Sammi: Good evening everybody and welcome to this evening’s twilight online Cannabis Medicines Part 1: Current Evidence and Availability. My name is Samantha and I am your host for this evening. Before we get started, I would like to make a quick Acknowledgement of Country. We recognise the traditional custodians of the land and sea on which we live and work and we pay our respects to elders past and present. Okay, I would like to introduce our presenters for this evening, Dr Harry Nespolon and Dr Jan Fizzell. Harry is the current Chair of Sydney North PHN and Principal of two general practices in Sydney. Harry is also a Fellow of the RACGP and a Quality Assurance Examiner for the OSCE Fellowship Exam and has been doing that for the last 10 years. Jan is a public health physician, working as a medical advisor in the Office of the Chief Health Officer at the New South Wales Ministry of Health. She has been working on facilitating the New South Wales clinical trials program for medicinal cannabis and cannabis-derived products and assisting in cannabis therapeutics policy development in New South Wales. So welcome, Harry and Jan.
Harry: Thank you.
Sammi: I will hand over to Harry now to take you through the learning outcomes for this evening.
Harry: Welcome everyone. My name is Harry Nespolon. I will be facilitating tonight’s webinar. I just quickly want to go through the learning outcomes that we are trying to achieve. By the end of the online CPD activity, you should be able to identify the difference between medicinal cannabis and elicit cannabis products, explain how cannabis medicines work, list the types of cannabis medicines available and explain the existing evidence for cannabis medicines’ use for specific health conditions and the importance of evidence-informed prescribing. We will be addressing questions throughout the presentation, throughout Jan’s presentation, but we will try and group the questions up so that we are not disturbing her presentation too much. Now I would like to hand over to Jan.
Jan: So good evening everyone. It is lovely to see so many people on line. My name is Jan and I am here to hopefully provide some interesting information for you. So going through our presentation tonight, I am going to first of all talk about what makes a medicine a medicine, some of the things we know about cannabis and medicine, and then talk about two of the most important cannabinoids available in medicines in Australia at the moment, and that is Delta 9 THC including some of its uses, and adverse events, and cannabidiol often abbreviated to CBD and how it is being used in some of the adverse events, the available combinations of THC and cannabidiol, and the evidence for use in certain conditions from some of the reviews that The Therapeutics Goods Administration commissioned last year.
So, talking about cannabis as a medicine. So, we have got this thing where we regulate therapeutic goods. We know that therapeutics have a known composition. They have got known likely effects and we generally know what their likely side effects are. We have usually got product information and quite a bit of information we can go to, to look up and understand what is going to happen when we use a certain dose on a certain patient. We generally know what the likely activity is in the body so that we know how long it is going to be active for that patient, and we usually know how long it is going to take for that product to leave the body. Now, cannabis is a plant, a fantastically complex plant. There is over 100 cannabinoids which are particular chemicals. We know that when we eat a cannabis plant, we convert some of the non-psychoactive cannabinoids from their acidic form to their active form. We know that there is also potentially other active ingredients in cannabis plants, and we also know that even if we have got exactly a cloned plant, depending on where we plant it, when we harvest it, the amount of light that plant is exposed to, where the product is grown including I think it is latitude, you are going to have a different cannabinoid content from exactly the same clone of a plant. We also know that in Australia, when the police seize cannabis being used illicitly, most of the cannabis being seized in Australia has got really high THC content comparatively and not a lot of the cannabidiol. So, if a patient is using a product that they have grown themselves, from seeds they have obtained in Australia, chances are they are using a high THC low cannabidiol product.
So when we look at the black market, products that people are using in Australia, or look at some of the foods that are available overseas and your patients might talk to you about brand names like Elixinol and so on. We know that overseas and in Australia, the cannabis plant is really, really good at cleaning up paddocks. It sucks up heavy metals where people use a lot of pesticides, but also once we have cut the cannabis it is also quite a good medium for fungal growth. And so there is often significant contamination from black market product. When people try and turn black market cannabis into a tincture, there are lots of different ways, you only have to google on YouTube and you can find ten different ways to make yourself a cannabis medicine if you are so inclined. But that means that we have got no standardisation of the end product, so a person might say “well I had a gram of cannabis that I did something with”, how much active THC they have got at the end of that process is going to vary significantly. So, people get different doses with each batch they make.
Overseas, people in some countries in Europe have cannabinoids available in their food products and we know that some of the companies that do food testing and are trying to market their products as you know, just about medicine therapeutics. Even their own testing by those companies show that there is significant batch to batch variability in the cannabinoid content. The US food and Drug Administration has done some testing of products being sold in America as foods. Some of them being sold as having high cannabinoid content actually have no cannabinoid content, some of them have very different cannabinoid content to what is on the label, and we know that even some food-grade products in some countries actually do contain THC even though theoretically you would think that they would not, because usually one of the regulations about having a food is that they are THC-free.
So when we look at cannabis as a medicine, you know, we have had a history of using cannabis and cannabis extracts as a medicine. And it is quite interesting, even when we look back in history and we look at some of the articles written in the 19th Century about cannabis. The doctors even then were complaining about the batch to batch variability of medicines because they were making it from a plant and at that time they did not have gas chromatography. So, you know, even doctors for 200 to 300 years have been using it as a medicine, but even so it has been difficult to get a standardised product. Towards the end of the late 19th Century, people who were concerned about the intoxicant qualities of cannabis started to see the medicines being moved into poison schedules. So Western Australia had cannabis or Indian hemp put into its poison schedule in 1899 for example, and we have seen increased regulation as people more are concerned about the intoxicant effect rather than their availability as a clinical tool. However, in Israel there was continued research throughout the 20th Century, and that led to us being able to recognise some of the endogenous compounds that our own bodies produce, and that gives us a clue as to how some of these cannabis medicines may actually work in us, on us.
So, we get to the endocannabinoid system and this is a busy slide and I am really sorry about that. But basically, the really exciting thing about cannabinoids are they work all over our bodies. But it depends on the dose. It depends on the person’s particular metabolism as to what effect that they are actually going to have. But, you have got two major ones that people talk about, which is anandamide and 2-AG, and basically they can really affect how your neurotransmitters work. They moderate things like your cyclooxygenase system. They can have immunomodulatory effects. They can help with inflammation because they work on your cyclooxygenase. They can help stimulate appetite. They have things to do with your homeostasis so there is interest in them as you know, potential medicines for diabetes. There is a whole lot of really, really interesting things that these molecules do, but we are still at the very infancy of really understanding how they do this in a standardised fashion.
