Lynch, T. and Neff, A. P. (2007) ‘The Effect of Cytochrome P450 Metabolismon Drug Response, Interactions, and Adverse Effects’, American FamilyPhysician, 76(3), pp. 391–396. Available at: www.aafp.org/afp. (Accessed: 3August 2021).

Moynihan, R. et al. (2000) ‘Coverage by the news media of thebenefits and risks of medications’, New England Journal of Medicine. NEngl J Med, 342(22), pp. 1645–1650. doi: 10.1056/NEJM200006013422206.

Nelson, D. R. (2018) ‘Cytochrome P450 diversity in the tree of life’, Biochimicaet Biophysica Acta (BBA) - Proteins and Proteomics. Elsevier, 1866(1), pp.141–154. doi: 10.1016/J.BBAPAP.2017.05.003.

Romach, M. K. et al. (2000) ‘Cytochrome P450 2D6 and treatment ofcodeine dependence’, Journal of Clinical Psychopharmacology. J ClinPsychopharmacol, 20(1), pp. 43–45. doi: 10.1097/00004714-200002000-00008.

Sansgiry, S., Sharp, W. T. and Sansgiry, S. S. (1999) ‘Accuracy ofinformation on printed over-the-counter drug advertisements’, HealthMarketing Quarterly. Health Mark Q, 17(2), pp. 7–18. doi:10.1300/J026v17n02_02.

?rejber, M. et al. (2018) ‘Membrane-attached mammalian cytochromesP450: An overview of the membrane’s effects on structure, drug binding, andinteractions with redox partners’, Journal of Inorganic Biochemistry.Elsevier, 183, pp. 117–136. doi: 10.1016/J.JINORGBIO.2018.03.002.

Stout, S. M. and Cimino, N. M. (2014) ‘Exogenous cannabinoids assubstrates, inhibitors, and inducers of human drug metabolizing enzymes: Asystematic review’, Drug Metabolism Reviews, pp. 86–95. doi:10.3109/03602532.2013.849268.

Wang, M. T. M., Grey, A. and Bolland, M. J. (2017) ‘Conflicts of interestand expertise of independent commenters in news stories about medicalresearch’, CMAJ. Canadian Medical Association, 189(15), pp. E553–E559.doi: 10.1503/cmaj.160538.

Yamaori, S. et al. (2011) ‘Cannabidiol, a major phytocannabinoid,as a potent atypical inhibitor for CYP2D6’, Drug Metabolism and Disposition,39(11), pp. 2049–2056. doi: 10.1124/dmd.111.041384.

Zanger, U. M. and Schwab, M. (2013) ‘Cytochrome P450 enzymes in drugmetabolism: Regulation of gene expression, enzyme activities, and impact ofgenetic variation’, Pharmacology and Therapeutics. Pergamon, pp.103–141. doi: 10.1016/j.pharmthera.2012.12.007.

Zendulka, O. et al. (2016) ‘Cannabinoids and Cytochrome P450Interactions’, Current Drug Metabolism. Bentham Science Publishers Ltd.,17(3), pp. 206–226. doi: 10.2174/1389200217666151210142051.

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