What does cannabis do to the brain? What is the "entourage" effect? Does having no receptors in the medulla make cannabinoids safer than opioids? Dr. Mike Namaka schools Trevor and Kirk about the neuroscience behind cannabis. What do we know? What do we not know? Where is the science taking us?
S1E5 - The Scientist
This Episode is sponsored by Evolve Green
- Canadian Family Physician - The official Journal of the College of Family Physicians of Canada
- CanniMed Announces Pre-Clinical Research Study of Cannabis for Multiple Sclerosis (MS)-Induced Neuropathic Pain
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(Yes we have a SOCAN membership to use these songs all legal and proper like)
Trevor: Dr. Namaka, how about you introduce yourself.
Mike: Well thank you very much for the invitation to participate in the radio segment. I really appreciate that especially given that I'm a homegrown Winnipegosis boy that grew up and went to school in Winnipegosis Collegiate. From there I went on to University of Manitoba and then to Emory Medical University in Georgia. And at the end of the day with all of that schooling I wound up being a neuroimmunologist that studies and established expertise in diseases such as multiple sclerosis chronic pain management and how basically the immune system modulates inflammation and pain to affect those type of diseases
Well right now we really you know have only just started I think to be fair uncover the role of what cannabis does in the brain because only back in 1964 which is three years prior to when I was born. We've only that was the first time that we identified THC or tetrahydrocannabinol that we all know as pot or or marijuana as the main psychoactive ingredient from the Cannabis sativa plant. So that's the first time I was there. You know when we looking at our brain we were only in 1988 were we able to identify for the very first time CB1 receptors which is the receptors in our brain by which cannabinoids are thought to work at and then we only 1992 we identified the second receptor called CB2 that was predominantly found not only in our brain but predominantly in our in our peripheral nervous system like outside of our brain and spinal cord or other words. So to answer the question what do we know about. Cannabis in the brain we've only just really been starting to look at things for the past really 40 to 50 years so it's relatively a new concept and in fact when we started to look at not only just the stuff that we get from the plant we actually were able to see that in 1998 I'm just quoting a little bit of history to give everybody you know background on it that we were able to to identify the body that the body had its own endogenous cannabinoid called anandamide. In other words it is a substance within our body that helps us control pain inflammation and other aspects of our of our body. And it's called anandamide that our body produces naturally that is like identical or very similar to what we get from the external source of using medical marijuana and since then in addition to anandamide they've identified other cannabinoids inside our body that work such as this 2-AG or PEA these are other acronyms that are used so you know back to answer your question what do we know about cannabis and brain. Well in the past 40 years we were able to identify that cannabis that we know works through certain receptors and the fact that our own body produces our own endogenous cannabinoid. So it's got to be there for a reason to do something hopefully beneficial for us in terms of disease management.
Trevor: That's fascinating just how recent has all been I'm just thinking that I was literally out of pharmacy school and working before they were finding the endogenous cannabinoid so well for old people like me it seems like it was just yesterday. So no that's a great overview. Thank you. How about specific ailments because you know we're going to be talking to people who are going to be promoting cannabis to treat everything from pain and nausea to seizures which I think are probably reasonable things to try to treat to you know just about every everything other ailment under the sun. Do we have an idea what cannabis might be good for treating and what ailments it's probably not able to to treat
Mike: Right. Well first of all you know I just want to back up a little bit before we jump into what we can use it for is that we have to make sure that when we are speaking of medical marijuana or medical cannabinoids and they use for these diseases that that type of nomenclature determines the fact that we need a medical health care expert a pharmacists a physician and nursing staff other people that are involved in a multidisciplinary nature to make sure that the people the patients are protected by ensuring that they are the ones that are receiving the product that they actually need for medicinal purposes and that the product that's being we're sending to them is regulated prescribed obtained from licensed producers. In my mind rather than a corner store that may not have the same regulatory storage requirements and other things to safeguard our patients. So that's just you know stepping back a bit before I get into addressing some of the ailments. And so when we look at some of the different ailments. Again I'm going to put another disclaimer before I get into that we have to realize the concept of medical marijuana but what's new and there's social stigmas and personal stigmas and societal stigmas associated that may be associated with its use the drug nevertheless is or the medicine that we believe is coming from these plants is being distributed on the market that is approved by Health Canada by the you know 29 to 35 licensed producers across Canada.
