James Beck 00:00:03
Hi there, and welcome to the fourth presentation in the Parkinson's Foundation's Expert Briefing series. This is our ninth year, so we've had a lot of success, and today's topic is Marijuana and PD: What Do We Really Know?
I'm Dr. James Beck, your host for today's discussion, and I want to let you know a little about who we have viewing today. We've got over 4,500 people registered from 36 different countries, and 500 of those happen to be clinicians and scientists. I've got some information about CEUs you might want to pay attention to in a little bit. I also want to say that we're talking about marijuana today, and these webinars aren't created in isolation.
These are really dependent upon the feedback of the community as a whole, which is why, when you received the reminder for this webinar, there was a link for a survey. We'll be putting that survey back up at the end of this webinar, so please, please, please give us your feedback so that we can design next year's webinar series to really match your needs and your interests as part of the community. We do this in collaboration with partner PD organizations, the Alliance of Independent Regional Parkinson's Organizations, or AIRPO. This is a really wonderful presentation.
It takes a fair bit of technology to get it off the ground and some financial support, so I'd like to thank our sponsors, AbbVie and Lundbeck. Without their support, clearly these webinars wouldn't be possible, so thank you very much for that. If you want copies of the slides that Dr. Kluger, our presenter, is going to be showing today, you can download them. If you look on the page on the left-hand side, in a blue box, it says Download Slides. You'll get a PDF of them so that you can look at them during this webinar or any time after.
As I mentioned, health professionals, you can earn one free CEU through the American Society on Aging. If you registered as a health professional and indicated you would like one of these credits, you'll receive an email by the end of today with steps on how to collect your free CEU. But remember, you only have 30 days, so that's until May 17 to collect this free CEU.
Now I'd like to introduce our guest speaker, Dr. Benzi Kluger. Dr. Kluger is associate professor of neurology and psychiatry in the movement disorder section and a director of the palliative care section in the Department of Neurology at the University of Colorado. He sees patients in the clinic and directs a very active research program working toward improving therapies for non-motor symptoms of Parkinson's disease, fatigue, dementia and other issues.
He's really focused on improving the standards of care for patients and caregivers through supportive and palliative care models. Dr. Kluger has received funding from a variety of sources and has served for many years as a faculty member for our Parkinson's Advocate in Research program. It's a program of the Parkinson's Foundation that helps train patients to work alongside researchers in a productive way so that we can accelerate therapies to the clinic.
Dr. Kluger did almost all of his training, from undergraduate to med school to residency, at the University of Colorado, then took a brief sojourn to warmer states at the University of Florida, where he completed his fellowship in movement disorders and behavioral neurology. And so now I'd like to welcome Dr. Kluger and his presentation. Dr. Kluger?
Benzi Kluger 00:03:09
Thanks, Jim.
All right, so this is a very popular topic, both inside of Colorado and out: marijuana and Parkinson's disease. It's something that I get questions about quite a lot from colleagues and patients, so I think it's a very timely topic, and we'll get into what we really know about this subject.
I don't have any financial disclosures related to this work. However, I do live in Colorado. Also, as you can see from the little picture in the corner, I have long hair and a beard, which, according to the TSA and others, may be a conflict of interest when it comes to drugs.
The learning objectives that I have are, first of all, to really define the terminology. What is cannabis? What are cannabinoids? What are endocannabinoids? We'll talk about some of the terms that can go along with that. We'll review the basic science of the potential of cannabinoids to affect Parkinson's and also some other movement disorders.
By basic science, I mean science that's done either in cells or in animal models. Then we'll discuss the current state of clinical evidence for cannabinoids as it relates to Parkinson's disease. The clinical evidence is research studies that have been performed in people. I'll talk about some of the most common side effects for cannabinoid-based therapies, and then I will also — I don't have a slide for this — talk a little bit about my approach in the state of Colorado and how I work with patients who are interested in using cannabinoids and cannabis-based products.
Welcome to Colorado. For the last few years, it seems like the capital of marijuana research, as well as recreational cannabis, for the country and possibly even for the world. To review the outline, we'll talk about these terms, talk about cannabis and how it affects the nervous system, particularly the cannabinoid system, which is very integral to the function of the basal ganglia, which, as some people on the call may know, is a part of the brain that's very affected by Parkinson's disease.
We'll talk about both motor and non-motor symptoms in Parkinson's, and I think a topic that a lot of people are excited about is whether or not cannabinoids have any potential to slow down the progression of Parkinson's disease, to be this magic bullet, the disease-modifying agent.
What are cannabis, cannabinoids and endocannabinoids? Just so that we make sure we're all talking the same language, cannabis is also known as marijuana, weed, dope, reefer, Mary Jane, stinkweed and chronic. We're all talking about the same thing when we talk about those other products.
Benzi Kluger 00:06:06
Cannabis is a genus of flowering plants, and it includes several species, including sativa, indica and ruderalis. I will mention this again later, but sativa plants tend to have a higher concentration of THC. The indica plants tend to have a higher concentration of CBD, and ruderalis also tends to have a higher concentration of CBD. When you hear about these things, either from friends or in the news or reading about it, then you can see that those things would be somewhat interchangeable, but not completely. We'll talk about why that is.
