Cannabinoids in healthcare – what's the science, and why do we need to know?

Knowledge
29 Jun 2021

Over the past few years, there has been a significant rise in the volume and variety of phytocannabinoid products in mainstream shops, as well as in interest expressed from the general public surrounding their use for medicinal or health supplementary purposes. Coupled with this has been a similar rise in misinformation and misrepresentation of phytocannabinoids and their interactions with human physiology and subsequent health.

The volume of misinformation has created a cloud of confusion around cannabinoids and the science has been lost amidst it. As a result, there is very little clear understanding of phytocannabinoids or their interactions with the human endocannabinoid system, both of which have a potential impact on our understanding of neurological messaging in the body.

Keen to address this challenge, several experts in neurology and pharmacology held three targeted sessions at the European Academy of Neurology's annual meeting, the EAN Congress virtual 2021 this June. Sharing their expertise and experience, they highlighted a new science-based educational programme, Cannabinoid Education 360, and encouraged neurology professionals to clarify their understanding of the endocannabinoid system and its interactions with phytocannabinoids to better support patients in making safe and informed decisions.

The endocannabinoid system

An interactive webinar opened discussions at the EAN Congress 2021 to test healthcare professionals' understanding of the endocannabinoid system and its interactions with phytocannabinoids.

Hosted by Dr Marco Colizzi, Clinical Research Fellow in Psychiatry at the University of Verona, and Professor Cris Constantinescu, Professor of Neurology at the University of Nottingham, the session has been attended by over 480 people to date. It included a helpful overview of the human endocannabinoid system, the various functions it affects, and the interactions that phytocannabinoids - like those found in the cannabis plant - have with that system as well as with other biological systems.

'The endocannabinoid system is an important modulatory system in the function of brain, endocrine, and immune tissues'

Jan Komorowski, 2007, from Postepy Hig Med Dosw (Online), 2007;61:99-105.

The human endocannabinoid system is 'an important modulatory system in the function of brain, endocrine, and immune tissues' (Komorowski, 2007) making it an important element in neurological function. Cris outlined some of the many functions and roles of the system (fig 1), citing three core journal articles and noting the endocannabinoid systems' relative importance in a variety of neurological disorders (Di Marzo 1998, Stasiulewicz 2020, Hillard 2015).

As naturally occurring ligands of the endocannabinoid system, the 'endocannabinoids' (called anandamide and 2-AG) are released from the postsynaptic terminals of nerves, binding to the CB1 and CB2 receptors on the presynaptic terminal - as well as other to targets in the body - regulating neurotransmitter release. This is called 'retrograde neurotransmission'. They are carefully controlled by enzymes - anabolic enzymes which synthesise the endocannabinoids, and catabolic enzymes which degrade them.

Figure 1: 'Physiological processes and functions that the endocannabinoid system (ECS) takes part in'

(Image reproduced from Stasiulewicz 2020 in the International Journal of Molecular Sciences)

Phytocannabinoids interact with the endocannabinoid system either directly, such as with tetrahydrocannabinol (THC) which is a partial agonist of CB1 and CB2 receptors, or indirectly as with cannabidiol (CBD), which is an allosteric modulator of the CB1 receptor and mainly acts outside the endocannabinoid system. This means that THC directly activates the receptors but to a lesser extent than the body's own endocannabinoids. CBD, however, has a low affinity for CB1 or CB2 receptors, and indirectly affects the system by binding to an allosteric site, influencing the agonists (usually neurotransmitters) which are binding to the receptors, and modulating their activity.

CB1 receptors are predominantly found in the brain, whilst CB2 receptors are mostly expressed in immune cells, although the presence of both is widespread throughout the body (fig 2). Cris also noted the variety of cell types that the receptors can be found in, including glial, adipose, skeletal and immune cells (including lymphocytes), as well as in presynaptic terminals throughout the central nervous system.

'The location of the cannabinoid receptors is crucial to the high number of functions performed by the endocannabinoid system including at peripheral sites.'

Dr Marco Colizzi, Clinical Research Fellow in Psychiatry, University of Verona

From the interactive questions with their audience at the EAN, it was apparent that understanding around the endocannabinoid system and its interactions with phytocannabinoids was not widespread; just a third of live attendees responded correctly to a multiple choice question around the phytocannabinoid THC and its action at a receptor site.

Figure 2: The predominant placement of CB1 and CB2 receptors throughout the body

'Do no harm'

Elinor Ben-Menachem, Professor of Neurology at the University of Gothenburg reiterated the physicians' code to 'do no harm' more than once during her discussion around the importance of an evidence-based approach. Talking with Philippe Ryvlin, Professor of Neurology at the University of Lausanne, they discussed in detail the safety of cannabinoid use, the potential risks associated with cannabinoid THC particularly, and the importance of understanding the long term implications of any treatment before prescribing it. Indeed, these areas featured in all three sessions during the EAN congress.