Mike: So, we first have to come to realize that although in based on our conventional medicine that we get for high blood pressure cholesterol diabetes a lot of those medications have went through preclinical testing in animals then in human clinical trials phase 1 phase 4 trials to get on to the market. For example in the case of medical marijuana the drug has been approved by the government for sale and distribution to humans. Before we had the preclinical and clinical evidence in that degree of strength that we would have needed in order for them to be considered for these particular indications that you indicated like pain, nausea, seizures. M.S. and so forth. So that's just another disclaimer that I just wanted to respond as well.
Trevor: No fair enough. So what do we think the cannabis might be able to treat and what's probably not reasonable.
Mike: Well we have to go back to my little introduction at the beginning when we look at the distribution of those receptors by which cannabis would work in the body because in order for cannabis to work it has to bind to a receptor and that receptor gives you an effect that can be positive or negative to help disease or hinder diseases. So what we do know when we look at the distribution of CB1 and CB2 receptors by which cannabinoids bind to exert their effects. We see that CB1 receptors are predominately located in the central nervous system that includes really your brain and your spinal cord. And that's like your powerhouse for everything that controls pain especially a lot of pain pathways other pathways that determines whether or not diseases kind of go on or go off in very simplistic terms. CB2 receptors are largely found in the periphery outside of the brain and spinal cord and they kind of regulate the immune system and inflammation. So when you understand the distribution of these receptors and you can see that some of the medications cannabinoids that bind to CB1 receptors for example may be may be more efficacious for pain and things like epilepsy or seizures for example because those involved the central nervous system which include the brain and spinal cord. On the other side there's other medication you know for inflammation like rheumatoid arthritis osteoarthritis things like that. Those medications may be also beneficial because of the anti-inflammatory or immune system suppression or modification effects that we believe that cannabinoids have. So, there is potential. But again, I err with caution that we need to do the preclinical and the clinical trials to gain the support for what we believe these medical and beneficial effects of these medications will have.
Mike: To answer the big million dollar question is if we believe these things work then the licensed producers that are out there should be investing money to again confirm that they work right. You would think that that would be the case and there are license producers that are out there that are investing money that do believe in their particular product that they have because these license producers are able to genetically modify the plants now to confirm certain ratios of the THC that active component that we all know that gives you the high in marijuana use CBD which is cannabidiol which is a medication that we're finding more and more or a component of the plant that's finding more and more beneficial and pain management inflammation as well as there's other forms or types of molecules that were just recently identified that are coming out of this plant mixture per se that have medicinal or could be potentially medicinal properties to help in these conditions.
Trevor: Oh that's great. So let's switch gears a little bit and go to young people in cannabis. We hear about this a lot. The federal government the provincial government have been throwing around this number a lot that the brain is still developing up to age 25. So you know there shouldn't be any cannabis use in people under 25. But on the other hand we have case studies of really young children who are have serious seizure disorders and many you know seizures an hour who seem to be helped by CBD. So let's start with do we is it true as far as we know that the brain is still developing up to age 25.
Mike: I believe first of all. Again just before getting into answer the question you have to take a step back. We have to ensure that we're speaking about the medicinal use not recreational use.
Trevor: Fair enough.
Mike: When we're talking about medicinal use and we're talking about children with these you know status epilepticus or other major seizure disorders that are there every few minutes. You know the brain is getting bombarded with this hyper excitability of cortical neurons in your head and you know that's triggering this seizure. The brain is still developing up to the age of 25. I think it's developing up to the age of 50 because I'm still having my knowledge synapses to keep learning more about different areas. But the bottom line is that it all comes down to risk benefit. And again, back to the distribution of the receptors when you're looking at the cannabinoid receptors unlike opioid products cannabinoid receptors are not found in the brains medulla area which is the area of the brain that controls our breathing. So, because of that when we administer cannabinoids in in part because it doesn't affect the respiratory system or suppress the respiratory system like we know with opioids overdose and the opioid crisis that's going on they can be more safe to use as not mainstream treatment, I think adjunctive treatment to conventional medicine that's already out there for these particular conditions that have been tried and true.