Cannabinoids refer to chemicals that act on cannabinoid receptors in the nervous system and other tissues. There are currently over 100 phytocannabinoids, or chemicals that are derived from the cannabis plant, that have some effect on receptors in the nervous system. I wanted to bring up that point to let you know that the effects of this plant are quite complex. Within those more than 100 chemicals, there are ones that will act as agonists, so they will stimulate parts of the brain.
There are chemicals that act as antagonists, so they would block those same effects. These things are all in balance within the plant. Synthetic cannabinoids, on the other hand, are man-made. They typically will include one or, at most, two chemicals in a single product, and they are very targeted to either single receptors or to mimic specific cannabinoids. Then endocannabinoids are chemicals that are produced by neurons and other tissues in the body and that act on cannabinoid receptors. This is fairly analogous for people who are familiar with the endorphin system within the body.
As we all know, there's morphine and opiates and things like that, but these chemicals that are very potent at blocking pain act on specific receptors in the body. The human brain and nervous system actually produce endorphins that also act on those chemicals, which is why these external chemicals in plants have such potent effects. The same thing is true with cannabinoids. This is actually true for any drug, but any drug that has an action in the body obviously has some kind of receptor within the nervous system.
Among the phytocannabinoids, I'm only going to talk about two, and this is really where most of the research is anyway. The first is called delta-9-tetrahydrocannabinol, or THC. This is really the primary psychoactive component of cannabis. When you read in Newsweek or other places that today's pot is 10 to 30 times more powerful than the pot that was available in the 1970s, they're talking about concentrations of THC. Those differences are actually pretty impressive.
Benzi Kluger 00:09:08
I think in the 1970s, THC concentrations would be maybe 0.3% to 3%, and now 30% to 50% is not unheard of. This is also higher in sativa strains. Sometimes when people will go to a dispensary, or are working with physicians or other chemicals that are man-made, they may be looking to get a dose of THC. We can talk about what things that would be good for, and we can also talk about what potential side effects could come from THC.
Cannabidiol, or CBD, is really getting a lot more attention recently. It appears to have more of a calming effect on the nervous system. There's significant interest in medical research, and I think this has been probably farthest along in epilepsy, where there is fairly good evidence that it may be helpful for certain types of epilepsy, including Dravet syndrome.
In the state of Colorado, there were actually a number of national news stories about families with children with Dravet and other epilepsy syndromes who were moving to Colorado to get a particular strain of marijuana known as Charlotte's Web, which is an indica strain that has a very high concentration of CBD.
Endocannabinoids are the naturally occurring chemicals within the body that act on these receptors. I'll talk just again about two of them. The first one is anandamide, and that was the first one discovered. It comes from the Sanskrit word for bliss, and it was discovered in 1992. It's also found in chocolate, which may be part of the reason why some people are addicted to chocolate or find chocolate to be more pleasurable than other desserts. There is another endocannabinoid, 2-arachidonoylglycerol, or 2-AG.
Anandamide seems to be the most analogous to THC, and 2-AG seems to be the most analogous to CBD. Overall, cannabinoids play a significant role within the body for pain, sleep, stress response, anxiety, exploration of one's environment, and they also seem to play a key role in development. I'm not going to talk about this very much, but most of the safety studies that have been done on cannabis and cannabinoids have been done in adolescents.
We know a lot about the effects of cannabis on the adolescent brain, and we also know about the effects of cannabis on the developing brain in animals. It tends to have a very adverse effect in developing animals, but it seems actually to not have the same adverse effect in adult animals. We have yet to know, quite honestly, what the effects are in older adults because there haven't been a lot of good studies, and I'll get more into that detail later. Nonetheless, I just wanted to let people know that it does play a role in the development of the nervous system.
Benzi Kluger 00:12:12
Synthetic cannabinoids are man-made. The first one that was produced is known as Marinol, or dronabinol, and it is a pure THC analog. It was first developed to try to stimulate appetite and to reduce nausea in persons with cancer and people undergoing chemotherapy.
Nabilone is a newer product, which is a cannabinoid receptor at the CB1 and CB2 sites, and it's an agonist, kind of similar to dopamine agonists, so it acts directly on those receptors. I also did want to mention that there are some legal alternatives to cannabis that go under various names, including K2 and Spice. These are predominantly used recreationally, and they have been associated with a number of adverse health effects, hospitalizations and even death. I would just recommend that people stay clear of those products.
How does cannabis affect the nervous system? We can ask these two experts here in cannabis. For people who don't recognize these gentlemen, this is Cheech and Chong. If I were giving this presentation in person, I would ask the audience at this point, for people who have ever inhaled or been around people who have inhaled, do people who smoke marijuana move faster or slower?
The overwhelming response would, of course, be slower. I bring this up because I think a lot of people come to clinic thinking that cannabis or cannabis-based products are going to solve all of their problems. That is definitely not the case. We know that cannabis actually reduces dopamine, or at least direct stimulation of those receptors. It can slow people down and can reduce motivation.
I just wanted to remind people that the marijuana plant that Cheech and Chong were smoking is not that different from the different cannabis products that we're using today, at least in terms of its basic physiological effects.
Going into the endocannabinoid system, there has been a great deal of research and excitement about the endocannabinoid system. There are two main receptors, CB1 and CB2. There are other receptors that get talked about a lot, including the vanilloid system, but I think CB1 and CB2 are enough for our purposes. The CB1 receptor is primarily in the central nervous system, and the CB2 receptor is primarily in the immune system.
