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I RECENTLY wrote about a “true life drama”: the struggling family of a disabled child who rejected conventional medicine fell into the arms of the organised antivaccination movement and treated his seizures with unregulated cannabis oil, supplied by a deregistered doctor. The child has cerebral palsy, microcephaly and epilespy, and is fed via a percutaenous tube. In the comments section, we discussed how families are vulnerable to charlatans who offer simple solutions – especially where medicine doesn’t “have all the answers”.
In the same issue of MJA Insight there was an article reporting a study of the efficacy of cannabidiol (CBD) in controlling seizures in the rare genetic disorder severe myoclonic epilepsy of infancy, known as Dravet syndrome. This syndrome – difficult to control with conventional anti-epileptics – has become a focus for the campaign for the so-called “medical cannabis”.
As I said in the comments section, the push to take advantage of the potential therapeutic effects of cannabis extracts has become muddied by the campaign to legalise recreational use. As potential prescribers, it is important for all of us to be as informed as possible about the various aspects of this debate: clinical, social and legal.
Like the opium poppy, the plant Cannabis sativa contains a mix of plant chemicals with physiologically active – including psychoactive – properties. Like morphine, cannabis can alleviate a range of symptoms and cause a range of side effects. Both can be used and misused, both are prone to habituation and addiction.
Like most so-called “medicinal herbs”, raw plant material is chemically and structurally very complex. The potentially beneficial compounds may be packaged together with toxic ones, or bound to fibrous material. The amount of the desirable chemicals varies from plant to plant – genetically, regionally and according to season. It is for this reason that herbal medicine developed into modern pharmaceutical medicine – where active ingredients are purified and standardised to maximise both safety and efficacy.
In cannabis plants, there is a wide variation in content of the two main active compounds. Tetrahydrocannabinol is responsible for most of the psychotropic effects and is also the constituent that promotes misuse. In the United States, it is sometimes prescribed as an extract – or analogue – for the treatment of nausea and appetite stimulation in oncology patients, and for control of spasticity in multiple sclerosis. In heavy regular use, it may also stimulate the bizarre syndrome of cyclical vomiting, where patients spend hours under a hot shower to relieve their distress .
The other major compound ( CBD) has been the focus of research for treatment-resistant epilepsy. As this article explains, human studies so far have been poorly conducted and have shown mixed results.
So, back to the study in Dravet syndrome that I mentioned above – published in May 2017 in the New England Journal of Medicine. The trial was funded by GW Pharmaceuticals, and the company was responsible for the trial design, trial management, site monitoring, trial pharmacovigilance, data analysis and statistical analysis, as well as preparation and provision of both the active CBD product and placebo. One hundred and twenty subjects with Dravet syndrome, aged between 2 to 18 years, and whose seizures were poorly controlled on their current treatment, were enrolled. In a randomised double-blind design, either CBD or placebo were added to their regime, with treatment spanning 14 weeks. The study found a reduced median seizure frequency in the CBD treatment group from 12.4 to 5.9 with CBD, compared with a decrease from 14.9 to 14.1 for placebo (adjusted median difference −22.8 percentage points; 95% confidence interval, −41.1 to −5.4; P = 0.01). CBD was also associated with a higher rate of adverse events, including diarrhoea, vomiting, fatigue, pyrexia, somnolence and abnormal results on liver function tests. However, there is also good evidence of improved seizure control in patients with Dravet Syndrome with the addition of the newer drug topiramate.
Findings like these have fueled the community campaign for “medicinal cannabis”, with proponents frequently campaigning for the use of the whole plant, homegrown, as “herbal medicine”. Outrageous claims have been made – well beyond the plant’s pharmacological potential – for cures for everything from cancer to Alzheimer disease. Growers and users are emphasising the “natural”, “herbal” aspects of the whole plant, invoking conspiracies about Big Pharma. This is a thinly-disguised bid for liberalisation of recreational use.
The “war on drugs” narrative has certainly complicated this discussion, and there are legitimate discussions to be had about the relative harms of different recreational substances. I won’t explore these here. What we do have, though, is a precedent for the prescribed use of restricted plant-derived substances: the narcotics.
While the use of potent narcotics is restricted in the community, morphine is a mainstay of pain treatment in both acute and chronic care and at the end of life. Morphine isn’t medicine in the sense that it cures pathology – but it provides much-needed symptomatic relief, while also often producing side effects.
Prescribed cannabis extracts and derivatives may legitimately sit alongside the narcotics in our pharmacological toolbox – especially at the end of life. Some people with treatment-resistant seizures may well benefit from the addition of CBD.