So when we're looking at that whole segment you also in addition to the breathing thing in addition to using these I believe the use of medical marijuana or cannabinoids can be used as adjunctive to conventional medicine that's tried and true. We also need to look at the patient each patient specifically and determine the risk benefit in that patient. And I will tell you that if you have seen a patient with status epilepticus that has seizures repeated over and over and over one by the other without stopping. There is huge risk associated with those people with intractable seizures like that to have permanent brain damage because of the hyper excitability or overactivity of your brain that you can't shut off. It's no different than you jumping in your vehicle and leaving it in park and revving your vehicle the accelerator right to the max for about 30 to 40 minutes and seeing if that's going to impact your motor. It sure will. So the point I'm trying to make is that when you ask a general question of should we be considering the use of cannabinoids for example as adjunctive medications for patients that are younger that may have intractable seizures status epilepticus and other life threatening type of medical conditions. I would probably answer. You know it probably would be beneficial because if we don't try anything on these people the conventional medicine is not working enough to control them. We will be leaving these people permanently with deficits that we could have tried. At least.
Trevor: That's fantastic. Thanks for breaking down the nuance on that.
Mike: Yeah and the other thing I wanted to mention Trevor too is that we have to realize that everybody is still in this societal misconception that when you think of marijuana you think of THC. I want to just step back again and realize that the new licensed products that are coming out have various ratios of THC to CBD and in fact the research is supporting that. There is more. Just as you've indicated earlier more benefit from some of the non-psychoactive ingredients like CBD and other forms of active ingredients that are in this plant extract that we have yet to determine. So although we equate medical marijuana with THC and the euphoric high that we thought of love you know peace and war you know in the 60s and 70s. Right now, we are genetically altering these plants to lower the psychoactive ingredient to levels that is tolerable to patients. That doesn't drive dependency issues that doesn't drive tolerance issues and we're beefing up more of the other ingredients in there that don't have those negative societal and personal attributes from the plant extract which we now know through what's called the entourage effect. That means that there's numerous molecules and chemicals within this plant to extract maybe from the stem maybe from the leaf maybe some you know the resin that we get from them. But all of which we can adjust the ratios consistently with a good licensed producer of it and we were not dealing with just high dose THC in a developing child brain where we're looking at it at a much more refined medicinal approach that is mirroring the conventional medicine that's out there.
Mike: Right. Well the producer is a producer that's involved in producing a product. You have to go into the health care professionals that have been involved I think with some of the use of the product in actual patients that come to our respective clinics you know in general we have a general idea of the patients that we put on these medical marijuana or medical cannabinoids from the different licensed producers for pain and we've had some you know anecdotally you know good good effects and bad effects from some people but most of the effects have been pretty good in regards to pain management in our group as well as you know published the use of a synthetic cannabinoid nabilone for example that we often use for patients with cancer for as anti-nausea because of the chemotherapy and we have determined efficacy of a synthetic cannabinoid in helping the pain and the immune system in people that have neuropathic pain when it was used as an adjunct to another common medication for neuropathic pain which you're aware of is gabapentin. And we published that. So that was kind of the first step that we said hey I think that there should be some merit in the use of cannabinoids in conditions such as pain. So I can speak to that. Not only just from my own personal thoughts but from peer review publication that we've put together on a clinical trial that demonstrates that the synthetics work. So if the synthetics work we often use as a guideline as people look after patients that have these conditions we may often try patients on nabilone for example to see if the person is responsive to that cannabinoid like material for pain for spasticity for other things that we may feel that it's deemed appropriate. If the person generally responds well in a positive direction on nabilone the synthetic conventional medication albeit it's used off label for this that we use it. But we've published it. We then once you reach a certain breaking point and that alone may not be enough to carry on and help these people with the pain management. So the next tier or logical transition would be to possibly suggest patients to use medical cannabinoids. And it doesn't really matter you know which company that is out there as long as there are licensed producer and they meet all the requirements on them. I know that that it's important that they meet all of those. And when we start usually when we're looking at pain we always go with the start low and go slow