'Natural means safe' was a misconception fully explored by Dr Amir Englund, psychopharmacologist at King's College London. He discussed in detail the potential health risks of cannabinoid use whilst tackling 'the Big Questions' with colleague Professor Andreas Schulze-Bonhage of the University Medical Centre, Freiburg.

Amir referenced just a few natural substances known to be dangerous, including certain mushrooms, tobacco, and even apple pips thanks to their low levels of cyanide. He also pointed out that all medications come with side-effects or potential risks. The health risks associated with very high levels of THC, for example, as found in medical and recreational cannabis, include an increased risk of psychosis, cognitive or attention impairment, loss of fine motor skills, and potential infant defects where pregnant or breastfeeding mothers are taking high doses. However, he also noted that there are less health risks or risk of mortality associated with THC than with alcohol, for example.

'No drug is completely safe, and the harm of the drug is relative. If we compare THC with alcohol, THC is not as linked to significant health conditions such as alcohol is, where alcohol is related to heart conditions and cancers, and acute over-intoxication can lead to death.

So far, we do not have an incidence of someone taking too much THC and having died from it, so it's not toxic in the same way - rather it is a risk factor for developing addiction and psychotic illness - but harms are always relative.'

Dr Amir Englund, psychopharmacologist, King's College London

Marco Colizzi and Cris Constantinescu questioned their audience on the modification of cannabinoid levels in cannabis and found that just 10% of the audience knew that genetics were the main determinant of the phytocannabinoid profile in cannabinoid plants. They were clear that this is important to note because of the ability to influence the concentration of specific cannabinoids such as THC or CBD. This ability has been utilised by recreational cannabis growers to increase the quantity of THC cannabinoids in their plants. A report from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) found that the concentration of THC in herbal recreational cannabis rose from around 5% in 2005 to around 10% in 2016 (EMCDDA, 2019).

Marco and Chris noted that other factors such as environment and manufacturing can also influence the profile to a lesser degree. Changes in light, growing, picking and drying are all able to impact the profile of the plant, making it difficult to maintain a reliable and controlled drug in studies - something Elinor and Philippe examined further in their session.

The importance of evidence-base

Any and every treatment used to support health should be subject to scrutiny and have a clear evidence-base. However, cannabinoid use can be cited as a plant-based supplement rather than a medicinal treatment. This enables its marketability without substantial clinical trials to back its efficacy, leaving its production open to far looser standards of manufacturing - something which Amir Englund shared in detail.

He highlighted that non-medical phytocannabinoid products do not follow the strict regulatory and manufacturing processes that a medicinal product must. As a result there are often discrepancies between the doses cited on the label and those contained in the procut. There is also little clinical testing or batch testing for quality control, and few regulations around manufacturing, leading to an increased potential for contamination or impurities. Amir cited a particular European example where carcinogens were found in a cannabidiol consumer product as a result of overheating during manufacture. This example is far from exceptional, however - the issue is widespread as demonstrated by a study published in JAMA (Vandrey, 2015) and a report from the International Cannabis and Cannabinoids Institute (ICCI) in 2016.

Professors Philippe Ryvlin and Elinor Ben-Menachem dedicated their session to the importance of developing a firm clinical evidence-base for the medicinal use of phytocannabinoids. This need, they agreed, is growing rapidly in correlation to the widespread discussions about, and use of, non-prescribed phytocannabinoid-based products to supplement health or to independently manage a widening array of health problems.

They outlined the differing forms of evidence gathering, from clinical trials and randomised controlled tests to public usage and commented on the various challenges that arise with all medical testing. These include the placebo effect, how representative a sample is, the deleterious effects of interpreting uncontrolled data such as social media reports, and the importance of longer-term and widespread testing.

They shared the need for caution, even in reviewing carefully trialed treatments. Citing the example of the recent COVID-19 vaccine produced by Astra-Zeneca and the side-effect of blood clotting amongst a small proportion of young females treated, they noted that even in clinical trials, not all side-effects or health implications of a treatment will come to light.

Support to patients and collaborative care

Both Elinor and Phillipe spoke of the often emotive aspect to discussing use of phytocannabinoid products with patients. Elinor highlighted that often, patients wish to discuss these products hoping for a panacea, because they have not responded to other options, or perhaps because they are trying to manage a side-effect of another medication.

In these circumstances, they felt that a physician ought to take time to review the evidence-base available currently alongside their patient, ensuring they have access to the most relevant data, but allowing the patient themselves to make the final decision. Educational site Cannabinoid Education 360 can help to support this need, with science-based information available for both healthcare professionals and the public.

'Social media has really taken over the role of science in many respects... [People] hear a significant amount of information which may be misinformation in the media, especially concerning powers of medication… Everybody is out there looking for a panacea…

Patients then come to us for approval when they are taking an unapproved medication and we have to be prepared to answer using evidence-based information.'