Harry: And so the cannabinoids that attach themselves at different affinities to the different receptors.
Jan: Yes. So for example, THC binds to your CB1 and your CB2 receptors, whereas cannabidiol tends to block uptake at your CB1 and CB2 receptors and tends to moderate things through other channels. I really encourage people who are particularly interested in the pharmacology of them to do more reading of it, because it is really complex and a lot of it is still, you know as I say, it gets published every day, something new that we have discovered works in a you, know, a rat model of a disease, works in a, how we understand receptors. So it is complex, it is not simple and however, like a lot of things in medicine, just the same as most of us cannot explain exactly how paracetamol works, we tend to be able to move on.
So, we do have registered medicines. So, we do have one registered medicine in Australia which is nabiximols, which is a 1:1 ratio of tetrahydrocannabinol and cannabidiol. Its trade name is Sativex. It is on the Australian register of therapeutic goods. It is marketed here in Australia. It is not available on the pharmaceutical benefits scheme. Its registered indication is spasticity and multiple sclerosis and a lot of the evidence that we will talk about later has actually been generated from clinical trials using this particular drug.
Overseas there are medicines registered, dronabinol and nabilone, THC only products. And just recently there has been a recommendation to the FDA that cannabidiol in sesame oil product manufactured by a pharmaceutical company that has been in clinical trials and has been used here in New South Wales for paediatric epilepsy, has been recommended for registration but is not registered yet.
So we have imported cannabis medicines. So, unlike a lot of other drugs where when they are unregistered in Australia, usually they are imported on a case by case basis, the Commonwealth Government has decided to allow shipments of cannabis medicines into Australia. So we have no home-grown products as of yet. They are largely coming from Canada where they are being held to good manufacturing standards, so there are two standards that have to happen. One is a good agricultural practice standard which is about growing things that are not contaminated with heavy metals and pesticides. And the next one is a good manufacturing practice standard which is about making things to pharmaceutical quality so that you have got some consistency between your products. So if your patient gets prescribed a medicines, then you know, for every batch of that medicine, you should be expecting the same sort of effects and side effects, unlike some of the black market and artisanal products that people are using at the moment.
However, we do not have a lot of phase one data. So there is not a lot of safety data for some of these products. But also, we do not know, you know, in hundreds of healthy people how a lot of these products are absorbed and we do know that they are variably absorbed. Some people are really good at metabolising cannabinoids, some people are slow metabolisers. We do not know all the metabolism because we know that for example depending on what carrier oil a cannabinoid is in, they will be absorbed and metabolised at different rates, and again they get excreted at different rates. The really important thing is to understand it that whilst they are used a lot in Canada, they have not actually been tested for safety or efficacy and we do know however, that some of these products if you are trying to look for which one of these might I look for, some of the products are used in clinical trials in Australia and overseas, so at least they have gone through a human research ethics committee scrutiny before they start being used, and so that gives you some hope that they have got, you know, at least had something go over them with a ruler.
Harry: Do we have any idea how long it will be before there is an Australian product?
Jan: Look, they are in development at the moment and you will probably read it in the share market reports before you read it in the medical reports to be honest, and that is how we are finding a lot of information about the cannabis industry in Australia.
So, one of the things that we often hear about is how much the imported cannabis medicines cost. Unlike a lot of other medicines where you are paying for a lot of the research and development, here a lot of the medicines are actually priced at how much cannabinoid per dose you are getting. So basically, if you have got a 10 mg dose, you are usually paying about 30 cents per mg for THC-containing medicines, so your patient if they are on a 10 mg a day dose, will be paying about three dollars a day. If however they had a THC to CBD medicine where they were using 10 mg a day, it would be about six dollars a day and for cannabidiol only medicines, these are the ones that you are often seeing in the press. Kids using cannabidiol for their epilepsy, are often using 20 mg per kilo, so we wind up it costs them about $120 a day and that is where the real affordability argument comes in. If we look at black market products, in New South Wales, we see hydroponic cannabis costing about $10 to $50 a gram. In Canada, we see patients using about 2 grams daily on average, so that would be about $20 of black market product a day. And I know lots of people can grow their own and do different things, but you are not necessarily doing your patient a favour by sending them down to the pub, because the cost may not be as different as you think. It depends a lot on the dose and we have seen very different doses from what we use in cannabis medicines.
Harry: So this is likely to limit its appeal to a lot of people?
Jan: Well, I think particularly, well if a patient is really interested in it, if they think it is going to cost so much that they do not want to talk to you about it, if you can actually reassure them that if you are on a lower dose it is possibly not going to cost you that much compared to what the black market is, that is a good conversation to have because the patient at least would be having something that is safe and quality controlled. If it a conversation about a child with paediatric epilepsy, like a lot of the really expensive drugs that are highly specialised drugs, they are usually prescribed in our public hospital system and we have mechanisms to do that, and so that is about sending people to the appropriate, you know, highly specialised centre that deals with high cost drugs all the time.
So, we can have a look at some of the components of our cannabis medicines that are available in Australia. So the first cannabinoid I will talk about is delta-9-tetrahydrocannabinol. Now, one of the myths is of course, that medicinal cannabis cannot get you high. But actually, using delta-9-tetrahydrocannabinol is actually, it is a very legitimate therapeutic, so trying to say oh you know, medicinal cannabis will not get you high and you should not use this product is probably not a good message, because this is actually a product that is quite well studied. It is responsible for a lot of the psychoactive effects of cannabis. We know that it reduces nausea and vomiting and that is in fact its registered indication in the United States and Canada. Dronabinol is the synthetic THC product, and that is its registered indication. We know that in animal models of pain, it can help reduce pain but that has not necessarily translated through to the human clinical trials. A lot of what I am talking about tonight is if you are a mouse or a rat, cannabis is an excellent drug for what ails you. But unfortunately, like a lot of things that we see working really well in mouse models, when we move it to human translation, it is not always as effective. We think it can improve appetite. We certainly know that, you know, there is the legendary munchies effect, however you know, some clinical trials have shown it to be more equivocal. And the really interesting thing about it is that in some doses it is anticonvulsant and in some doses it is proconvulsant and you sometimes do not know until a person has actually had it. We usually see oral doses starting at about 2.5 mg twice a day and the usual maximum is about 30 mg a day, because after about 30 mg a day, most of the product information from the drugs register overseas, that is when you really start seeing the psychoactive effects well outweigh any clinical benefit from anything else.