Benzi Kluger 00:14:44
Endocannabinoids that act on the presynaptic neuron decrease neurotransmitter release at these CB1 receptors. Their net effect is that they tend to increase GABA, which is an inhibitory neurotransmitter. It's also the same neurotransmitter that's involved with alcohol and benzodiazepines. They tend to decrease glutamate, which is an excitatory neurotransmitter and also associated with excitotoxicity, which is one reason why cannabis and cannabinoid products may be neuroprotective. It also tends to decrease dopamine release in the basal ganglia.
Again, if we directly stimulate these receptors, we're going to decrease dopamine in the basal ganglia.
The action of cannabinoids, particularly ones from plants, is complex. Some cannabinoids, THC being one of them, act as an agonist at CB1 receptors. Others are antagonists; they block this effect. Some are partial agonists, meaning that it depends on the state of the system whether they're going to have a net excitatory or a net inhibitory effect.
Cannabinoids also have antioxidant and anti-inflammatory effects, and this is part of the reason why there's a lot of interest in cannabinoids as potential neuroprotective agents for both Parkinson's as well as other neurological disorders. The CB2 receptors, which I said acted in the immune system, also are active on microglia, which are the primary immune cells within the brain.
For this reason, there's interest in microglia for other therapies for Parkinson's disease to potentially try to slow down the progression of Parkinson's, but cannabinoid agonists may be one way to do that, to turn down the immune effects. There are also cannabinoid receptor effects that are independent of these receptors. One that I'm going to bring up is the adenosine A2A receptor, which is something that's acted on by caffeine, but it's also been a target of interest in a number of recent pharmacological agents for Parkinson's disease.
It seems that adenosine A2A antagonists are actually maybe therapeutically beneficial for people with Parkinson's.
Benzi Kluger 00:17:06
Moving on to the more clinical part of our talk, do cannabinoids improve motor symptoms in Parkinson's disease? I bring this up because there was a controversy in the early 1990s. There was a Canadian snowboarder, Ross Rebagliati, who won the gold medal and then had it temporarily taken away because he was using a quote, performance-enhancing drug. That performance-enhancing drug was marijuana. Within a few days of deliberation, he was given his gold medal back, and they decided that cannabis was truly not a performance-enhancing drug and didn't improve motor performance.
Just as another interesting aside, Dock Ellis, in 1970, pitched his only no-hitter, and he was using another questionably performance-enhancing drug, namely LSD, which I don't think anyone would call performance-enhancing. When he describes his strange day, he reported that he was unable to see the batters that he was pitching to.
In terms of animal models, published studies generally support motor improvement, but there are mixed effects. In fact, cannabis and cannabinoid products and cannabinoid agonists have been used to induce parkinsonism in some animal models. There is certainly a great deal of evidence that shows if you directly stimulate these receptors, you can slow down the motor function of animals.
CB1 antagonists, when you block this receptor, appear to be the most consistently helpful way that you can improve motor symptoms in parkinsonian animals, and this may be in part through non-dopaminergic mechanisms. Both CB1 agonists and antagonists have been reported to improve dyskinesias, and these effects appear to be much more consistent than effects trying to help other symptoms of parkinsonism in animals, such as slowness.
Regarding clinical reports and trials, the largest study was actually a survey of 339 people in the Czech Republic. Twenty-five percent of those surveyed reported that they were using some form of cannabis, and about half of the people described some benefit, with 31% reporting improvement in their tremor, 45% reporting some improvement of bradykinesia, and 14% reporting some improvement in dyskinesias. I would like to remind people that this is a survey, and there are a number of sources of bias.
Benzi Kluger 00:19:52
It's possible that people who use cannabis were more likely to complete the survey. People who had a positive experience with cannabis may have been more likely to respond to the questions, and also there's the potential of placebo effects. This was not a double-blind controlled trial. In the United States, we reported on our experience in the state of Colorado, and we did a more systematic way of surveying. In our survey, only 5% of patients reported that they used cannabis, and most of them reported benefit only for non-motor symptoms, things like pain, sleep, appetite, anxiety and also muscle stiffness.
That would be pretty consistent with my experience with patients I see in Colorado. There have been four randomized controlled trials to date, and they have all been negative, although I would say that probably, to be more honest, we should describe them as inconclusive. The reason I would make that distinction is that, one, as we remarked earlier, there are a number of different chemicals in cannabis, and these four trials picked only a single dose or single formulation, so it may be that we were using the wrong product or the wrong dose.
Secondly, all of these trials have been very small. I think the largest trial was about 40 people, and with such small numbers of people, it's easy to have a falsely negative conclusion, in that if you had a larger number of people, you might be able to see smaller effects. For some things that we're studying, you don't need a lot of people because the effects are so dramatic. But for other things, and this is true of most Parkinson's medications, because we have to deal with the placebo effect, we actually need larger numbers of people to be able to see whether all of the benefit was from placebo or whether it was from other factors.
There's been a more recent report from Israel, 47 people, that also showed a pretty high degree of satisfaction among people who were using cannabis regularly. But again, this was a survey and it was a case series; it was not a randomized controlled trial. We are currently doing a study of cannabidiol, or CBD, at higher doses for tremor in people with Parkinson's disease. Dr. Leehey at the University of Colorado is leading that trial. It is a larger, I think better-designed trial.
It's also using a dose of CBD that is more comparable to the doses that are used in kids with epilepsy. Hopefully, within the next year or so, we will get the results of that study, and I think that'll be a more definitive look at least at one particular compound, namely CBD, for one particular symptom in Parkinson's.