kind of formulation. And I like to always try for example a product that is low in THC because obviously the psychoactive components that we spoke of earlier. And higher in CBD so say a 1 to 20 formulation for example that it could be different ratios with different companies so I'm just you know picking one you know non-discriminantly. So if we did have one to 20 formulation and say you came in and you seen me and we had to put you you know we decided it would be a good candidate for the use of medical cannabinoids. We would start you on a formulation like 1 to 20. One part THC 20 parts CBD. I would prefer to use an oral formulation. That's our own preference. Now there's oral oils there's capsules that have a milligram content in them as well the inhaled vaporization is also okay but I'm not a supporter of smoking medical marijuana due to obvious health risks. Why we counsel all of our patients to stop smoking to begin with
Trevor: And I think that's an important point. Just I know we've got two or three patients in our various care homes on medicinal marijuana and just the two or three years ago they stopped letting the residents their smoke at all. So not surprisingly they weren't a real big fan of us bringing in smokable medicinal marijuana or even or even the inhalers. The nurses thought to be too complicated so it definitely went to the oral oil. In that case
Mike: Right and the benefit of using say a vaporizer is that when you take the medical marijuana and you put it into the vaporizer it doesn't make it combustible to get the carcinogenic or cancer-causing agents that are there you're just aromatizing the medicine into the air and breathing it in without causing combustion. That's why vaporization is safer than an actual smoking but right now because I practice using conventional medicine in my own personal preferences to use the oral oils or the oral capsules from whichever licensed producers that are involved in those because for me they're a little easier to titrate. And now getting back to say some of you know what what dose do we go where do we start. You know I think that was a question.
So when someone comes in and I determined that that they're on conventional medicines already for their pain. We first do different a variety of pain assessments to determine that hey we've kind of capped out on maximizing the conventional medicines that their doctor normally would prescribe opioids analgesics other things like that and then we decided that we had a trial of nabilone and person's acceptable and they have no other you know contraindications to using the medical cannabinoid product from a licensed producer we put them on it we put them on it starting with the one to 20 formulation for example and we start dosing anywhere from a quarter or 250 milligrams to zero point five grams per day okay and we do that dose for a week. So if you came in and you said hey depending on what stage of chronic pain you were in say you had very high control or a high pain you tried a bunch of conventional medicine you're still on conventional medicine. We're not proposing that cannabinoids are going to replace or make you get off of the conventional medicine but we are looking that maybe this cannabinoids can actually help as a synergistic effect to conventional medicine to help take an additional edge off these people with chronic pain. So we often would start in that type of a person with point five grams of an oil or an oral formulation a capsule whatever the milligram capsules come in and we would then divide that point five grams into two doses. So in other words 250 milligrams in the morning and 250 milligrams in the evening. OK. And we would keep a person on that dose for about a week to two weeks to determine every day they'd take it twice a day on how they're feeling and we would ask them basically and it's a simple assessment that patients can be involved in their care with their doctors on a scale of zero to 10 based on standardly accepted that it's a qualitative visual analogue scale where zero is no types of discomfort associated with your neuropathic pain and ten is incapacitating where would you rate your pain. And people that report a pain greater than five still require medical management because the reality is like for M.S. like for some seizures like for chronic pain we don't have a cure for these. So, at best we're able to use them all the medicines in our tool cabinet that we have to reduce the pain or discomfort to a more tolerable level that does not interfere in your normal daily activities. So we start with the low THC content because we don't want to have people with that stoned effect or that you know glazed over effect you know where you're cognitively really impaired because that is no good either and we want to slowly build up some tolerance in our patients so we start with a say the 1:20 formulations and we go at point five gram titrations approximately every two weeks okay or as tolerated by the patient. This is just a general titration. It does not apply to everyone. You may have to go slower. You may have to go half of that amount but we eventually most people from our professional experience respond to treatment between 1 to 3 grams per day in the divided doses And some people may even need to divide the dose to three times a day depending on how they're like the daily dose three times a day depending on where where and how their pain presents. So to give you an idea we would be titrating by point five grams approximately every couple of weeks to a dose which we believe is a therapeutic dose between 1 and 3 grams per day in divided doses.