If we look at the adverse effects of using a THC product. For this slide I have used the product information from one of the registered products overseas. We see asthenia which is a general weakness and malaise. I had to go away and look that one up because it was not a word I use often in my clinical practice or in my public health medicine practice. We do see palpitations, tachycardia, vasodilation and facial flush, none of which would be you know, hugely concerning. Interestingly, paradoxically, it can also cause nausea and vomiting. I am not going to talk about chronic cannabis dependence and some of those other issues that come with cycle vomiting with that. But you know, it can actually contribute to nausea and vomiting. With the CNS it can also cause dizziness, euphoria and of course depending on who you are, that euphoria is either a benefit or a negative. It can cause a paranoid reaction in some people. It causes people to feel sleepy. People find that they have trouble organising their thoughts. Some people feel nervous and anxious when they take it, confused, feeling out of body and hallucinating. So, if you look at the ones with the star, they are not really uncommon, you know if you treat 100 patients, you will have three patients with that as long as you do not go too high with your dosage.
When we look at cannabidiol, this is the one that is a particularly interesting molecule. We are still learning how to use it and what the likely side effects are and even what the long term effects are going to be of this. One of the really interesting things about cannabidiol is that it seems to modify some of the psychoactive effects of the THC when it is co-administered. It does not completely ameliorate them though, so we cannot say if give a 1:1 ratio of cannabidiol and THC that somebody will not have a bad psychoactive effect from the THC, but we do have some hope that people will have less problem. We have seen it become a sedative at around 300 mg a day. We do however know and this is really important when people are prescribing it, that it is a potent inhibitor of lots of enzymes in the people, so any of those drugs that are completely notorious for it, welcome to cannabidiol it will have a nice interaction with them. In refractory paediatric epilepsy syndromes, they are using quite large doses, around 15-20 mg per kg a day. We actually do not have a lot of evidence, so some of the preparations that you will see imported say have a 50 mg capsule. Now, we do not have a lot of evidence for cannabidiol alone having a particular clinical effect at low doses. There is lots of theoretical things it might do. It seems to be an antioxidant. It seems to be an anti-inflammatory. It seems to be neuroprotective. It some of its immunomodulatory effects one of the interesting things is you know, are we getting some of the effects of cannabidiol in paediatric epilepsy because you know, they respond to prednisone, is it the immunomodulation of the cannabidiol that is actually helping to control some of those seizure disorders in those kiddies. So it is not however, completely side effect free. When we look at the results from the clinical trials for paediatric epilepsy, we can see that they are documenting common adverse effects, and they include the kids getting diarrhoea, they become sleepy. Some of them can run an unexpected temperature for no good reason. Their appetite can be decreased which you know, you can understand if it is opposing some of the effects of THC. THC stimulates appetite. Cannabidiol opposing those effects may decrease the appetite. Some of the kids vomit and what we do see in paediatric epilepsy, is we are seeing really high levels of some of the anti-epileptics. And so they are getting high levels of rufinamide, piramate, clobazam, and so then when you have a look at other drugs that your patients might be using, for example, warfarin, metoprolol, amitriptyline, paroxetine, some NSAIDs, you might find that they get increase serum levels. So it is really important that if for whatever reason a patient is doing something with a cannabinoid, that you have got an open and honest relationship with them because otherwise if suddenly they are having postural hypertension and really sleepy, it might be their amitriptyline that they are also on for their pain, rather than the cannabinoid itself. It is not the cannabinoids doing it, it might be their drug interactions. So it might be about if they are getting a benefit from the cannabinoid, dropping back on some of their other medications.
Harry: So we have had two questions. The first question is, what are the effects of the cannabinoids and alcohol, and secondly, can you drive while you are taking them?
Jan: Okay. So we tend to see an additive effect of cannabinoids and alcohol as far as adverse events go. So they tend to potentiate the intoxicating effect of THC. It has not had a lot of studies that I am aware of, cannabidiol and alcohol, so I cannot comment on that, because believe it or not, people with paediatric epilepsy are not heavy drinkers largely. So that is where most of the clinical trial data has come from, and there has not been a lot of systematic collection of adverse event data and drug interactions with alcohol and cannabidiol because the number of adults who are taking cannabidiol alone are small in the reported literature. As far as the THC, alcohol certainly potentiates the intoxicating effects of THC. Now with driving. With driving, we put together an expert panel in New South Wales to talk about driving, because is there a safe time to drive, how long to drive after. And unlike alcohol, where we see a fairly linear response between blood alcohol goes up, impairment goes up, cannabinoids are really interesting. Some people have significant impairment at a certain blood level. Other people have got zero impairment. People who have got heavy use will have cannabinoids washing around their system for longer times than people who are using low doses. So the answer is, we have no safe answer. What we do know, is that there are good driving studies with people using THC which says that they have trouble staying in their lane because they get this inattention thing happening. We do know that generally it is an intoxicant so people’s judgement about making decisions about “oh, so I have got to do something right now” are there. So we also know that authorities overseas, so Canada says if you are on a THC product, do not drive. Israel says if you are on a THC product, do not drive. The product information for Sativex says, if you have spasms from multiple sclerosis and you are using Sativex, you probably should not be driving. So, our advice that we were given at the Ministry of Health from our expert group was generally people will be impaired and as such they probably should not be driving. And it is also not a defence under the Drugs Misuse and Trafficking Act to have had a cannabinoid prescribed to say that you can, you know, “I have been prescribed this, I am right to drive.” It is not a defence under that Act. And at the moment, we do not have the collective evidence to be able to go to our colleagues in justice and say we need an exemption for this group of people, because one of the levels of impairment which I think is like five nanograms per mil in blood of THC, also crosses the therapeutic boundary of what you actually want somebody to be achieving for some of the therapeutic effects. So, by definition, if you have got a therapeutic effect of the drug for some people, you also have impairment. So, we are not at the stage where we can go to our colleagues and make a clear case for why it should not be an offence to drive with THC in your system.
