Why medical cannabis is still out of patients’ reach—an essay by David Nutt
BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1903 (Published 01 May 2019) Cite this as: BMJ 2019;365:l1903Linked Commentary
Why I campaign for children like my son Alfie Dingley to be able to get medical cannabis
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David Nutt describes some of the interesting history of cannabis as medicine and notes the wide variety of maladies for which it is claimed to be useful (1). His enthusiasm for medical cannabis extends to a call for its efficacy and adverse effects to be assessed with “open effectiveness studies” rather than formal clinical trials. While the delays and expense incurred by conventional trials are regrettable, rigorous assessment is a foundation of evidence-based practice, and it seems unwise to exempt medical cannabis from this scrutiny -- especially when considerable uncertainty persists regarding both benefits and harms (2).
One harm associated with cannabis, namely psychosis, is of particular concern because of the profound social and occupational disability that can result. Recent epidemiological data from New Zealand and elsewhere strongly suggest a causal role for tetrahydrocannabinol (THC) in schizophrenia (3). Nutt acknowledges the problem of strains of cannabis with high THC relative to cannabidiol (CBD), and implies that making medical cannabis more widely available will help to rectify this imbalance (1). This optimistic view is challenged by the fact that THC content drives not only recreational use but also reported symptom relief and side-effects as well (4). Thus, while the presence of CBD may mitigate the psychotogenicity of THC (5), seeking to mandate sufficiently high levels of CBD in medical cannabis will be challenging, and may amount to 'wishful shrinking'.
1. Nutt D. Why medical cannabis is still out of patients’ reach—an essay by David Nutt. BMJ. 2019;365:l1903.
2. Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis‐based medicines for chronic neuropathic pain in adults. Cochrane Database of Systematic Reviews. 2018(3). https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012182.pub2/...
3. Mellsop G, Tapsell R, Menkes DB. Testing a hypothesis arising from the epidemiology of schizophrenia in New Zealand. General Psychiatry 2019;32(2).
http://dx.doi.org/10.1136/gpsych-2019-100048
4. Stith SS, Vigil JM, Brockelman F, Keeling K, Hall B. The association between cannabis product characteristics and symptom relief. Scientific Reports 2019;9:2712. https://www.nature.com/articles/s41598-019-39462-1
5. Wall MB, Pope R, Freeman TP, Kowalczyk OS, Demetriou L, Mokrysz C, et al. Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity. Journal of Psychopharmacology. epub before print: 23 April 2019. https://doi.org/10.1177/0269881119841568
Competing interests: No competing interests
Nutt’s remarks do not mention that cannabis is commonly used around the world today in large folk festivals where hundreds of thousands of people get stoned and wasted, or that cannabis has been used for these allegedly “magical properties” for most of the lengthy historical period to which he repeatedly refers.
Pointedly Nutt does not observe that the touchstones of modern medical practice are the dual pillars of randomized clinical trials and associated safety tests – tests which cannabis has largely failed.
Of the 57 supposed and mythical indications for cannabinoids robust clinical data exists for just the single indication of refractory childhood epilepsy. That is to say that only one indication is proven: the rest are – just hype.
The strict modern system of pharmaceutical approval was introduced worldwide after the horrors of the other known genotoxin thalidomide was introduced with horrific consequences in the late 1950s. Like cannabis, thalidomide was also introduced by commercial interests who were well aware of its genotoxicity.
Whilst Nutt is correct to state that cannabidiol does ameliorate many of the psychiatric side effects of cannabis, he does not mention importantly that the damage it causes as a genotoxin and a mitochondrial toxin – which also impairs genome maintenance – is comparable – or even exceeds – that of Δ9-tetrahydrocannabinol, or that since the 1960s it has been clear that cannabis given to the experimental animals which best predict major teratology and congenital abnormalities in humans – namely, rabbits and guinea pigs – reproduces a teratological spectrum which closely overlaps that of thalidomide including absent limbs, anencephaly, omphalocoele, meningomyelocoele and in utero death and resorption. Nutt does not mention that this teratological profile is now being played out in many nations including USA, Canada, Australia, by the worldwide gastroschisis epidemic - and in Europe.