Trevor: Eventually I do want to get on to MS but first something can you do. Just a quick run through for us the difference between medicinal marijuana for medicinal cannabis and nabilone. Like what. What's the difference with this between the synthetic and what we would get from a licensed producer.
Mike: Well the synthetic product that is out there that I said is used off label that means it doesn't have an indication for pain but it's used for pain. You know no different than aspirin is used for fever. We always knew about it. Now it's used for cardiovascular protection. So when we look at nabilone it's a synthetic product that means that we use medicinal chemistry to prepare a product that looks like our bodies own endogenous cannabinoids that I spoke of the anandamide and other ones that are in our body we prepare those medicines synthetically because we're hoping that they will have a higher binding affinity to those CB1 and CB2 receptors that I spoke of to ultimately effect how the drug works in our body.
Mike: So to answer your question I can't tell you how exactly nabilone will compare to the genetically altered plant material extract because we haven't done that type of study with all the licensed producers and all the different strains and so forth of product that they produce through this genetically altered process to determine the binding affinity and clinical or therapeutic effect of that drug compared to nabilone. Those are studies that still need to be done Trevor. So, we need to do a head to head study of where we put nabilone as an adjunctive to conventional medicine against for example you know a plant derived to extract to this you know as an adjunctive medication to the same thing. We also have to realize that when we look at medications that you're familiar with as well like digoxin for example that helped with congestive heart failure and other cardio conditions that medication was derived. Like other things from a plant. Right. No different than opium from a plant. So, we can be skeptical of what is coming from a plant because aspirin was also developed from a birch tree or like the bark of a birch tree. So, there's different things that we have to look back and realize that you know we can't give you the answer of a direct comparison between a synthetic and a plant derived. My gut instinct would be that maybe the plant product because of this entourage effect not only because it has THC CBD and other components it's the other hodgepodge of material that's in that plant extract that makes it better when they're all together than each independent component that we know of that we think we know off right now that we're trying to titrate it to. But I do believe that the entourage of other active ingredients within the plant extract may be way better than any synthetic product that's out there that's focusing just on one or two components like THC CBD and the binding effect when in fact maybe we needed the trace element of something else in the plant extract that make it work better.
Trevor: Oh that's fantastic and I would really be amiss with all the research you've done to not talk about M.S. and cannabis. So, I know you've done research with cannabinoids and nabilone and M.S. and M.S. pain so how about for because we've got lots of them in the Parkland area as you know how how but what's what do we know about cannabis and multiple sclerosis.
Mike: Well when we had I think that there to be just a start with a conclusion before I start with an explanation I believe from my own personal experience and my research expertise I believe that medical cannabinoids would potentially have a place and select patients that have multiple sclerosis because M.S. patients also have pain. They also have an overactive immune system that is destroying their myelin coating that causing a lot of the symptomatic issues like spasticity pain blocking abilities other things like that. And because I there's reports and research that's previously been done and the research that we're also involved with all of these things are suggesting more and more that cannabinoids are able to not only help with you know suppressing pain but they're also able to. And we don't know the answers to how. But they're also able to modulate or modify the immune system of which M.S. patients may get benefit from because if you have an overactive immune system and you have patients are also in pain we know that if cannabinoids are able to kind of suppress that inflammation and pain side of things and alter the immune system to suppress it a little bit that can also have a beneficial effect in patients with multiple sclerosis. So, although our published study that we did with nabilone as an adjunctive to gabapentin in M.S. patients proves that the drug did work for synthetic cannabinoid did work to help with pain in that particular study. It also we noted helped with the M.S. But we weren't sure how and that's where some of the research preclinical and clinical research on I'm embarking on now that are trying to set up so that we can add you know do a societal responsibility and try to answer or publish some of our work that will from the University of Manitoba that will actually speak to for example do these agents work how do they work with more than just binding to a CB1 or CB2 receptor what is the exact pathways molecular pathways they work so that we can put it in the same order of evaluation by which we have established conventional medicine guidelines from. So that we know if you're giving cholesterol medication that it effects the cholesterol pathway. We need to do the same type of research right now in medical cannabinoids so that we can move forward with this these million-dollar questions. Where we're seeing all these anecdotal reports that you speak of as well but we have to prove that how they're working and that's still just going to be. That's all of this stuff is just starting to be involved and I'm happy to be working with a very strong team of people here that have similar interests to try to answer that particular question.