Benzi Kluger 00:22:49
Do cannabinoids improve non-motor symptoms in Parkinson's disease? They're certainly associated with some non-motor symptoms. This picture here shows a pretty common known side effect of cannabis, namely the munchies.
To date, there have been no randomized controlled trials. There are some case series, including our own, that suggest a benefit for REM behavior disorder. There was actually a very interesting study of CBD for people with Lewy body dementia and psychosis that showed it could be calming. Of note, there was also a study using THC for people with dementia that, not surprisingly, showed an adverse effect. For people with dementia, we definitely would want to stick to CBD if calming is the goal.
There was a recent study looking at restless legs syndrome that suggested a benefit, again in an open-label trial. In our experience in Colorado, it definitely can be helpful for appetite and nausea. It can be helpful for pain. There are some very good data in multiple sclerosis suggesting that it can be helpful for muscle spasms and spasticity. It can be helpful for anxiety. In the Israeli study that I just mentioned, they also reported some effects for depression and sleep.
The depression one, I would say I would be cautious about, namely that there are no clinical trials of cannabis for depression, but there are a number of studies that show that cannabis use and chronic cannabis use may actually increase the risk for depression. Also regarding these survey studies, I did also recently come across a web-based survey, which was the largest study to date but not necessarily the best-done survey.
Just pointing out some of the flaws of this: they found that people who use marijuana tended to be younger, tended to have less disability, tended to have better memory, and one of the conclusions that they drew was that cannabis may be associated with better memory, which is not true. They may as well have drawn the conclusion that cannabis may be associated with being younger and being a fountain of youth, which is also not true. These are just associations; they don't imply any causality.
Nonetheless, in our experience, there do appear to be some benefits. Some of these are better explored in other diseases.
Benzi Kluger 00:25:14
There is definitely a need for greater and more research. The last thing I'll say before leaving the clinical arena is that I do have a few patients who feel that marijuana may help smooth out some of their motor fluctuations and help them some with dyskinesias, and that would be consistent with the animal data. That being said, it's only a handful of patients, and it definitely is not a substitute for taking levodopa or conventional medications.
The most common side effects from both case series as well as from the clinical trials are not very surprising. Number one is cognitive effects: people can feel dopey, they can have problems with their memory. It can worsen apathy or problems with motivation.
Cannabis can have effects on blood pressure, and it can cause people to be dizzy and may contribute to falls. There is some evidence that smoking cannabis may increase risk for cancer or other pulmonary issues. There are some ways around that, including vaping, which appears to have a lower risk than simply burning cannabis. Vaping is a process whereby typically a liquid form of cannabis or cannabinoid products is heated up and sucked in as a vapor, as opposed to being burned. Edibles also have side effects in that they may have less predictable absorption and dosing.
Within the state of Colorado, there haven't been a lot of adverse effects from cannabis, but the most common one is either children getting into candies that have cannabis, or people who have never used these products beginning to eat a brownie, not noticing any effects, finishing the rest of the batch, and then an hour or two later, it really kicks in and they find themselves in the emergency department having difficulties walking and feeling generally unwell.
Do cannabinoids slow down the progression of Parkinson's disease? There's definitely a lot of hype out there when it comes to cannabis. I think this book is a good example of hype. I didn't put it up here, but I would not recommend anybody read this book.
I definitely do get questions from people who are generally doing well but ask me, should I be taking CBD oil or should I be taking cannabis just to try to slow down my Parkinson's disease?
Benzi Kluger 00:27:38
In preclinical models, in animal studies and cell-based models, most of the published studies suggest that there is a neuroprotective effect in toxin-based models. There are two ways that we do studies in Parkinson's disease. One of these is that we give animals toxins such as pesticides, or there's also a chemical called MPTP that can mimic the effects of Parkinson's in the brain.
These studies can be helpful in some ways, particularly for seeing how treatments for Parkinson's work, but tend to be less helpful when it comes to understanding really how the disease progresses and how we might slow it down. To my knowledge, there have not been any studies in genetic-based models, which more closely mimic human illness. Nonetheless, the mechanisms of how cannabis and cannabinoid products may help include the anti-inflammatory effects, antioxidant effects and microglial effects.
Most of the studies suggest that the cannabinoid receptors are really not involved in these protective mechanisms, and that is not too surprising. To date, there really is no data in people, and so this is not something that I or any of the other colleagues I know of in Colorado currently recommend. I think it is an intriguing target for future studies, and certainly I would be all in favor of doing more research to try to move this ahead, but currently we have no evidence that this is really going to be something that's helpful in people.
Before going through my take-home messages here, I would like to talk a little bit about how I work with patients with cannabis and cannabinoid products. In the state of Colorado, which is fairly similar to other states where cannabis is legal for medical purposes, I do not write a prescription. This is one area of confusion. What I can do is fill out paperwork so that people can get a license to go to medical dispensaries, and then they work directly with the dispensary to get their product. I know that this works differently in certain states.
I think in New York there are dedicated pharmacies that carry cannabis products, and they may take prescriptions. But in the state of Colorado, it's licenses and dispensaries. Also, like a lot of alternative medicines, this is unregulated. When you go to a dispensary in Colorado or California or certain other states, there may be a 10-milligram label of CBD on a product, but there is no licensing body, there's no regulatory agency that ensures that this 10 milligrams of CBD is going to be the same across different dispensaries.