Harry: So currently in New South Wales, do not drive.
Jan: Do not drive.
Harry: If you get picked up you are in trouble.
Jan: Yes. And if you ask me how long after a patient has been administered THC, can they drive for, at the moment the advice from the guys who are doing the chemotherapy-induced nausea and vomiting trial, so those patients are only having it for a very limited time because they are only going to be feeling sick from the chemotherapy for a window of time, I think they are sort for saying 48 to 72 hours. But that again is assuming those patients are not regular users of cannabis. They are de novo. But it is not 12 hours like you might see on the RTA website. They are being quite conservative with their advice to their patients, and for a patient being administered it every day, we do not have a safe level to say yes, you can drive.
Harry: And that is because THC has got quite a long half-life, does it not?
Jan: Absolutely. And it is variable. And, the saliva test does only test for THC. It is not testing for metabolites, but to get a blood level going and keep it going, particularly for an oral product, you are probably going to cross that impairment boundary. So that is the really hard part. It is a bit like you know, you are assessing all your patients that you are prescribing potentially sedating medications for, and again, if you have got a patient that has got such a severe condition that they might need the THC, that condition in itself might be an impairment that suggests that they should not be driving. Yes, so again, it is about assessing your patient with the impairment and so, if they have got a general impairment that you are treating, really have a consideration about what am I treating? Has this person got such terrible pain that they are distracted anyway, that they probably should not be driving. Has the person got epilepsy that they probably should not be driving? Cannabidiol in and of itself, will not get picked up on a saliva test, but because of all those drug-drug interactions and the fact that it is usually being used for refractory epilepsy, the person probably should not be driving.
So, the last drug I am going to be talking about is nabiximols and that is that registered product, Sativex. It is registered in Australia for MS spasticity. Per spray, there is 2.7 mg of THC and 2.5 mg of cannabidiol per spray. You will notice that I am not abbreviating my cannabinoids to CBD and so on that you might have heard in some other presentations, and that is because we are trying to encourage good prescribing practice, because what we see is people either not being familiar with the abbreviations and trying to prescribe a cannabinoid that is actually not commercially available because they have got mixed up. One of the classic sayings is that it is cannabinoid scrabble, you know CDN, CBG, CBD and so on. So we are really encouraging doctors when they are prescribing it, THC is a fairly well known abbreviation for delta-9-tetrahydrocannabinol but we would really encourage people as more cannabinoids become commercially available, please spell out your cannabinoids when you are writing a prescription. This one is administered as an oro-mucosal spray. You do not need to go to the TGA to get off-label use approval, just like you do not need to go to TGA to be able to prescribe amitriptyline off-label for example. It does need State authorisation, as it is a controlled drug and it has been investigated for use in chemotherapy induced nausea and vomiting where it was promising, that study had 16 patients in it. There have been huge studies done for it in chronic cancer pain and across the different studies it was a non-significant improvement in pain. So there was a tendency towards an improvement but it was not significant and whether it was clinically significant is something else to debate. But what they do seem to see is an improvement in quality of life in these chronic cancer pain patients, which if you are thinking about what are you really after in a person that you are looking after in palliative care, that is important. There has been a small pilot study in rheumatoid arthritis and that has tended towards disease severity improvement and pain improvement, but it does not suggest that tomorrow everyone with rheumatoid arthritis should be prescribed nabiximols. And there have also been recent clinical trials in New South Wales around mitigating cannabis withdrawal syndromes, so it has got a really interesting role perhaps in mitigating cannabis withdrawal syndrome and I think overseas it has been investigated with some of the narcotic withdrawal syndromes.
So I have just mentioned some of the other cannabinoids, and as I said at the beginning, there is over 100 cannabinoids in the cannabis plant, and they are really interesting. The really important thing to understand is, by the time they are usually in a medicine, they are in a very different concentration to what you would normally see in a cannabis plant and that is because usually they are extracted and refined and then put back into some sort of medicine so that we get that standardised cannabinoid ratio. So we are starting to see people being exposed to much larger doses of cannabinoids than they would have had through normal mechanisms. Currently they are not commercially available in Australia. There is this idea of the entourage effect where it is the combination of cannabinoids and other phytochemicals that are available in cannabis that work together to give its clinical effects. It has been difficult to quantify because of that idea that you know, different plants will have different things, so how much of the entourage effect is important. And also, it is really hard to quantify because a lot of the chemicals are not unique to cannabis. They are found in rosemary. They are found in lemons. They are found in other things that we eat, so how much of it is because it was present in the plant and how much was different. And again, these other turpenoids, limonene, all of these are very different proportions in different products.
There are very few studies examining the differences between plant derived cannabis medicines and synthetic cannabis medicines. It is usually synthetic cannabis medicine or comparator or plant derived cannabis medicine or comparator. People are starting to do more studies looking at you know, if we have plant-derived full spectrum extract type thing where you have got trace cannabinoids in it versus pure, but they are not mature. Everything available in Australia is pretty much plant-derived. Nabiximols is plant-derived. It has got trace other cannabinoids in it. All the goods coming in under TGO 93 have trace cannabinoids in everything else. So there are traces of other things in all of these drugs.
So, when we talk around where are we seeing the real interest at the moment. On my list here is not paediatric epilepsy and we will certainly talk about epilepsy, but one of the things is with paediatric epilepsy, is it is being used in really refractory kids. And so generally, our advice would be just like any other significantly refractory condition, you probably do not want to take responsibility for prescribing an experimental drug to a patient with really refractory disease unless you are working with the specialists in that particular symptom or disease and that is just for everybody. We do not expect an adult gastroenterologist to be prescribing for a pain medicine problem. We do not expect an intensivist to be prescribing for anorexia. We just expect people to be thinking really carefully about what they are doing and what is in my normal scope of practice. Where do I work with my colleagues and to try and make sure that the patient has got coordinated care so that we do not wind up with this problem of either a doctor feeling compelled to prescribe and they are not comfortable to do it without support from their colleagues, or a patient sort of being led up the garden path a little bit I think with an idea that something might help when it might not.