Trevor: Now that's fascinating and honestly this is the first time I've heard good explanations about why even if we don't know exactly how but why we think because like you said MS is an autoimmune disease you know the immune system is doing bad things to the myelin sheath around the nerves. So you know it might be the CB2 receptors or might be something else but there is that there really is some evidence that cannabis cannabinoids are doing something to the immune system and that's that's fascinating. That's the that's the place to go
Mike: That we have to look out and I'm presently looking at that and we'll be coming out hopefully with a publication in the next few months that will look at for example an animal model of multiple sclerosis and the effects of some of these medications at a molecular level so that we can see or answer that that burning question that we all have as clinicians and healthcare providers. It's not enough to just say that we think it's working we need to prove that it's working that it's affecting things at the gene and protein level at the molecular grassroots that are changing by which why the person in your office or that comes to your pharmacy is telling you that they're having beneficial effects and pain spasticity post-traumatic stress epilepsy other conditions. You know these medical cannabinoids are thought to be beneficial in.
Trevor: Thank you very much. Now before we wrap because I know it's come up in both my College licensing who gives me a licence every year and Kirk's College the College of Nursing. Both of them have thrown this quote at us that there is no evidence that cannabinoids are or cannabis is useful in medicine and helping people. If I happen to be in a room with say my registrar what would you have them have me tell them.
Mike: Well I would tell them what the story that I really described is that we have only been in the cannabinoid research field realistically starting from the time it's been you know licensed where the license producers are you know the horse has left the barn. The drug is already in the way in the human population for being used medicinally. So, one because it's legislated already for that we have to step up and acknowledge that we have to safeguard the public so we have to continue the research that we're doing. I've indicated for the last 50 years we've only just established the receptors and other things and the endogenous cannabinoids that we've identified we have to continue looking at molecular pathways and doing research to identify mechanisms and for the regulatory bodies and licensing bodies of the various health care providers. We have to realize that if we don't have a cure for things like pain or multiple sclerosis or epilepsy we have to look to alternative treatment approaches to try and help our patients and do a societal responsibility to determine their place in therapy and the fact that we have more cannabinoid receptors anywhere in our body than opioid receptors and other things. We have thousands of years with opioids in terms of knowledge. We've only have less than 100 with cannabinoids. So, this is coming. It is not going to go away. We will find the answers we're looking for and we have to be proactive and be prepared because I would rather have for example pharmacies involved in the direct distribution of the medicine than going down from the corner store where somebody doesn't have the proper storage regulation. You know patient's best interests you know on follow up and judicious administration of quantities and follow up the pharmacy always does with the patients with their physicians to safeguard everybody in this process. The bottom line it's coming and I believe we have to move forward and embrace that and figure out how best we are going to accept what has already left the building
Trevor: Dr. Namaka It's been a fascinating talk. Thank you very much for letting us get into your busy schedule. Thanks a lot. That was fantastic. Rene do we need anything else from him.
Mike: I want to reach out and say a big hello to my father William Namaka out in Winnipegosis. And to everybody else that's out there that supported my career and involvement all my teachers and everybody out there that from a little collegiate it's pretty nice to realize that a home grown kid can actually gain the knowledge and expertise that you've acquired and other people have acquired from small towns. So kudos to everyone out there and educational services that gave us a foundation to provide us with this ability to shape our career and hopefully shape the way people are looked after in the health care profession.
Trevor: That was really nice. Thank you.
Mike: Have a good day guys.