Nutt does not mention that the now exponentially rising autism epidemic in the USA closely parallels reported cannabis use across US states and tracks cannabis legalization 1.
The European experience is of particular importance as it is understood that cannabis is permitted in the food supply. Based on birth defect registry data, three areas in France were recently in the news as having rates of phocomelia (no arms) 58 times that of background. Cows in some of these areas had no legs. However, a few miles away in Switzerland where cannabinoids are prohibited in the food chain – after previous negative experiences – no such problem exists 2 3.
Modern science agrees that pure cannabinoid derivatives may potentially have therapeutic applications. But to correctly, beneficially and rigorously harness this yet to be manifested power it is mandatory that we progress beyond magical and fantastical thinking – and drug money.
References
1. Reece A. S., Hulse G.K. Effect of Cannabis Legalization on US Autism Incidence and Medium Term Projections. Clinical Pediatrics: Open Access 2019;In Press [published Online First: 2019]
2. Agence France-Presse in Paris. France to investigate cause of upper limb defects in babies. The Guardian 2018. https://www.theguardian.com/world/2018/oct/21/france-to-investigate-caus... (accessed 3rd November 2018).
3. Willsher K. Baby arm defects prompt nationwide investigation in France. Guardian 2018. https://www.theguardian.com/world/2018/oct/31/baby-arm-defects-prompt-na... (accessed 3rd November 2018).
Competing interests: No competing interests
When considering the position of medical cannabis, the old adage "First do no harm" is of overriding importance. Cannabis is known to be an addictive drug and is also known to be associated with psychotic illness. That it has been around for a long time makes no difference either way - so have cocaine, LSD and heroin. As pointed out in a letter to the BMJ only a few weeks ago, the indications for cannabis are not at all clear. Caution should be the watchword. Pressure groups and vested interests should be recognised for what they are and the attention that they are given should be appropriate to their position.
Competing interests: No competing interests
A thorough and well researched overview, yet marred with the misuse of legal constructs, in particular falling into the trap of imputing transferred epithets as used in common parlance into law with dire consequences for reality. In particular David Nutt subscribes to this false paradigm where cannabis is supposedly legal or illegal. This, legally speaking is complete nonsense; drugs have no innate legality or illegality they are just objects. Legality and illegality can only apply to a human action, and such actions are regulated according to laws and rights. If cannabis could be illegal as Nutt suggests, then how could companies such as GW pharmaceuticals grow tons of it? The answer is of course that they do it by using exemptions and licenses and these are all available via sections 7,22 & 31 of the Misuse of Drugs Act. It is not ‘illegal’ at all, it is designated as a substance that we are ‘controlled’ with respect to.
Spinning the myth of cannabis illegality completely obscures the true regulatory action of the law, and makes us beholden to a binary objectification rather than exist as subjects judged by our actions, this serves the interests of corrupt politicians and prohibitionists.
I have communicated this to Prof Nutt for over a decade. I wish he would show the same respect for legal accuracy as scientific, for words in law are every bit as important if not more so! Given this disregard for legal accuracy, I must caution that whilst his scientific credentials are beyond reproach, I do wish that when making these forays into law and policy that he would adopt the correct legal constructs.
Competing interests: No competing interests
Medical cannabis is a class of drugs, not a single drug. Adoption of usage requires culture change and far more government action.
Nutt’s article on medical cannabis (1) outlines a number of potential reasons behind the limited impact of the UK legal reform. He alerts us to a number of important issues, such as unmet educational needs and problems with the supply chain. I question though, how much difference resolving these will make unless there is also a significant change to the system in which doctors operate.
Attempts to shoehorn medical cannabis into the current pharmaceutical paradigm of single molecule drugs limits our ability to appreciate its utility. The complex cannabis plant (2) has an infinite number of strains. Each strain has its own unique array of chemical constituents which does not lend itself neatly to evaluation through randomised control trials (RCTs). Although there are a number of RCTs on medical cannabis (3), they cannot be combined easily due to the diversity of strains and differing relative proportions of active ingredients used.