So, the TGA guidance documents - so as I said earlier, the Therapeutic Goods Administration along with a whole lot of groups - they involved RACGP as well as consumer groups, as well as groups with special interests in the various conditions, to develop some guidance for the use of cannabis medicines. What it really is, is an evidence review. It does not help you a lot if you want to know what dose I should use or what medicine for what condition. But it does give you a broad understanding of what is the state of the evidence of systematic reviews for the common conditions that people are interested in prescribing for. So, one of the big conditions of course is palliative care, and the messages that come through is that it is adjunctive to standard palliative care management. You do not abandon your normal tools for looking after your palliative care patients to use a cannabis medicine. You think about where could this cannabis medicine fit? What symptom am I trying to target? And then you chose your cannabis medicine for that. It is really probably not going to modify the course of a patient’s disease, although sometimes you know, patients feel that it has made a huge difference to their quality of life and so they feel like things have happened. And one of the things that is really difficult in this space, is when we do the clinical trials, such as the one I talked about, there is large, large clinical trials for the Sativex for chronic cancer pain, we get “it might help a bit”, is really different to patient’s personal stories about you know, “I took it and it was the best thing,” “I could sleep for the first time,” “I felt so much better.” So we are still trying to understand what it is that the patients are responding to. Is it the placebo effect where you know, the harder it is to get access to a treatment, the more likely we are to feel that it works? Is it the fact that you had that dissociative experience where the pain is still there but actually doc, I do not care about it? That is what one of my palliative care colleagues has said when she talked to her patients using it. You know, the pain is still there, but I just do not care about it when I am taking cannabis. Which you know, is a relief for that patient. And so what we often found when we were trying to work out what to do with the clinical trials, was that the studies were often missing the primary endpoints, but sort of consistently what was being found was this improved quality of life and they seemed to be fairly well tolerated. So we have got this clinical trial underway in New South Wales looking at appetite stimulation and there will be a new trial announced soon that is just about trying to pitch some of that quality of life thing and it is more of an access trial that will be available to patients across New South Wales. We are running that with the new Cannabis Research Institute up in Newcastle and they have got a number of GPs, palliative care providers, so that we are trying to design that trial so it is accessible as possible and there will be more information about that once we have got that all solidified and the ethics committee has approved it and all those things.
Harry: And these guidelines are very easily found if you just google the title.
Jan: Yes, they are. Absolutely. So what did they find when they actually looked at it? And this is this problem that I am talking about where there was no differences between cannabinoids and placebo for improving caloric intakes. So we would really expect that to have worked. You know, everyone knows somebody who did something at uni and got the munchies. But when we see it in clinical trials, we are not seeing it. We are not seeing that huge improvement in appetite. We are not seeing a huge difference in nausea and vomiting. We are not seeing a big difference in pain. We might, you know, we are seeing a trend towards it helping, but we are not seeing a statistically significant effect. But we do know it is fairly well tolerated and we are not seeing a huge number of adverse events. So if it is something that you have tried your standard manoeuvres in palliative care and you have got a patient who would like to try it, then perhaps that is what you are taking into account. We have also seen some interest in dementia and it is not helped by the headlines, like “Cannabis will help reverse dementia.” I think a lot of us have got a family member with dementia or know a close friend or, you know it is a very common condition and it is a very distressing condition for family and for patients and for everyone. Unfortunately, we know with dementia that pharmaceutical interventions are not ideal and it is behavioural management and everything, and so we have got to take that all into account before anyone thinks about using a cannabinoid for dementia. There have been two trials done overseas where they looked at the dronabinol which is that synthetic THC product, versus placebo in Alzheimer’s type dementia. In the trials they had small numbers. They had difficulty recruiting to them and that is something we are seeing commonly with cannabis trials. They often fail because people do not want to be recruited into them, either because they are already using something and they do not want to move on to it, or there is a stigma about using cannabis as a medicine. What we see is that for dronabinol, there was some weight gain and using dronabinol we had negative effect decrease in therapy phases and we saw a greater reduction in patients receiving cannabinoids. So it could help, because we know that with dementia, we can see you know, a problem with weight loss and so you know, something that stimulates appetite not necessarily a bad thing, something that might help with anxiety and depression. But again, it is very experimental. We are not going to reverse dementia at the moment, again unless you are a mouse. Really good if you are a mouse. I cannot help wishing I was a mouse. But at the moment, we have not got the evidence in human studies.
So, moving on to epilepsy. And so, we have had that historical use of cannabis tincture for seizure control, and to be honest it largely fell out of use because we got better drugs and those better drugs were things like bromide and phenobarbital which most of us would not think of using in a human any more. However, we do know that we have got kids who are still fitting after lots of exposure to lots of different anti-epileptic drugs and so we have got clinical trials currently focussing on higher dose cannabidiol in treatment resistant epilepsy syndromes. If you talk to the paediatric neurologists, they will talk to you about significant drug-drug interactions and the fact that this needs to be monitored really closely. They have seen liver function tests get very, very deranged. We have already talked about the fact that it is already a very high cost thing, and so if you do have paediatric patients who are interested, usually they are refractory, they have failed at least five drug therapies. They are probably under the care of our paediatric neurologist, but all paediatric neurologists in New South Wales are actually authorised prescribers for the cannabidiol and all children who meet those particularly refractory criteria are actually eligible to go into our pool to receive compassionate access and at the moment that is being triaged on clinical necessity by a team of paediatric neurologists who set up that criteria.
Harry: And so do they get the cannabinoids through the hospital?
Jan: Yes. So they are being supplied directly from the four centres that have got paediatric neurologists operating from them.
So, if we do look at epilepsy patients, and of course some of these studies have not just been done in under 18’s, they are actually being done in people to 25 and 30 with some of these complex epilepsy syndromes such as Lennox-Gastaut and Dravet syndrome. I am not professing to be an expert in any of these particular syndromes, but they are very refractory things. And so, it favours CBD as far as working. It can help in some people achieve a 50% reduction in seizures. But what we do not have is the evidence that you would sort of see in the media, where you would expect that every child being administered CBD would suddenly stop fitting for life. We also do not have a lot of evidence that it is useful as a rescue medication, so again you will see some of the parents in the media sort of, you know, putting out a dab of cannabis and rubbing it in the cheek. There is not a lot of evidence that it actually works as a rescue medication and I would probably prefer any relative of mine to be given an urgent benzodiazepine. I think that is still the treatment of choice, rather than have cannabis rubbed in their cheek. But it is an interesting drug. There are other cannabinoids that are being investigated for anti-epileptic effects, but we are not there yet.
