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In November 2018 the British Home Office made the prescribing of Cannabis on the NHS legal in certain restricted circumstances. In the same year Canada became the second country to legalise Cannabis for recreational use. Similarly, in the USA, Cannabis is legal for recreational use in some states and in others for use in certain medical conditions. As society has become more progressive the subject of Cannabis or Marijuana has slowly slid in to an acceptable window of public discussion, yet still remains a burning political hot potato. For centuries chemists have harnessed the power of what mother nature had provided, distilling it to enhance the benefits and formulating it in to medicines, take digoxin from the foxglove plant as an example. Is it now time for those twentieth century taboo substances to have the same fate?

This is part of a wider theme of breaking the mould with previously untouchable substances. For example, according to MAPS (multidisciplinary association for psychedelic studies) on August 16 2017 the FDA approved Breakthrough Therapy Designation to MDMA for the treatment of PTSD in Phase 3 clinical trials with exciting results being born out the earlier phases of testing.

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It seems a cultural tide is shifting

Anecdotal evidence of the efficacy of Cannabis for a whole heap of aliments isn’t hard to find and stretches back 1000’s of years (4). Insomnia, cancer, chronic pain, Multiple sclerosis and epilepsy are some of the pathological claimants shouting the loudest.  But whether any of this stands up to rigorous clinical testing isn’t yet known.

Numerous early studies have suggested the endocannabinoid system plays an important role in appetite regulation, GI motility and secretion, peripheral energy metabolism, obesity and associated metabolic systems, pain and inflammatory response, neuroprotection, nausea, emesis and motor function (4). This poses multiple possible therapeutic targets within the endocannabinoid system and modulation of certain targets in some studies has produced interesting results.

Anecdotal evidence of the efficacy of Cannabis for a whole heap of ailments isn’t hard to find and stretch back 1000’s of years.

Pharmacological activity of the Cannabis plant itself is complex, containing over 80 terpenophenolic compounds called cannabinoids. (1) The largest constituents of these being THC and CBD, tetrahydro-cannabinol and cannabidiol respectively. Depending on the strain of the plant the proportion of these two compounds can vary drastically and thus alter the pharmacological properties of the strain (2).

THC is the compound responsible for the psychoactive properties, affecting information processing, sensory perception and memory, leading to the ‘high’ commonly associated with smoking or ingestion of the Cannabis plant. There are two endogenous cannabinoid receptors found within the body, CB1 and CB2. CB1 is the most abundant receptor in the mammalian brain (4) and is largely located within the CNS. It is the site in which the psychoactive effects of THC are derived. CB2 receptors are mainly located within immune and hematopoietic cells among others. Interestingly a metabolite of THC, ajulemic acid, was found to have ‘potent anti-inflammatory and analgesic properties without any overt behavioural or psychoactive effects (4)’.

So far, the story of Cannabis mirrors that of opium in the 20th century. Recreational opium use, the discovery of opium receptors and then the discovery of endogenous opioids leading to pharmacological and therapeutic understanding.

CBD has little to no effect at CB1 or CB2 receptors (4). However, its hypothesised that the main therapeutic effects of cannabis come from this exogenous cannabinoid such as anticonvulsant activity (6). This is important as the political will in the UK to bring Cannabis to  medical use was largely through cases in which children had intractable epilepsy but responded to Cannabis treatment. The pharmacological explanation for this is yet unknown.

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In comparison the synthetic cannabinoid Nabilone is both a CB1 and CB2 receptor agonist (4) and is already licensed forNausea and vomiting caused by cytotoxic chemotherapy, unresponsive to conventional antiemetics (5)’. Moreover Sativex, a mixture of synthetic and naturally derived cannabinoids holds a licensed in the UK for ‘Adjunct in moderate to severe spasticity in multiple sclerosis (5)’.

It follows that the body produces endogenous cannabinoid receptor ligands and the best known of these are anandamides and 2‐arachidonoylglycerol (3). So far, the story of Cannabis mirrors that of opium in the 20th century. Recreational opium use, discovery of opium receptors and then discovery of endogenous opioids leading to pharmacological and therapeutic understanding. With that as a reference, Cannabis research is years behind.

The subject is extremely complicated and at present relatively unexplored, the possibility for endocannabinoid modulation in the treatment of multiple conditions is extensive, but so is the research needed to make that a reality. With that being said, let’s explore some of the negative impacts and side effects exogenous cannabinoids can elicit.

Around 30% of Cannabis users will experience marijuana use disorder (7) and around 9% will develop addiction/dependence (8, 9). Here the lines become blurred, evidence is controversial, marijuana use disorder encompasses characteristics of dependence and one can exhibit dependence without addiction. Interestingly the effects seem to be more pronounced if Cannabis use was started in childhood with prevalence of dependence rising to 17% if use began in the teens (10). The withdrawal effects from Cannabis are like that of alcohol and opioids, characteristically; restlessness, insomnia, anxiety, increase aggression and muscle tremors. In the ‘British Journal of psychiatry, Pharmacology and effects of Cannabis: A Brief Review’ numerous negative psychological and systemic effects are described.  Psychological reactions such as panic, anxiety, paranoia and psychosis can occur which are seemingly dose and drug naivety dependant. Respiratory effects such as bronchial irritation, acute and chronic bronchitis and even suggestions smoking Cannabis can be as, if not more detrimental than the inhalation of tobacco smoke (11).