As experts in therapeutics, it is essential that we are familiar with the evidence – what is known, what is plausible and what is not. In that way, we can make good use of the evidence-based effects, anticipate and manage side effects and debunk the multitude of myths. I would urge readers to explore the references in this article, and continue to explore further.
Dr Sue Ieraci is a specialist emergency physician with 30 years’ experience in the public hospital system. Her particular interests include policy development and health system design, and she has held roles in medical regulation and management. She is an executive member of Friends of Science in Medicine.
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In response to “Anonymous” above, I can only say that I agree. As you report, CBD is just one of a toolbox of drugs for a very difficult condition to treat, which has both advantages and side-effects. I apologise if my use of the word “extreme” offends you, but I’m sure you’ll agree that a child who still has over 50 seizures a day while on multiple medications is a much more severe situation than the vast majority of epileptics, who get good control with one or two medications.
My comments on Topiramate come papers from Dr Catherine Chiron, who has collaborated with Dr Charlotte Dravet, the French neurologist who described the syndrome. Both are members of the Intractable Childhood Epilepsy research group.
I also agree that the use of cannabis derivatives for therapeutic reasons should not be confused with recreational use – that is the main point of my article.
As both a Doctor, and a mother of a child with Dravet Syndrome, I would like to say Sue that your information regarding Topiramate vs CBD, is inaccurate. While some children with Dravets experience reduction in seizures with Topiramate, like all drugs in this condition seizure freedom is uncommon. It has the delightful common side effects of speech and cognitive impacts and heat intolerance, not great in a condition where seizure frequency is often temperature related! It is a drug in the kitbag and works for some kids but not others. Additionally, if you looked at the research you would see that the majority of children with this “extreme” condition are on polytherapy usually without seizure freedom. My son, aged 5, is on 5drugs at lower doses as evidence suggests that this is what works better for many. Despite that he clocks up to 55 + seizures a day. There are currently no other drugs on the market and we are waiting to get access to trial Epidiolex. Those with limited understanding of this complex Paediatric condition often site only a 50% reduction. This reduction is up there with the best any other available pharmaceuticals offer. 50% of 55 is a significant reduction, would you agree. To those who cite long term, I can tell you with certainty that many available have very significant long term side effects. Additionally, we as families are often told that this condition is a life limiting condition, with around 17% not reaching adulthood, and we need to balance seizure control vs side effects and quality of life. I would ask that before you cite these studies about “extreme” conditions that you think about the results in context of the condition, and familiarize yourself with the condition if you are not. The attachment of the CBD stigma, and basketing it in with the legalisation argument, has to stop in order to obtain access to the very best this medication MAY offer. Like all medications it has limitations and side effects, and should be treated as another OPTION..
Ok, unlike many here I have prescribed a cannabis legally in Australia. I’m a rehab physician who treats severe spasticity. My patient used Savitex for a period of months but found other options better. (Botox, lyrica, baclofen, dantrolene). I have at least four other patients who illegally use cannabis for symptom relief of severe spasticity and pain. They say it helps them and I believe them.
However Cannabis obtained and used by many other patients is simply a social drug. It is abused. There is clear evidence of impairments in concentration, attention, motivation and emotion. The commonest delivery system (smoking) is disastrous. There is no quality control on the illegally sourced product. There is very little solid scientific understanding of the many psychoactive substances contained. There is NO agreed serum concentration at which it is safe to drive.
I have no problem prescribing plant derived opiates, cocaines, foxglove, anti-platlets, anti-inflammatries, antispasmodics, etc etc. One day when I can prescribe a cannabanoid orally, safely and predictably I will. Until then whats the rush?
I could not have summed it up better, Sue- and I completely agree with every word.
Thanks for such a thought provoking exchange- it’s been a real pleasure chatting, and you’ve shown that it IS possible to discuss these issues amicably between differing opinions.
You’ve certainly made me sharpen up my thinking on the issue like few others…!
Thanks, David. I won’t prolong the discussion, except to say this: there are many evolving areas of progress within palliative care and pain medicine – the development and use of cannabis products is only one of them. Foremost is the issue of access – to clinicians and services as well as products. If, in a decade, all people, urban and rural, who need these services are able to access them in a timely way, we will definitely have made progress, whatever drugs are in the toolbox. Best wishes to you.
Sue, I appreciate your thoughtful comments.
I would whole-heartedly agree that “to say that the provision of [palliative care] services, in the absence of cannabis, is somehow a breach of Hippocratic principles is nothing short of astounding.” Of course, that’s nothing like what I said.