Now, here we are moving onto chronic pain and this is the really challenging area I think for everybody, because again, we have got a cluster of symptoms that at this point we know drugs are not the answer for, but at the end of the day, drugs are sometimes the only answer we have got. We have got this problem of a lot of anecdote in the community about how it will really change somebodies pain and what we really want to do is help people understand where the actual evidence is on chronic pain. And again, it is being studied in clinical trials, some of which are quite large. But the real thing to emphasise here again is that drugs are not the core component of therapy. Patient education is really important particularly when they are expecting that the drug is going to do wonders for them, and the real take home is that there is this need for larger trials of sufficient quality, size and duration to help us understand what role if any, the cannabinoids have in chronic pain.
So when we look at these in clinical trials, the review evidence suggested that to actually get an outcome we are going to have to treat somewhere between 22 and 26 generic chronic pain patients to get one to have some benefit. So we have a look at our therapeutic guidelines for analgesia they will usually say around an NNT of about 7-8 is where we want to be at for chronic pain. So we normally would not pick up our prescription pads for this drug. We also know from other studies, it is not in this guidance, but it has been discussed by the authors of the guidance, that the number needed to harm if we can get that at about 7-9. So we have got a terrible number needed to treat to number needed to harm ratio. We do see with people with MS related neuropathic pain that they seem to get a better effect from it. We see a non-statistically significant increase in the proportion of pain who achieve a 30% reduction in pain intensity, and for non-MS related neuropathic pain, we see a 50% reduction in pain and reduction pain scores compared with patients taking a placebo. But when we show these to our colleagues in our Faculty of Pain Medicine, they are not very excited about this. And one of the things they are concerned about is, at the moment, a lot of people do actually self-medicate with chronic pain and if we look at a study that is taking place in Australia at the moment, and has been published. It is called the POINT study, and this is actually looking at people who are using pharmaceutical opiates. And what is happening, they have gone and had a look at these people, so it is over 1,500 people who have been prescribed opiates for chronic non-cancer pain. And so they had a look on cannabis use, the cannabis use disorder that could be diagnosed and cannabis used for pain. So out of those 1,500 people, 16% had used cannabis for pain relief, including 6% in the past month. 25% reported that they would use it for pain relief if they had had access, and the really interesting thing is, it is a younger group who report a greater pain severity, they get a greater interference from it, they do not cope with their pain as well, they have more days out of role in the past year. And that is actually something that we are seeing reflected in Canada as well. They looked at 1,000 people coming through the doors of one of their large rheumatology clinics and looked at who was using cannabis for medical purposes as they have it in Canada, versus their other people, and again, they were younger, they were poorer, they had less coping with similar objective measurements of disease. And so one of the questions is, are we actually seeing cannabis use because people are having trouble negotiating a potentially expensive and difficult to navigate healthcare system, and so people feel that by self-medicating, they are actually doing themselves some good. But having said that, we do not usually recommend that people go home and drink alcohol for their pain, either. So, we do know that it is being used for pain relief in Australia at the moment with a lot of people self-medicating. So it is a difficult question for GPS, because one of the questions is, “Well if my patient is self-medicating, would it not be better to put them on a legal standardised product?” But the problem is, we still do not know whether that is an appropriate thing to do. We do not know if that is going to stop them using other cannabis sources. We do not know what to prescribe them. There is a whole lot of thorns in that particular argument that we have not quite got to the end of that discussion. So I think it is you know, it is not an unreasonable question, am I doing a harm minimisation gesture, but the problem is, we may actually just be prolonging somebodies difficulty with rehabilitating from their chronic pain syndrome. So it is a difficult thing.
Harry: And they are much more likely to be driving.
Jan: And they are much more likely to be driving. And so there are all those harms coming into contact with the criminal justice system or losing your licence and all of those things. So we are better off possibly recommending other therapies as best we can.
For multiple sclerosis’s best studies we have got a registered medicine and this is what people are using for other cannabinoids or complexes we have got limitations because we do not have quality evidence for those other cannabinoids being used. We do not have a lot of evidence around disease activity or disability progression, although there is some theoretical immunomodulatory effect and some of the large registry studies overseas are starting to monitor for are we getting better outcomes for people if they are using baclofen versus nabiximols. But we do not actually, also one of the problems is, often it is not baclofen plus nabiximols versus baclofen. It is often nabiximols versus nothing. So we actually do not know how well nabiximols goes against for example against some of our current standard treatment, so that makes it complex as well.
When we talk about chemotherapy-induced nausea and vomiting, the general guidance from the document is high THC medicinal cannabis products can sometimes be effective for nausea and vomiting but we have had a lot of revolutionary treatments since the clinical trials were being done using dronabinol. And you know, they include, you know the advent 5HT3 antagonists and there are newer things like NK1 aprepitant and so on, those ones. And even more recently, olanzapine has been shown in a large RCT to have a significant impact in chemo-induced nausea and vomiting. And so, we are actually having trouble recruiting patients into our CINV trial, because actually we are doing a much better job of controlling chemotherapy-induced nausea and vomiting even than what we were doing three years ago, which is really, you know, such a change because there are some people who do not tolerate the 5HT, that cannot tolerate the old drugs, like you know they get the terrible dystonias and the akathisias. So you know, there are a group of people who actually are a bit stranded for anti-emetic therapy. But for general nausea and vomiting, generally you have got to be really careful before you would start recommending a cannabinoid. But for chemo-induced nausea and vomiting, we have actually got a clinical trial available in a lot of our centres at the moment. It is using a THC and cannabidiol capsule that is being manufactured by one of those Canadian companies who have got GMP certification. It is at all of these centres around New South Wales and so if you do have a patient that is particularly interested, it is probably worth talking to them about getting involved in the clinical trial. The trial methodology is that they are exposed to cannabinoid or placebo in cycle 1, and then switch, and then choice of therapy for cycle 3. So everyone gets a cannabinoid at some point, and then it is unmasked at the end and if the patient has actually responded to the cannabinoid, they are then eligible for ongoing treatment with those cannabinoids. So in helping us generate the evidence which is what we really want to do, we want to see what place these have in therapy, so that as doctors when we are actually asked to pick up a pen and prescribe, what do we do?