Benzi Kluger 00:30:24
I bring that up because when I recommend patients work with these products, I generally tell them to work with the same product and the same dispensary. Another reason for doing that is that even if the 10 milligrams of CBD were the same, the other cannabinoids in the product may be different, and it could result in a very different effect.
For most people, when I ask them to start, we'll start with a CBD-based product. This would be if people are interested in help with sleep, with anxiety or with pain. There are some symptoms where THC appears to be more effective, and that would include nausea and appetite. THC may be a good adjunct to help more with pain. We really don't know fully what are the most helpful things when it comes to motor symptoms, but it is possible that THC may also be more helpful when it comes to dyskinesias or smoothing motor fluctuations.
When it comes to how to take these products, we generally recommend that people stay away from smoking if possible. For people who are having problems with pain that's focal, we can use creams or patches. Oral drops tend to be fairly reliable, and for people who do want to use smoking, which can result in a more immediate and controllable response, then vape pens or other alternative delivery mechanisms are useful. Lastly, as with all medications, we like to start with a low dose and go up slowly.
There are interactions with these medications, such as Comtan and Celexa may actually be increased by interactions with CBD, so it's also important that people know about the side effects and that they keep their doctors in the loop when using these products. I'm sure we'll have more questions about how to use them when we open up for question and answers.
Again, to summarize the talk, there are many different, over 100 different psychoactive chemicals in cannabis, and products derived from cannabis may vary widely in terms of their benefits and side effects.
As just another example, within the state of Colorado there are cannabis products that are almost like stimulants, kind of similar to Ritalin, and at the same dispensaries, they have products that can help people sleep. Really, this mix of agonists and antagonists is very important.
There is currently no conclusive evidence supporting the benefit of cannabis for any aspect of Parkinson's disease. There is anecdotal evidence that suggests that cannabis may help pain, sleep, appetite, nausea and anxiety, and this is also supported by other studies, including large randomized controlled trials in multiple sclerosis that show benefit for muscle spasticity. But there is definitely a need for more research in Parkinson's.
The research to date on motor symptoms and dyskinesia, including several randomized controlled trials, have been, I would say, probably safer to say inconclusive rather than negative. But nonetheless, there have been no positive trials.
The potential side effects include confusion, worsening apathy, low blood pressure, dizziness, falls and pulmonary issues if smoked. Again, this should be treated like a medication or like a drug, and so we need to not just keep our eyes on the benefits but also on the potential side effects. With that, I would like to thank you all for your attention, and I will turn things over to Jim and to questions.
James Beck 00:33:50
Dr. Kluger, that was fantastic. I really appreciate your delivery on going through and helping, I think, our community recognize there are a lot of things that are not well understood and helping to dispel many misconceptions about it. Before we go into Q&A, I just want to give a shout-out to some of our viewing parties. We've got a chapter in Columbus, Ohio. I will be coming to visit next week, and we have well over 50 people there in attendance. We've got a chapter in Kansas. I was there recently with a large number in their viewing party and another one in Minnesota as well. So hello to folks there, and welcome to our discussion.
I also just want to say thanks again to our sponsors for this. As our discussion and Q&A goes forward, you'll see some slides coming across, and one of them in particular, as I pointed out, is an opportunity to help us select next year's Expert Briefing topic. When that appears, please take a look at that. We would all very much appreciate it. The slides are up right now, too, for those of you who want to do that. Benzi, I think your take-home message is that there's a lot that people are thinking about, but there's no evidence to date that suggests that people with PD will experience benefits from medical marijuana. Is that a fair summary?
Benzi Kluger 00:35:22
Yeah, I would say that's a pretty fair summary. As I mentioned, there's anecdotal evidence, and there's evidence from other diseases like multiple sclerosis that strongly suggests that the symptoms you would expect marijuana to help, it does help—things like pain, anxiety and sleep. I think those things are pretty fair to say, although they haven't been proven definitively. But when it comes to motor symptoms, and particularly when it comes to trying to slow down disease progression, then we absolutely do not have very strong evidence.
James Beck 00:35:55
Yeah, okay. Thank you. This is great because I know your research focuses on non-motor symptoms, and this is where we think, if there's going to be benefits from medical marijuana, this is the area where you can do that. You mentioned THC as a potential utility for people with pain. Creams—is that something that, where does one get these creams? Is it a dispensary? For those of us who are not in Colorado, do you have any concept of how one goes about getting this particular form?
Benzi Kluger 00:36:31
Sure. Within states where it is legal, and there are also countries and provinces where it's legal, in the state of Colorado, for example, if somebody has a medical license, they can go to a dispensary, and there are CBD and also CBD combination with THC creams and patches that people can use.
For people who are not living in a state where these are legal, it's my understanding that pure CBD products that do not have THC can actually be used in other states and can be shipped across state lines. So that is one potential option. As I mentioned earlier, CBD may not be quite as efficacious as CBD with THC for pain, but that is a potential. As I live in the state of Colorado, I haven't really advised patients outside of the state on how to use these products.
I don't know what the availability or ease of use for these things will be. Certainly, in states where there's no recreational and there's no medical, then patients are definitely on their own and would take all of the legal risks of anyone else who is using those products. People definitely need to be worried about that.