The absence of robust RCT data is a significant issue because the medical industry has become heavily dependent on RCTs to guide and assure us that seemingly impressive results are not due to chance or bias. This absence of RCT data has resulted in the respective Medical Colleges being unable to make supportive recommendations. This has had a paralyzing effect the medical community, and leaves individual clinicians expected to shoulder all the risk should they decide to prescribe. NICE are due to issue their Guidelines in October this year. I fear however that these new Guidelines will contribute little to resolving the issues as NICE are likely to draw the same conclusions as the Colleges. Doctors quite rightly fear causing harm to patients in addition to subsequent litigation, although it would appear that the latter fear may be overestimated (4). The evidence base is growing slowly, but it appears unlikely that medical cannabis will conform to our existing regulatory frameworks in the near future.
Beyond the issues with the data is equally important issue of cost. The legislation moved at a faster pace than any discussion about funding. NHS England, almost entirely, points to the providers (5) suggesting costs should be ‘in tariff’. Meanwhile, providers are hindered by the exorbitant costs and look towards the CCGs for funding. In the vast majority of cases, the individual patient is forced to try and fund it themselves for as long as they can manage to. Costs are currently prohibitively high. A large part of the cost is likely to be due to an imbalance in supply and demand and issues of economies of scale with suppliers. Treatment with medical cannabis in the UK can cost upwards of £100,000 per year depending on the preparation used. This high cost is neither sustainable nor necessary for a plant extract.
Doctors are right to be cautious of any new treatment option, but must also be realistic in terms of the extent to which the risk can ever be known for any new medication. There is a substantial amount of short-term trial data on medical cannabis already (6), along with some longer-term follow up studies (7, 8). Additionally, we have safety data from other countries, such as the Netherlands, who have now issued more than 170,000 prescriptions of medical cannabis (9).
We need to adopt a more balanced initial position, endorsed by the Colleges, that supports doctors to make reasoned decisions with a minority of patients for whom our conventional approaches have failed. Deciding not to prescribe is itself an action, and it cannot be right that we limit access to what may be a helpful treatment for people with ongoing pain, seizures or suffering.
We must evolve our position by benefiting from the other models such as in the Netherlands and in Israel. By producing our own supply, becoming self-sufficient as a country, making our limited resources stretch, and properly supporting doctors, we may begin to meet the needs of our patients.
References:
1. Nutt D. Why medical cannabis is still out of patients’ reach—an essay by David Nutt. BMJ. 2019;365:l1903.
2. Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol. 2012;2(6):241–254. doi:10.1177/2045125312457586
3. Allan GM, Finley CR, Ton J, et al. Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms. Can Fam Physician. 2018;64(2):e78–e94.
4. Marlowe DB. Malpractice liability and Medical Marijuana. The Health Lawyer, American Bar Association. 2016 Dec; Vol 9(2): 1-17.
5. NHS England. Supplementary information on cannabis-based products for medicinal use. Gateway Publications clearance: 08652. Published Tuesday 20th November 2018. https://www.england.nhs.uk/publication/additional-guidance-to-clinicians...
6. Wang T, Collet JP, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: a systematic review. CMAJ. 2008;178(13):1669–1678. doi:10.1503/cmaj.071178
7. Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol. 2013 Jan;260(1):285-95. doi: 10.1007/s00415-012-6634-z. Epub 2012 Aug 10. PubMed PMID: 22878432.
8. Bar-Lev Schleider L, Mechoulam R, Lederman V, Hilou M, Lencovsky O, Betzalel O, Shbiro L, Novack V. Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. Eur J Intern Med. 2018 Mar;49:37-43. doi: 10.1016/j.ejim.2018.01.023. PubMed PMID: 29482741.
9. De Hoop B, Heerdink ER, Hazekamp A. Medicinal Cannabis on Prescription in The Netherlands: Statistics for 2003-2016. Cannabis Cannabinoid Res. 2018;3(1):54–55. Published 2018 Mar 1. doi:10.1089/can.2017.0059
Competing interests: No competing interests