What I actually said was that, all things being equal, if we can provide relief to patients, with a product that has significantly fewer side effects than those currently in use, at a fraction of the price, don’t the very fundamentals of medical ethics oblige us to at least consider their use? The religious imperative I mentioned from one particular faith is to provide relief. It’s a little beneath our level of debate to suggest that classical medicines aren’t included in that space as well.
Is it possible that you didn’t review the author affiliations of the paper you cite? The paper that suggests that Sativex, a drug that costs roughly AUD$16,000 p/a, manufactured by GW Pharma, is superior to botanical product? It’s not a bad paper, but one might have anticipated the conclusions had one seen who the single author was employed by. Care to guess? Yep- GW Pharma. Conflicts of interest currently abound in the field, which is why at the ANU, our course is offered pro-bono, with no industry support.
I don’t think anyone is exaggerating the urgency for the need for cannabis products. You and I work in emergency. We only infrequently see the sort of patients that stand to gain most. I think that the urgency is experienced more on the patient side of the equation, and for them, it is very urgent indeed.
Finally, I would offer you the opportunity to acquaint yourself with a phenomenon known as the ‘Entourage effect’, a phrase coined several decades ago. It might actually be the case that there ARE advantages of whole plant material- for now at least- over synthetically manufactured compounds we are only now beginning to understand.
I know that you are busy, (and I’m hardly helping!) but let me leave you with 2 references that, as good medical writer yourself, you might enjoy reading.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165946/
http://www.cell.com/trends/pharmacological-sciences/abstract/S0165-6147(15)00171-6
This last link is to a clinical trial of a novel medical device- a thermal metered dose inhaler for cannabinoid medication.
https://www.ncbi.nlm.nih.gov/pubmed/25118789
The global science has come much further than we are being lead to believe in Australia.
I’d like to take this chance to applaud you on the tenor that you have chosen to take in our very enjoyable exchange- it is a credit to your appreciation of science, and respect for colleagues that you may not necessarily agree with.
I look forward to catching up in person one day- maybe we should make a date for a decade, and see where we have got to by then…:-)?
David – my comments about the variability of plant material have nothing to do with scepticism, but with biology. I don’t say that a whole plant substance CAN’T be used for symptom control – of course it can. My point is that there is no advantage to a “herbal” or “whole plant” preparation, therapeutically.
From the journal Drug Testing and Analysis 2013: A review of the cultivation and processing of cannabis (Cannabis sativa L.) for production of prescription medicines in the UK. “The quality demands of the pharmaceutical industry require prescription medicines to be consistent in their active ingredient content. Achieving this, using raw cannabis as a feedstock, is especially challenging. The plant material is extremely inhomogeneous, and the ratios of active ingredients are affected by a range of factors. These include the genetics of the plant, the growing and storage conditions, the state of maturity at harvest, and the methods used to process and formulate the material. The reasons for this variability are described, with particular emphasis on the botanical considerations. To produce the complex botanical medicine Sativex®, which contains the cannabinoids Δ9–tetrahydrocannabinol (THC) and cannabidiol (CBD) and a range of other ingredients, GW Pharmaceuticals had to manage these variables. ”
Using cloned plant material can only standardise one cause of variability. It is for that reason that pharmacology has moved beyond plant material to standardised pharmaceuticals.
You claim to be dispassionate, yet you say “Many of the religious elders of Judaism see it as moral obligation to provide this relief- are we so far removed from the concept our Hippocratic Oaths to see otherwise?” Do they see it as a moral obligation to provide Fentanyl patches? Ondansetron? Subcutaneous administration rather than oral.
Palliative care doctors and nurses work daily to help the suffering. Their tools get better all the time – different formulations and routes for narcotics, ondansetron is widely available, psychological and psychiatric care is improving – to say that the provision of these services, in the absence of cannabis, is somehow a breach of Hippocratic principles is nothing short of astounding.
I don’t question your motivation, but I would caution against exaggerating the urgency of need for cannabis products. A scan of Palliative Care and pain management journals reveals developments in the use of various treatments for fatigue, nerve blocks, subcutaneous lignocaine, nutrition, hospital chaplains and methadone (to name a few) as well as pros and cons of cannabis extracts. I look forward to further developments in the use of all these tools – I don’t need to “change my mind”.
Great discussion Sue and David!
As a palliative care physician I have a number of patients interested in cannabis products for obvious reasons (esp for refractory nausea and pain). Having heard some of the Canadian experts speak at a pall care conference in Montreal last year, I am more than happy to explore the option of cannabis with patients who enquire about it.
Like any medication, it will have risks and benefits – we deal with that all the time. Like other mediations for these distressing symptoms it will only work well in a proportion of patients (notwithstanding the placebo effects).