James Beck 00:37:51
Yeah, absolutely. I think you bring up some other issues about some of the negative interactions regarding these drugs. THC, as you mentioned, was hallucinogenic. We just had a really great Expert Briefing by a colleague of yours, Dr. Christopher Goetz, talking about psychosis. How does medical marijuana interact with people who are at risk for psychosis? Is it something to steer clear of?
Benzi Kluger 00:38:20
Yeah, absolutely. I think the literature does provide us some good guidance. For people with dementia and people with more advanced Parkinson's disease, as with any product, any medication, any alternative medicine, we have to definitely be more cautious because their propensity to develop side effects is going to be higher. The study that was done with THC, which did not have very surprising results, showed that hallucinations, agitation and paranoia can all be made worse, particularly by THC.
The study of CBD for Lewy body dementia was interesting in that it showed that, in those cases, it actually helped people. I have had a few patients in Colorado who have been able to use CBD safely. So I would suggest that if that is something people are interested in, following the guidelines I outlined above would be to use a CBD-only product, start with a low dose, and go up very slowly and very cautiously.
James Beck 00:39:26
Excellent. We're talking about CBD, THC and some terms. Some people have been asking, what's the difference between medical marijuana and recreational marijuana? Are they the same, or is one a higher standard? Or is that something you alluded to that people need to be concerned about?
Benzi Kluger 00:39:47
Yeah, it's a good question. In the state of Colorado, where we have medical dispensaries and recreational dispensaries, the products are generally pretty similar.
However, the purpose, the reason for existence, of a recreational dispensary is not to help people with their pain or help older people to sleep. Their products tend to be more focused on having higher THC, although they definitely do have CBD products. In the state of Colorado, the two reasons for getting a medical license are, one, that you would have access to more products with higher CBD content. You would have more access to products like creams and patches that don't really have any clear recreational uses. The other thing in Colorado is that it exempts you from a 40% tax.
So if you have a medical license and go to a medical dispensary, you're able to get the products a lot cheaper.
James Beck 00:40:43
Speaking of price, do insurance companies pay for this? Out of curiosity, in Colorado—I know that you can't speak to other states because we have some of those questions coming in—but how does that work within your state?
Benzi Kluger 00:40:57
As far as I know, it's definitely not covered by insurance in Colorado, and as far as I know, it is not covered by insurance in any state. I don't know if there are maybe some cannabis lobbies that are pushing for parity, but with very few exceptions, any alternative treatments are generally not covered by insurance. That's a clear downside for using cannabis and cannabinoid products.
James Beck 00:41:25
I've got a question from our Ohio viewing party. People with Parkinson's disease, unfortunately, have to be resigned to the fact that they often have to increase their dosage in order to see the same benefit as their disease progresses. Would the same thing happen with trying to see benefits from marijuana?
Benzi Kluger 00:41:44
Yeah, that's an interesting question. I don't think we have enough experience with cannabis to say that, although, to my knowledge, there really haven't been any long-term studies. Even the studies that were done in multiple sclerosis were relatively short-term. But it actually appears that the dose that works is relatively stable.
For people who were using cannabis to help them with their pain, it seems like once we get them, whether that's with cream, oral formulations or a combination of the two, things seem to be relatively stable and it tends to maintain good pain control.
Actually, one point which I didn't mention but does come up sometimes is that with other medications, such as opiates like morphine, Vicodin and Norco, and benzodiazepines like Valium, cannabis can sometimes provide an alternative to those medications that actually has fewer side effects, is less likely to need an escalation in dose and is less clouding. Contrary to the “just say no” message of the 1980s and the gateway theory, it actually seems that marijuana—and there are some research studies out there that support this—may be almost like an anti-gateway drug to help people get off opiates and benzodiazepines, where there is more tolerance and more addictive potential.
James Beck 00:43:08
You mentioned a couple things I want to follow up on. This was a question we had from someone in Missouri about the addictive potential of marijuana, because we have another person asking from Pennsylvania when to use it in the stage of their PD—early versus late stage. You can envision someone who starts it early in their PD progression. PD is not a short disease. It lasts for a long time. Do people need to worry about getting addicted to cannabis?
Benzi Kluger 00:43:39
Yeah, that's a good question. It's actually one that we researched when we were putting together a review article on cannabinoids for movement disorders.
It does not appear that cannabis or cannabinoids create a physical dependency or a significant withdrawal syndrome in the same way that benzodiazepines or opiates or morphine do. With alcohol withdrawal, for instance, it can be life-threatening; people can have seizures. With opiate withdrawal, it can be very uncomfortable. Nonetheless, chronic cannabis users can definitely develop a psychological tolerance. Those would be things to be aware of.
That being said, with opiates and other products that are being used for medical purposes, it appears that the risk of addiction is much lower. My bottom line would be that if you are a younger person who is considering cannabis and you have a symptom that would actually be helped by it, let's say sleep or pain, I wouldn't have any trepidation about trying it, and I don't think that there's a long-term downside to using it long-term.
James Beck 00:44:55
Excellent. Access to cannabis and marijuana is not uniform throughout the country, but hemp, I understand, is related. I don't recall you touching on this part of your discussion. Do you know anything about hemp versus these other cannabis strains?
Benzi Kluger 00:45:15
Yes. Hemp, as people may know, is part of the same genus, but it does not include—and I'm definitely not an expert on hemp products. Hemp oil has been used, and that is legal. There's hemp ice cream. The Constitution was written on hemp paper. People can use hemp fiber to make clothing. I believe the way hemp is described is that it's pretty much the same plant but without the psychoactive chemicals.