So moving on to what they are doing in Canada. So, Canada is often held up as the model for care. One of the things to recognise in Canada, is that in Canada doctors actually do not prescribe cannabis medicines. They can make a recommendation that a patient can access cannabis, but as part of that recommendation, they do not actually specify which cannabinoids are being used, and the patient can take that recommendation for 1 gram of cannabis per day for example, and take it to the local dispensary where the cannabis guru there will inform them what will work for them best. So the doctor does not have a lot of control over what their patient actually receives. So it is a very different system of accessing cannabis and in fact the Canadian, I think it is the Society of Physicians and Surgeons in Canada, have said now that we are going to decriminalise cannabis, we want that whole regime gone. But there is a different argument for a different day. So basically though, what they have done in Canada is where the physicians have been, particularly family physicians are being asked, this is the flow chart that the family physicians in Canada have suggested that people have a look at. And this is trying to put things into perspective as to what a general practitioner, a family physician might actually want to do. And so they are basically saying, is it for neuropathic pain, palliative pain, CINV or spasticity or spinal cord spasticity, because you know if you have got spasticity from one neurological disease, you are probably going to get similar effects for a different neurological disease with the same outcome of spasticity. Let’s not get too precious. If it is not for those things, as a family physician, you would recommend against use. Now that is not saying a specialist, one of the things they discuss in this article that I have listed there, and it is freely available, you do not have to be a subscriber, is you know, why as a family physician you might not want to be prescribing for refractory paediatric epilepsy for example. So that is why it is not addressed in this flow chart. These are things they say, you know as a GP, as a family physician you may be confronted with. And so, you know, they are sort of talking about for people with neuropathic pain have you done more than three medications? Have you done more than three standard interventions for that patient? For the palliative pain, have they had two different interventions? Because you know, lower standard different pain mechanisms again for all the different ways people get pain and discomfort from cancer. And again, are they refractory to standard therapies for these things? Then maybe try one of the medical cannabinoids as an adjunctive therapy. And so in Australia we have got more control over the cannabinoids that we use here. We do not have dronabinol for example available here, but we do have TGO 93 regulated THC products. They generally say do not let your patient go off and do it themselves, because particularly smoke, because of the high risk of bias in available studies and we still do not know what is going to happen if people are exposed, a lot of these at much higher doses than we are used to. But always talk to your patient. That is the really important thing about not shutting down the conversation. It is about talking it through with your patient.
One of the questions I have just seen coming up was, can we monitor blood levels, and the answer is we have just resourced the University of Newcastle Centre to actually do some of that work with us and that is around being able to get some blood levels, so that if a person has started at what they thought was a low dose of THC and the patient has a very abnormal reaction, such as seeing fairies or fitting or doing something really abnormal and you want to know what has happened, I understand that if you get a serum tube collected and send it to John Hunter Hospital, you know, you can request your normal pathology collected divert it to John Hunter Hospital to ACRE for cannabinoid studies, that can be done. But as I say, we still do not understand a lot about what a blood level versus a symptom means. But it certainly can be done, but it is not routinely done at the moment. But considering how little we know about how these medicines are absorbed and how they are acting and at what doses they are acting, and at what blood levels they are acting, we are certainly encouraging as part of that big palliative care study I was talking about, you know, we are sort of saying 24 hours after studying we would like to get a tube of blood out of everyone please, so we can see how very different people are.
Look, we have also got a laundry list of things that people are also interested in and that you will see in the media as something that it is really important that we have access to cannabis medicines to be able to fix. So PTSD is a big one. We have seen, the things that I am showing here are things that people have studied. We have seen studies for THC, THC cannabidiol and nabilone. In the RCT using nabilone we saw some decrease in nightmares for PTSD but there was a high risk of bias. One of the hard parts about doing research with cannabis medicines is that people usually know when they have got THC on board. I am sure that will come as a surprise to everyone, but it is really, really hard to blind people to whether they received THC or not, because a lot of people do actually get those side effects, well side effects or effects again depending on your personal predilection. For anxiety, people are interested in studying cannabidiol and nabilone. Basically at the moment, we are seeing a person given a single dose of cannabidiol and seeing whether they can be made as anxious as when they have not. We have not got long term exposure to cannabidiol for anxiety. For depression, we have not got much human evidence. For Tourette’s, we have seen some case reports in the literature. There has been use of THC which has seen some tic reduction, again uncontrolled studies, high risk of bias. For Parkinson’s disease, there is a lot of interest and anyone who has watched YouTube would think that it was going to fix tremor and fix micrographia and fix everything. There might be some improvement with dyskinesia with cannabidiol, but we do not have really good hang your hat on it evidence yet. For Huntington’s disease, there was some small benefit from nabilone. People using cannabidiol and nabiximols probably did not see an effect. For psychosis, people have used cannabidiol and we are likely to see in the future much, much better studies around schizophrenia and psychosis because cannabidiol seems to be a really interesting anti-psychotic but we are not there yet. We have got to use our standard treatments at the moment.
Moving on to the slightly more – curing cancer. Anyone who wants to google “Can cannabis cure cancer” they will find out that the answer is of course it can. There are thousands of studies, where is the government deliberately hiding the cure for cancer because we are in bed with big pharma. And I only wish that was true, but unfortunately, we seem to be, there are some really interesting results of cannabinoids, because they can promote angiogenesis, they can inhibit and promote mitosis and some of them are likely to be pro-mutagenic and some of them are likely to be anti-mutagenic, and as I have said to a number of disappointed people I can cure cancer in a petri dish. It just involves bleach and I am sure you would not like to me to advise you to drink bleach. So we just do not know. What is really interesting though, is that they did some interesting mouse models using cannabidiol in a model of glioblastoma multiform, and what they found was if they gave the mouse just cannabidiol it did not work. If they gave it temozolomide it kind of worked, and when they gave it cannabidiol and the temozolomide together, the effect was much better. So they have moved that on into a human study, which for glioblastoma multiform, it might work synergistically with temozolomide. But it is not like we have got live studies with lots of evidence. And then we wind up with all those problems of it is a rare disease, how do we generate good evidence in rare diseases, which I am sure we can all have a good conversation about another day.