Prof Elinor Ben-Menachem, Professor of Neurology, University of Gothenburg

Ensuring that patients are also aware of the lack of regulation in non-medical phytocannabinoid supplements and products, and that they understand the effect this can have on quality of product and accuracy of labelling, is also important.

Another reason that open conversations with patients is essential around phytocannabinoid use is the potential interactions that it can have with other medications. The phytocannabinoids THC and CBD are both metabolised via the liver's cytochrome P450 system, which has implications because many other drugs are metabolised in this way. Cris Constantinescu was very specific about the potential complexity of this, noting that 'there are 139 medications that interact with these drugs and this will have an influence on the levels of the cannabinoids.'

This interaction may be further affected by the method of administration that a patient is choosing. Different products are taken in different ways, and the differences in ingestion versus inhalation have been studied. Both Amir and Cris touched on how inhalation causes a rapid onset of five to 10 minutes with a short duration and high peak, whilst ingestion causes a slower onset of one to two hours, along with a longer duration and lower peak in plasma concentrations.

Conclusion

It has been clear from the information shared and viewpoints expressed during the EAN congress 2021 that healthcare professionals have relatively low levels of understanding about the endocannabinoid system and cannabinoids in general, yet that this system has a widespread impact on many biological functions. This includes neurological function and interaction with prescribed medications, and it is clear that this growing field is one which healthcare professionals need to have a sound knowledge of.

There is a clear need for improved education and science-based information across biological function, clinical testing, interactions with other medications, and quality and regulatory elements of production. Ensuring that everyone has access to accurate, relevant, unbiased and clear information, such as provided via Cannabinoid Education 360, is an important first step.

The EAN symposia mentioned in this report were initiated and funded by Cannabinoid Education 360 (developed by GW Pharmaceuticals). This report has been supported by sponsorship from Cannabinoid Education 360. Whilst the sponsor has reviewed the content of this report for medical and scientific accuracy, they have had no further input in the educational content of this activity.

References

  • Komorowski J, Stepień H. Rola układu endokannabinoidowego w regulacji czynności dokrewnej i kontroli równowagi energetycznej człowieka [The role of the endocannabinoid system in the regulation of endocrine function and in the control of energy balance in humans]. Postepy Hig Med Dosw (Online). 2007;61:99-105. Polish. PMID: 17369778.

  • Di Marzo V, Melck D, Bisogno T, De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1998 Dec;21(12):521-8. doi: 10.1016/s0166-2236(98)01283-1. Erratum in: Trends Neurosci 1999 Feb;22(2):80. PMID: 9881850.

  • Stasiulewicz A, Znajdek K, Grudzień M, Pawiński T, Sulkowska AJI. A Guide to Targeting the Endocannabinoid System in Drug Design. Int J Mol Sci. 2020 Apr 16;21(8):2778. doi: 10.3390/ijms21082778. PMID: 32316328; PMCID: PMC7216112.

  • Hillard CJ. The Endocannabinoid Signaling System in the CNS: A Primer. Int Rev Neurobiol. 2015;125:1-47. doi: 10.1016/bs.irn.2015.10.001. Epub 2015 Nov 6. PMID: 26638763; PMCID: PMC6813823.

  • European Monitoring Centre for Drugs and Drug Addiction, 'Developments in the European cannabis market' EMCDDA, Lisbon, June 2019 accessed at www.emcdda.europa.eu/publications/emcdda-papers/developments-in-the-european-cannabis-market

  • Vandrey R, Raber JC, Raber ME, Douglass B, Miller C, Bonn-Miller MO. Cannabinoid Dose and Label Accuracy in Edible Medical Cannabis Products. JAMA. 2015;313(24):2491–2493. doi:10.1001/jama.2015.6613

  • Jakub Večerka, 'Warning for consumers of CBD and cannabis oils sold on the EU market', International Cannabis and Cannabinoids Institute (ICCI), 16 February 2018

Citations specifically for figure 2:
  • Zou 2018,'Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System', Int J Mol Sci. 2018 Mar; 19(3): 833. Published online 2018 Mar 13. doi: 10.3390/ijms19030833

  • Mackie, 'Cannabinoid Receptors: Where They are and What They do', Journal of Neuroendocrinology, First published: 17 April 2008, doi.org/10.1111/j.1365-2826.2008.01671.x

  • Kaur R, Ambwani SR, Singh S. Endocannabinoid System: A Multi-Facet Therapeutic Target. Curr Clin Pharmacol. 2016;11(2):110-7. doi: 10.2174/1574884711666160418105339. PMID: 27086601.

  • Dhopeshwarkar A, Mackie K. CB2 Cannabinoid receptors as a therapeutic target-what does the future hold?. Mol Pharmacol. 2014;86(4):430-437. doi:10.1124/mol.114.094649

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