Any of the hemp products or hemp oils or other things like that that are legal, that you can pick up at General Nutrition Center or at other alternative health food stores—if they're being sold in that way and they're not being sold in a dispensary, then they've been checked and they don't have the active cannabinoids in them. They're just products that are derived from that same plant.
James Beck 00:46:10
Interesting. I'm just curious. If the research is not there—and the question's been asked about what studies are available online in PubMed to do that, and I think you've covered a number of them—and you have this great review you led the authorship on that was in Movement Disorders, talking about the review of it. How do you think this works? I remember going to a meeting on dystonia, where primary dystonia is the subject, but many people with Parkinson's disease experience secondary dystonia, that cramping of the muscles.
The clinicians who were talking about their patients using cannabis seemed to think that it was the relaxation, so it seemed to have more of the psychoactive—maybe psychoactive is not the right word—but just kind of a calming effect that seemed to produce a lot of the benefits. Pain could be a result of perhaps rigidity, dystonia. What do you think is going on as far as why people are seeing some of these benefits?
Benzi Kluger 00:47:20
Yeah, that's a good question. As people on the call may know, persons with Parkinson's disease may experience pain for a number of different reasons.
I'll just talk about two of them. The first one you mentioned is muscle cramping or dystonic pain. As I've alluded to before, there have been a few large randomized controlled trials of CBD, as well as CBD combined with THC, that show a benefit for muscle spasticity and for muscle spasticity-related pain. It probably has to do with a couple of things in that regard. One is that CBD—and this is part of why it's being used for epilepsy—seems to have general relaxation effects.
The effects in the central nervous system are also increasing GABA, which is similar to the action of a lot of muscle relaxants. So from a pharmacological perspective, it would make sense. The cannabinoid system and the endocannabinoid system, as I alluded to earlier, are also importantly involved in pain perception. Actually, a recent study—which I did not mention, just published within the last year—wasn't a randomized controlled trial, but what they did was test people with Parkinson's disease pain perception pre- and then a half hour post-use of cannabis.
This was a study—it may have been done in Vancouver—but it was done in a place where people could use cannabis legally. It showed that people's pain thresholds increased, so that people were able to tolerate more pain with cannabis. When they tested people again after 12 weeks of use, those thresholds were even better. So it does appear that cannabis and cannabinoid-related products do have effects in terms of quieting the nervous system and improving pain thresholds.
Interestingly, for people with neuropathic pain, and this includes people with Parkinson's disease as well as people with neuropathy, cannabis-related products, particularly the creams, have been one of the few things that I've found to be really helpful. For people who either experience this condition clinically or for clinicians and other people on the line, we know that the oral medications that are available can be somewhat helpful but are oftentimes dissatisfying in terms of how helpful they are.
For a lot of these people who have failed multiple drugs and who do not want to try opiates or other stronger narcotic-type medications, cannabis has oftentimes filled that gap with giving them better pain control, probably through the effects of the cannabinoid system both peripherally and centrally on pain, without having the same burden and the same side effects that they would have gotten with moving on to opiate or other stronger narcotic medications.
James Beck 00:50:15
Do the creams just—I mean, do the cannabinoids just go right into the skin? I mean, the cream's just a base with which to help spread it at the right concentration?
Benzi Kluger 00:50:27
It seems like, and again I'm not an expert on this, but it seems that the creams predominantly have their effects locally. We've known actually for a while that there's something called a vanilloid receptor that's important in neuropathic pain. Some of these receptors peripherally are acted upon by the CBD creams.
With the patches, they may have both local as well as more systemic effects, but with the creams, it tends to be more local. If people are having, you know, a pretty common symptom of neuropathy is burning and pain in their feet, using the cream either at night or during the day can provide them with some focal relief, similar to using lidocaine cream or some of the other topical analgesic creams that are available.
James Beck 00:51:18
If you're a person with Parkinson's, tremor can be an issue. Does cannabis help with tremor?
Benzi Kluger 00:51:27
That's what we are studying right now. We're doing a randomized controlled trial of CBD.
The anecdotal reports or the case series, including the most recent one from Israel, a number of people report that cannabis has been helpful for their tremor. These were unblinded studies, and so these were not done with a control group. There may be some bias involved. We also don't know the mechanism. Certainly, we know that people who have tremor, it tends to be made worse by stress. So if cannabis helps with stress or helps with relaxation, that could be part of the effect. There's certainly the potential for placebo effect. The bottom line is that we don't know definitively whether or not CBD or other cannabis products would help with tremor, but a number of patients have reported that they found it helpful.
James Beck 00:52:21
Excellent. For those of you who are listening to us, on our screen should be a survey to rate Dr. Kluger's talk, which I've found very good, so no bias from me on how you should do it. For a person with Parkinson's who wants to get into this realm, what kind of conversations do they need to have? Are your colleagues receptive to this? Is this the new world order, where patients are beginning to experiment with this?
How do you counsel them to approach their clinician saying, I want to use cannabis as a potential therapy for my symptoms of PD? What should they do? How should they talk to their doctor?
Benzi Kluger 00:53:05
Yeah, it's a great question, and I would say that things are pretty mixed even within the state of Colorado. A number of my colleagues, probably even the majority of neurologists who I know in Colorado, aren't comfortable filling out the paperwork for writing a license.