This is something that parents are often really interested in and there is a study underway in Israel, but it is certainly too early to be encouraging people to be taking it up as a medication. One of the things that you know, is potentially as I said, cannabidiol can be a sedative, so if you have got a disruptive small child that you give a large dose of sedative too, they become a less disruptive small child, and so we do not know how much of it is that and how much is actual behavioural modification. So that means the same in ADHD they tried using nabiximols and we had a non-significant trend to improvement in symptoms. So they are really interesting things, but we are not there yet.
Inflammatory bowel disease is one of the really interesting areas, where Israel did a randomised control trial and they have also done, they did a big retrospective trial of people smoking a particular blend of cannabidiol and THC and then they sort of said, well that is actually probably not how we are going to be delivering this treatment to people with inflammatory bowel disease in the future, so we do need to do randomised control trials and so I think there is that underway in Israel and there is certainly a lot of interest in it, because it is a really disabling thing and you will have seen it in the media here with families who are using it.
Fibromyalgia. One of the things that people are suggesting is that fibromyalgia and irritable bowel syndrome and any other disease that we are not particularly good at characterising the pathophysiology of, are of course because of an endocannabinoid deficiency. So how do you fix that? You give somebody cannabinoid. So there is a lot of interest in the people that we have trouble giving a diagnosis to. People who are feeling abandoned. People who a doctor has said to there is nothing more I can do. And they are searching for something, and here we have got this really interesting group of molecules that can do really interesting things and who can blame the patient for wanting to hang their hat on that. I mean, it is a really normal, human reaction, especially if we as doctors do not have much more to add. But for fibromyalgia they have looked at THC. The TGA guidance suggests it is not robust enough for comment. There has been a study looking at dronabinol which is that synthetic THC versus amitriptyline. It was as good as amitriptyline. We know a lot more about amitriptyline and it is very easily available, so if you were going to treat it, I would not suggest that we went straight to THC. But again, you know, some people do not tolerate things, so.
Harry: So Jan, just a few questions.
Harry: So one of the questions was, can you become addicted to the medicinal cannabinoids?
Jan: So, as far as THC goes, we know that with long term use, about 10% of people will develop some form of dependence. As far as if you stop it abruptly, do you have those physiological problems? People might not feel great, but it is not like it is highly dangerous to stop suddenly.
Harry: And one of the other questions is, if someone is pre-disposed to psychotic problems, should they be getting cannabinoids?
Jan: Well, they should not be getting THC, that much is certain. So basically there is a number of contraindications to any of these medications, and they are the standard. For THC in particular, personal history of psychosis, personal history of intolerance of the drug. We would even go as far as to say family history of psychosis, so if you have got a strong family history of schizophrenia because there is some genetic component to it, we would probably say do not go mucking around with THC if you can help it. We would also suggest for developing brains, probably not for under 25’s preferentially. Now there is debate you know about that, but generally developing brain plus psychoactive substance is not our best thing to do. So it is usually recognised as contraindication. Now as I mentioned, cannabidiol is actually being explored for its anti-psychotic effects, so it may be that in 10 years’ time, we will have a very different conversation about the place of cannabinoids in psychiatric disease, but I reckon we will be having that conversation in increments over the next 10 years.
Harry: So Jan, can you whet our appetite for the second part of this presentation please?
Jan: So look, what I think we have talked about tonight is the evidence and one of the questions is, why is New South Wales Health investing so much time in an area for which we have got such equivocal evidence? Why is the government going out and spending all this time, almost promoting the use of these medicines? And I think what we are really interested in doing with this is trying to help GPs have really good conversations with their patients about these, because I think it is one of these things, that if we do not engage, patients will go away and try to manage it themselves, and so I think that is really important. And so in our next one, we will be talking about the prescribing processes, we will be talking about some of the reasons why the controlled drugs are controlled drugs. I know that everyone usually knows it, but we have had this really interesting constellation with the cannabinoids, because we know general practice use of special access scheme and authorised prescriber is pretty rare. There might have been some use of authorised prescriber early on in the piece for some of the medical abortion type drugs, but it has not been a common thing in general practice to use unregistered medicines, and that is because usually we would like to have a lot of information before we do use medicines. And again, the use of the highly controlled drugs like the psychostimulants are again usually the province of paediatricians or psychiatrists or respiratory physicians, not something that GPs have often had to fill out forms with. So if we can help navigate the processes, that is something that will be very helpful in the future, you know, in the times when you do have the patient, that I know what the evidence is, I know how much information I have got and on the balance I think this would be a good thing to do, what do I do next? And so one of the things that we can do in the meantime between now and the next webinar, is we have invested money in putting together a cannabis medicines advisory service. It is available 9-5 Monday to Friday. They are there to help. You want to know what the evidence is for use in a condition? They can help you with it. If it is a weird and wonderful that the TGA have not done, they can go away and do a literature search and come back to you with it. They can tell you about the different cannabinoids that are available. They can help you with the paperwork. They can tell you which form you are going to need to fill in. So I would really encourage people if they have got questions or are super excited between now and the next couple of weeks, this is what I suggest is your first stop. Call the service. They are there to help. We have got drug information and pharmacists there and we have got a clinical pharmacologist there. So they are there. They are experts in medicines and they are there to help and they can also tap into that huge network. And they are located in Newcastle and Hunter New England, so they understand the issues that we are all GPS, and also have an accessing specialist services. So that it what we are there for.
Harry: I would like to just quickly go over what our learning outcomes were. I would like to hope that we have been able to demonstrate the difference between medicinal cannabis and illicit or black market cannabis. We have briefly spoken about how cannabis works in our body. We have looked at the cannabis medicines that are available at the moment in Australia, and we have also looked at a range of the existing evidence for where cannabinoids may be useful. Part of this discussion tonight is to help us as GPs to have these discussions with our patients. Whether we like it or not, there will be more patients coming to see us and asking about whether or not this is something that will be useful for them. So once again, thank you very much for your attention tonight.
Sammi: That is great. Thank you Harry and Jan for joining us tonight and presenting this webinar. Thank you again everyone for joining us tonight and enjoy the rest of your evening.