Abstract

Cannabis has been used as a medicine for centuries but in recent history has been made illegal worldwide. Now the barriers to use are breaking down and over 40 countries have legalised the plant for medicinal use. There is surprisingly good evidence of efficacy in a number of conditions, particularly pain, spasticity, nausea and vomiting after chemotherapy, anxiety and childhood epilepsies. The side effects in medicinal compounds are relatively mild and well tolerated, although varieties high in THC can undoubtedly cause mental health issues. Overall, the risk:benefit profile is very favourable and the Government has now recognised the need to reconsider cannabis as a medicine, to the potential benefit of many tens of thousands of people in the UK.

Out-of-date rules must not come before compassion for those who need medicinal cannabis

Nick Hurd, Drugs Minister at the Home Office, in a recent edition of The Times. 

This neatly sums up the current dilemma in the UK. We do indeed have out-of-date rules that still label cannabis as a Schedule 1 drug in the Misuse of Drugs Regulations which, by definition, means that it has “no medicinal value”.  That is patently untrue and the government must at last be congratulated for recognising that fact. However, the quote also outlines the other dilemma. We are now used to prescribing medicines which have a solid evidence base, but the debate about cannabis is more based on emotion and compassion than hard evidence. This article discusses what evidence there is for the efficacy of cannabis and how we can overcome the tension between evidence-based medicine on the one hand and compassionate use of a drug that undoubtedly helps many people but without a hard evidence base on the other hand.

Background

It is regrettable that the illegal status of cannabis has impeded modern research.  However, this is at last changing in many international jurisdictions.  It is now legal for medical purposes in 29 US states and medicinally legal, in differing ways, in Australia, Austria, Belgium, Canada, Croatia, Czech Republic, Denmark, Germany, Israel, Italy, Netherlands, Portugal and Spain and 30 other countries. There are many tens of thousands of people in the UK (some estimate up to a million) that use cannabis for medical purposes. The government has at last reacted to increasing pressure from individual families and has set up a panel to recommend individual cases who should have access to cannabis.  It now seems likely that cannabis will be rescheduled in the near future.

The Cannabis Plant

The two most studied components of cannabis are THC (tetrahydrocannabinol) and CBD (cannabidiol).  However, there are many other constituents from the actual plants which include over 100 other cannabinoids and many terpenes and flavonoids. THC is psychoactive and gives the recreational “high” but CBD does not give a “high” and indeed can counteract some of the psychoactive effects of THC.  CBD is legally available as a nutritional supplement in the UK whereas THC is not legal. There are two cannabis formulations that can be prescribed: Nabiximols (Sativex – GW Pharma) which is a natural product with about a 50:50 ratio of THC to CBD. It is licensed for resistant spasticity in multiple sclerosis. Nabilone (Cesamet) is a synthetic cannabinoid which mimics THC and can be used for chemotherapy-induced nausea and vomiting.

Endocannabinoid System

It is only recently that the scientific rationale of the effects of cannabis have been elucidated. In 1990 Matsuda and colleagues described a cannabinoid receptor in man.1 This was eventually called the CB1 receptor and a few years later a CB2 receptor was also identified.2 These receptors are not only present throughout the central nervous system but in many other peripheral tissues, including the immune system, reproductive and gastrointestinal systems as well as the heart, lung and bladder.  There are natural ligands to these receptors (Anandamide and 2-Arachidonoylglycerol). The whole system, including the precursors and the metabolic pathway, is known as the endocannabinoid system. This system is involved in a whole variety of metabolic, endocrine, neural and other functions. In neurological terms, for example, it is involved in brain protection, modulation of pain, regulation of motor activity, as well as having a role in neurogenesis, neuroplasticity and memory processing. The phytocannabinoids found in the natural plant are able to mimic the effects of the endocannabinoid receptor ligands although they also have interactions with other neural transmission systems.3

Evidence of Efficacy

Given that the drug has been illegal in most countries for many years there is surprising evidence of efficacy. However, more studies certainly need to be undertaken, particularly with regard to the efficacy of different strains, different THC:CBD ratios, different methods of ingestion and further investigations as to whether the whole plant is actually more efficacious for medicinal purposes than the individual cannabinoids – the so-called “entourage” effect.  So, briefly, what are the most researched indications?

Pain

There is a surprising amount of literature on the efficacy of various cannabis formulations for chronic pain. A recent review by Whiting and colleagues, for example, found moderate quality evidence to support the use of cannabinoids.4 A review for the All Party Parliamentary Group on Drug Policy Reform in the UK also found good evidence for pain relief for a variety of conditions (cancer pain, musculoskeletal pain, neuropathic pain) and with a number of different products, including the natural plant, as well as Nabiximols and the synthetic cannabinoids.5

Spasticity

There is good evidence of the use of cannabinoids in spasticity. Most of the work has obviously been done for the Nabiximols but studies with other cannabinoids do exist.6

Nausea and Vomiting in the Context of Chemotherapy

Cannabis is a very useful antiemetic and has been the subject of a recent Cochrane systematic review of 23 randomised controlled trials that have confirmed this.7

Epilepsy

In the last couple of years there has emerged good evidence of efficacy of a particular CBD product (Epidiolex – GW Pharma) for the management of various drug resistant childhood epilepsies, particularly Dravet and Lennox-Gastaut.8 There is also now emerging evidence, although still mainly anecdotal at this stage, that indicates that a small amount of THC in addition to the CBD can be additionally beneficial. This was confirmed, for example, in the recent case of Alfie Dingley who responded to full extract cannabis oils containing both CBD and THC.