I agree totally with David; if we were to wait for convincing randomised, double-blind controlled trial results before we used any drug for symptom management then we would be denying potential relief to a group of “time-poor”
patients. The clinical experience with cannabis should help guide us in its use – there are more routes to knowledge than pure evidence-base medicine!
The fact that you are skeptical about the ability to standardise plant material does not mean that it isn’t possible, Sue.
The entirety of the Israeli and Netherlands experience over the last decade would suggest otherwise. I would invite you to get in touch with Bedrocan, or even just Google them. Or any of the 9 producers in Israel. By using clones, in identical growing conditions, producing a product of reproducible and identical character has become a matter of facile agrononomy. Neither Israel or the Netherlands support a ‘grow your own’ medical policy- they are quite clear that doing so can not guarantee a product that can be used medically.
I was struck by the approach of Israeli regulators- all doctors- at a recent meeting in Sydney. Much to the chagrin of many Australians in the audience, their position was as follows: sure, we don’t know everything that there is to know about cannabis yet. But if some stand to gain real benefit, and after all of these years of study in Israel, we cannot demonstrate a harm that even approximates that of the alternatives, what sort of people are we- what sort of doctors are we?- to ban the use of something, while we investigate it? Many of the religious elders of Judaism see it as moral obligation to provide this relief- are we so far removed from the concept our Hippocratic Oaths to see otherwise? The obvious rebuttal is ‘primum non nocere’- but in the scenarios we are talking about, the harm lies in doing nothing.
As you might appreciate, Sue, I find myself unwittingly in this field, from the perspective of the harm of illicit drugs. Despite your convictions that a herbal product cannot be used medicinally, the global experience is otherwise. It will be wonderful when we know why it works as well as it does, in those that it does- but if harm cannot be demonstrated in a medicinal context- wherein lies the sin? My view is entirely dispassionate. It is a facile debating ruse to create a straw man by suggesting that supporters of medicinal cannabis are somehow naïve, or conned by compassion, or supporting home grown cannabis, or seeking recreational cannabis legislation- it is much harder, and more honest, to question whether what we have been taught, or not taught, stands up to scrutiny.
If you are ever of a mind to learn why a growing number of really clever, scientifically trained, truly skeptical, compassionate medical practitioners are looking into this field, let us know. We don’t need you to change your mind- but you might be surprised about how much information is already out there.
Thanks for your comments, David. You say “Globally, it has been very easy to separate legal and medicinal cannabis markets.” And yet, since this has been so difficult with narcotics, benzodiazepines and other psychoactive drugs, it seems implausible that cannabis products would not be used in the same way. For all these substances, there is a compromise between use and misuse.
I repeat – it is not possible to standardise raw plant material in the way one can standardise pharmaceuticals, That is the reason that modern pharmacology developed from herbal medicine. Certainly it’s possible to grow crops with a largely similar content of one active component, and to conduct quality control over the crop and cull the wider variants, but plant-to-plant variation must occur – much like the difference between opium and morphine. The “herbal”, “whole plant” references are demonstrably not about medical use, but about the right to grow and use one’s own crop (which is a different discussion altogether). For similar reasons, we use standardised morphine doses, not opium tincture.
When considering anti-convulsants, it’s even more important to look to an evidence base since, in contradistinction to end-of-life situations, medication is likely to be required life-long. While, in the past, barbiturates and benzodiazepines have been used for seizure control, there are many newer anti-convulsants that make life much better for epileptics, without the sedative effects. The limited evidence for CBD in Dravet syndrome suggests that cannabis is no panacea for epilepsy – though it may contribute to control in some extreme cases. Again, newer drugs like Topiramate might be superior.
In considering this issue as doctors and potential prescribers, it’s important to take a dispassionate view. The fact that some families are desperate to access cannabis for suffering relatives does not mean that cannabis is the optimal solution for them. Like snake oil, many cannabis oil purveyors are profiting from false hope.
Shane Moloney appears to have misunderstood my point – which is about the prescription use of substances that are restricted in their social use. In that context, alcohol is irrelevant – it is neither prescribed nor socially restricted. Having said that, while many people at university use alcohol to excess, only a minority develop long-term addiction.
I have not seen anyone argue that every user of cannabis – or narcotics – becomes addicted. My analog ystands: like the narcotics, use of cannabis risks habituation and addiction. Clearly, like morphine, this clearly doesn’t occur in 100% of users. This has nothing to do with “bias” – it’s reality.
As ever Dr Ieraci has some sensible points to make on the issue of medicinal cannabis.