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So, where did this story begin?

In June 2018 the DOH launched a review in to the scheduling of cannabis and cannabis-based products for medical use. The review in short concluded there was sufficient and conclusive evidence regarding the therapeutic benefits to support the medical use of Cannabis or Cannabis-based products in humans on prescription (13).

Who can know prescribe Cannabis and in what circumstances? Current NHS and DOH guidelines explain that the decision to prescribe Cannabis or Cannabis-based products is restricted to clinicians on the specialist registrar of the general medical council. Furthermore, the prescribing must follow current guidelines surrounding unlicensed medicines or ‘specials’ and is only prescribable where there is clear published evidence on the indication, a clinical need currently unmet and where current treatment options have been exhausted (13).

What advice should Pharmacists and other healthcare professionals provide patients who have been newly prescribed Cannabis or Cannabis-based products?

Practical counselling based upon guidelines is in short supply and due to the tightly controlled prescribing the patient should be in close contact with their respective specialist who will have explained the treatment in detail. However, without clinical evidence we should reasonably assume that the risks and side effects of treatment may be like that of recreational Cannabis use. As such it would be the judgement call of the supplying Pharmacist or healthcare professional as to what detail they felt the patient would benefit from knowing about the possible risks and side effects. Advice about driving during use is also important and should be tailored to match that of other controlled medications that can affect driving, such as methadone for example (14).

Specific Drug-Drug interaction data isn’t available yet, but current data suggests THC and CBD undergo some level of hepatic metabolism catalysed by the cytochrome P450 enzymes (14, 15). Both have a large range of metabolites which may or may not also be active. It would be sensible to express caution with patients taking other medications known to be metabolised hepatically, especially those affected by CYP450 induction and inhibition. Furthermore, medications which can elicit psychological changes may also want to be treated with caution.

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Being a political hot topic, when the British Home Office decided to allow the rescheduling of Cannabis the media went in to something of whirlwind, who can blame them, it makes outstanding headlines. “Paul McCartney was right — cannabis WILL make the world a better place thanks to its medical uses” was the claim of one large tabloid newspaper (12). This likely has something to do with the general public’s interest in the subject. But as explained previously, the supply is to be very tightly controlled.

Is Cannabis going to be the breakthrough wonder treatment some are hopeful for?

I think that’s the wrong question to ask. But could Cannabis be a doorway in to a previously unexplored area of pharmacology and medicine? That question sounds more realistic and I’d be inclined to say yes. Currently there is evidence to support the use of Cannabis in some pathologies in restricted cases and as such government policy has followed that. But that’s where it ends for the time being and far more research is needed across a wide range of subjects within this fledgling field of pharmacology before any further conclusions can be made.


References:
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707667/#R13
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852027/
3. https://www.ncbi.nlm.nih.gov/pubmed/18426493
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2241751/
5. British National Formulary
6. https://pdfs.semanticscholar.org/612a/2bc8076e8c00c6d08e118d987f5b28e201a8.pdf
7. Hasin DS, Saha TD, Kerridge BT, et al. Prevalence of Marijuana Use Disorders in the
United States Between 2001-2002 and 2012-2013. JAMA Psychiatry. 2015;72(12):1235-
1242. doi:10.1001/jamapsychiatry.2015.1858.
8. Anthony JC, Warner LA, Kessler RC. Comparative epidemiology of dependence on
tobacco, alcohol, controlled substances, and inhalants: Basic findings from the
National Comorbidity Survey. Exp Clin Psychopharmacol. 1994;2(3):244-268.
doi:10.1037/1064-1297.2.3.244.
9. Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, et al. Probability and predictors
of transition from first use to dependence on nicotine, alcohol, cannabis, and
cocaine: results of the National Epidemiologic Survey on Alcohol and Related
Conditions (NESARC). Drug Alcohol Depend. 2011;115(1-2):120-130.
doi:10.1016/j.drugalcdep.2010.11.004.
10.Anthony JC. The epidemiology of cannabis dependence. In: Roffman RA, Stephens RS,
eds. Cannabis Dependence: Its Nature, Consequences and Treatment. Cambridge, UK:
Cambridge University Press; 2006:58-105.
11.https://pdfs.semanticscholar.org/612a/2bc8076e8c00c6d08e118d987f5b28e201a8.pdf
12.https://www.thesun.co.uk/news/7652563/paul-mccartney-cannabis-medical-use-tony- parsons-opinion/
13.https://www.england.nhs.uk/wp-content/uploads/2018/10/letter-guidance-on-cannabis- based-products-for-medicinal-use..pdf

14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570572/

15.  https://www.liebertpub.com/doi/pdf/10.1089/can.2015.0012

Author: Matthew J Burgoyne MPharm

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