Anxiety

There are a few double-blind placebo-controlled studies that have shown that CBD has useful anti-anxiety effects.9

The above indications are those with most evidence but there are studies that illustrate there is some evidence of efficacy for other disorders, including problems with sleep, appetite stimulation, fibromyalgia, post-traumatic stress disorder and some aspects of the motor symptoms of Parkinson’s disease as well as the management of agitation in dementia, bladder dysfunction, glaucoma and Tourette’s syndrome. There has been widespread media publicity for other indications which at the present time do not have much evidence in human studies. These indications include dystonia, Huntington’s disease, headache, brain protection in the context of traumatic brain injury, depression, obsessive compulsive disorder, gastrointestinal disorders and anti-cancer effects.5

Side Effects

Obviously with any medicine we need an analysis of the risk : benefit ratio. Is cannabis safe? The answer, broadly, is yes. The side effects will generally depend on the amount of THC in the product. High THC levels can cause psychotic issues, particularly in those with a history of schizophrenia / psychosis10 or a family history, and in my view such a history should be a contraindication to prescribing THC – although not to prescription of CBD. However, in medicinal cannabis, generally, lower THC levels are often combined with CBD which tends to counteract the effects of THC and thus the risk of psychosis in such products is minimal. In the short term THC products can have effects such as dizziness, euphoria, drowsiness, dry mouth, confusion, disorientation, somnolence, balance problems and fatigue, whereas those effects are generally not seen in CBD products. Dependence on cannabis occurs in around 9% of users (once again those using high THC products) which compares to a figure of around 15% dependency for alcohol and 32% for tobacco.11

There is a theoretical risk of lung cancer from smoked cannabis but there is no definite association and in any case smoking cannabis is not the recommended form of medical administration.

Cannabis high in THC can also impair psychomotor performance and cognition in the short term (and thus impair driving) but there is conflicting evidence regarding neurocognitive effects in the long term.12

Availability

If cannabis has such a favourable risk : benefit ratio, why is it not more widely available? It may be, at least up to the last couple of weeks, political inertia or political prejudice although it is certainly worth noting that a majority of MPs now support legalisation for medical purposes.

The main hurdle is with regard to the licensing of the natural plant product. Approval of medicines in the UK and worldwide will generally focus on a single compound. However, cannabis contains a whole variety of cannabinoids, terpenes, flavonoids and there are several thousand different strains of cannabis with varying proportions of THC, CBD and other components. There are also many different ways of ingesting the product with wide variations of bio-availability. The medicines approval system in the UK is simply not geared to recognising such a plant product.

Many countries have got round this problem simply by developing alternative licensing systems for a plant product. Many jurisdictions have successfully controlled the quality and consistency of cannabis by approving specific suppliers, monitoring the quality of the product and making it available only through licensed pharmacies with appropriate medical prescription or supervision.

At last the UK government is taking the issue seriously and has established a cannabis panel for consideration of individual cases. There is the real possibility of  rescheduling of cannabis from Schedule 1 to at least Schedule 2 of the Misuse of Drug Regulations 2001 in the near future. This would allow doctors to prescribe cannabis legally.

We need more research on the efficacy and side effects, we need to understand the most beneficial type of cannabis and the best mode of ingestion and, more particularly, the best dosage range. There is much to be done but the work will certainly be facilitated by legalisation. It is time we moved beyond “reefer madness” to a more enlightened use of a plant which has so much potential benefit for so many people in the UK.

References

  1. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA.  Nature 1990; 346(6284):561-64
  2. Munro S, Thomas KL, Abu-Shaaar M. Molecular characterisation of a peripheral receptor for cannabinoids. Nature 1993; 365: 61-5
  3. Pertwee RG. Endocannabinoids and their pharmacological actions.  Handb Exp Pharmacol 2015; 231:1-37
  4. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA 2015;313:2456-73.
  5. See http://www.drugpolicyreform.net
  6. Nielsen S, Germanos R, Weier M et al. The use of cannabis and cannabinoids in treating symptoms of multiple sclerosis: a systematic review of reviews. Curr Neurol Neurosci Rep 2018;18:8
  7. Smith LA, Azariah F, Lavender VT, Stoner NS, Bettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev.2015 Nov 12;(11):CD009464. doi: 10.1002/14651858.CD009464.pub2.
  8. De Caro C, Leo A, Citraro R, et al. The potential role of cannabinoids in epilepsy treatment. Expert Rev Neurother 2017: 17;1069-79.
  9. Bergamaschi MM, Quieroz RH, Chagas MH et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology 2011;36:1219-1226
  10. Henquet C, Krabbendam L, Spauwen J et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ 2005b;330:11
  11. Nutt D, Keen LA, Saulsbury W, Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse. Lancet 2007; 369:1047-53.
  12. Broyd SJ, van Hell HH, Beale C, Yücel M, Solowij N. Acute and Chronic Effects of Cannabinoids on Human Cognition-A Systematic Review. Biol Psychiatry 2016;79:557-67.

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