Perhaps the first is to acknowledge that there are unscrupulous individuals in this field, particularly in Australia, and they continue to emerge.
It is possible that this extremism is not emerging in a vacuum, but instead in response to the perception of desperate patients that the medical profession seems to know very little about a product that they perceive, rightly or wrongly, is of benefit to them, or their loved ones.
Globally, it has been very easy to separate legal and medicinal cannabis markets. Numerous states in the USA now have medicinal programs in place, and no corresponding recreational market. In both the Netherlands and Israel, global leaders in the science of medicinal cannabis, recreational use remains illegal.
There is a suggestion in your piece, Sue, that because a product is botanical in origin, that a) it is not possible to standardise production, or that b) even if it were, that would not be desirable. The former is self-evidently incorrect; several international companies now manufacture to GMP (Good Manufacturing Practice) a standard recognised by the international pharmaceutical community. Indeed, a GMP product is critical to ensure that appropriate dosing is possible. And before anyone gets overly excited about the possibility of dosing- it’s already being done. The Office of Medicinal Cannabis in Israel has dosing guidelines, readily available, and I believe shared with NSW and the TGA. So whereas recreational cannabis re-purposed for medicinal intent may have all of the problems that you have mentioned, they are rarely seen in medicinal use.
The National Academy of Sciences, one of the most august scientific bodies on the planet, released their “Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research” report in only January of this year. It is available here http://www.nationalacademies.org/hmd/Reports/2017/health-effects-of-cannabis-and-cannabinoids.aspx. In it, they find the evidence for several conditions ‘conclusive’ and ‘compelling’.
This field is not helped by those who claim that cannabis is panacea for all ills. It seems to work very well for some conditions. But those who would have us accept that it should never be used, on the grounds that it is botanical, or has been previously classed as illicit, are merely extremists on the opposite side of the coin. There is a middle ground, occupied by a very large and growing global experience in this space. As my dear friend Simon Eckerman, the health economist from Woollongong reminds us, we need not to consider the potential benefits for individuals, but also to society at large (the important concept of ‘net health benefit’). In jurisdictions that have introduced medicinal cannabis legislation in the US, morbidity and mortality from opiate abuse has dropped by as much as 30% (Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999–2010. JAMA internal medicine. 2014;174(10):1668-1673). This a problem that in Australia that both Sue and I are very aware of.
So it is time to unmuddy the waters. It is time for clinicians to pay attention to what is happening globally, and to apprise themselves of the science that stands behind the possibility of using both derived and botanical product from the Cannabis spp.
In the Helen Kapalos movie, ‘A Life of it’s Own’, one of the author’s of the study NEJM is seen, berating the lack of evidence to support CBD for convulsive disorder. She has produced a significant article demonstrating what many patients have claimed for many years. I think that with artificial and historical restraints removed from research in this field, we will see more of these Damascene conversions. But in the interim, is it appropriate to prevent access for a limited number of patients who have already been shown to benefit globally, at no demonstrable cost?
SInce various States have either commenced trials or developed procedures for prescribing, the requests from patients has been increasing. In my experience, none of the requests are from patients in groups for which any purported benefit has been shown. Given that these should require specialist review, I also disagree with prescribing by GPs, except where this is a continuation of a specialist intiated script. I agree with the thrust of Sue’s analysis, the claims made for so called “medicinal” cannabis are generally far in excess of what can be demonstrated in proper trials, and it is almost certainly influenced by the push for decriminalising or legalising cannabis.
My preference would be to legalise cannabis and be done with it as has been the case in several States of the US, and elsewhere, but to completely separate this from the therapeutic use of any products derived from cannabis. It is important to repudiate the notion that the use of plant products which have not been subject to standardised and quality controlled methods of production and licensing have any place in modern clinical practice.
Adverse events are common; therefore those who are to be prescribed medicinal cannabis for whatever reason must be made fully aware of them so they can give their informed consent prior to initiating treatment.
The immediate risks are effects on cognition (impairment of memory), psychomotor function (impairment of coordination and judgment), cardiovascular system (a trigger of adverse cardiovascular events) and mood (anxiety, panic attack, paranoia, psychosis).
Some of the risks of chronic use include impaired mental ability, chronic bronchitis, risk of cancer (from smoking dried product), and cannabis dependence (9% of adults, 17% of adolescents).
The article by Dr Ieraci shows some bias. She states that like morphine cannabis is prone to habituation and addiction.This seems a harsh comparison. I would link it to alcohol addiction likelihood not morphine.Anecdotally about 20 % of my medical year smoked on a regular basis whilst at uni but didn’t seem to have any problem stopping as we got older.