There was actually an interesting course that I saw coming up, and it suggested that medical schools should have a class or two on cannabis and cannabis-related products so that physicians can provide better counsel. I think a lot of the reasons why doctors don't want to get involved is that they don't have the knowledge or the background to guide people adequately. Some people may have other personal reasons for not wanting to promote cannabis use or things of that matter.
It's unfortunate because one of the things that I emphasize, not just with cannabis but with other complementary and alternative medicine when I talk about it, is that I think it really works best when it's complementary, meaning that your doctor knows what you're doing, your pharmacist knows what you're doing, and everybody is working on the same team and working together. Unfortunately, a lot of times people are in a situation where their doctor does not want to hear about it, is not open to it, is not receptive. In that case, unfortunately, patients are stuck doing things on their own.
One of the things that sometimes comes out of that is that people may have a side effect related to cannabis. Actually, a colleague of mine in Canada had a patient who was using cannabis on their own, did not talk to her about it, and was developing worsening apathy. The patient and the family were really concerned. They were trying to figure out what was going on, and then I think it was just a slip of the tongue or something else came up, where it turned out that the person was using cannabis. When they got them off the cannabis, the apathy got better and they got back to their usual self. I think that's one of the dangers with the medical community not being as open and receptive as they could be, and also with patients not having that access.
If this is something that's very important to a patient, I definitely have had a number of my colleagues refer patients to me just to provide counsel on that. There definitely are people in the community who are more open and receptive to it. I have found that many of the people who work at the medical dispensaries are fairly knowledgeable and can potentially provide even better guidance sometimes, although from a different perspective than other medical providers. Again, I would say the bottom line is to, as best you can, try to keep all of your providers, your pharmacist and your physician on the same page.
If you really feel like you're being blown off or dismissed, and it's not a good match for you and you want to explore it, seeking a second opinion may not be unreasonable.
James Beck 00:55:52
Absolutely. One thing we didn't cover was about people who've had surgical interventions for their Parkinson's: DBS. Is there any concern about medical marijuana, cannabis and DBS? Or is it just the same general cautions that you've given for those who haven't undergone that procedure?
Benzi Kluger 00:56:12
Yeah, I would say that the same general cautions apply. Certain side effects of DBS, for instance speech, for some people balance, for some people cognition, those side effects might be magnified by cannabis. There's no reason to believe that there would be any specific interaction, that cannabis would either block or enhance the effects of DBS. But the general caveats that we gave earlier would definitely apply to somebody with DBS.
James Beck 00:56:40
For people who are maybe taking a dopamine agonist as part of their medication, there's a concern for those who are on agonists that they could develop impulse control disorders, and they're counseled by their physicians to watch out for that.
Is it a good idea or a bad idea to bring cannabis into that mix? Is there a potential for confounding or exacerbating these types of other symptoms from the drugs you're taking?
Benzi Kluger 00:57:11
Sure, it's an interesting question. To my knowledge, there are no reports of cannabis or cannabis products exacerbating or causing impulse control disorders. That being said, impulse control disorders take a number of shapes and forms, and there would be some caution that cannabis could become the focus of one of these impulse control disorders. Certainly, excess cannabis use can become problematic.
But yeah, it's actually a good question that hasn't really been adequately investigated, and there really aren't very many studies on how cannabis, outside of even pharmacological effects, may interact with dopamine agonists. I think it could certainly worsen certain side effects that we see with those, including sleepiness and low blood pressure. With any new medication, going back to the basics of starting with a low dose, going up slowly, and watching out for common side effects would definitely apply for people who are on a dopamine agonist, but there's no absolute contraindication.
James Beck 00:58:17
Just a couple more questions because I know we're coming to the top of the hour here. We've talked about Parkinson's disease, but many people in our community have atypical forms of parkinsonism. Again, I think we're talking similar type of advice to apply for them. Are there any caveats for someone who maybe has multiple system atrophy or PSP regarding cannabis?
Benzi Kluger 00:58:43
Yeah. Not surprisingly, there is one study, as I mentioned, for people with Lewy body dementia that suggests CBD may be somewhat helpful. But in general, and we definitely in Colorado have used these medications for those other disorders, we have to be cognizant of the major side effects. In somebody with multiple system atrophy, I would be very concerned about low blood pressure and would want to make sure that we monitor that carefully. With PSP, we'd want to be very cognizant of falls.
So it would be kind of the same caveats, and just in some ways magnified based on the oftentimes more severe symptoms that we see in these other related disorders.
James Beck 00:59:26
Thank you very much, Dr. Kluger. As we go, one final question: how can people get involved with research or participating in these things? Is it a matter of just finding a locality? Is it your study in Colorado, or I presume enrollment is full for yours? What's your advice?
Benzi Kluger 00:59:45
Yes. The advice would be kind of similar to, and may have been touched on in other talks in the series. There are a number of resources that can be helpful. There is a website, ClinicalTrials.gov, which has all the clinical trials in the world listed. If you put in Parkinson's disease and cannabis, you would come up with trials, and they also have contact information. Fox Trial Finder, which is run through the Michael J. Fox Foundation, is another great resource if people want to get involved with clinical trials.
Other ways that people could get involved with research include, one resource which I share with patients a lot, something called PubMed, which is a general search engine, and you can look up research studies on there. It tends to be more reputable and reliable than just looking things up on the internet. If you come across an author or a research group, you can get their manuscripts. If people are interested in philanthropy or contributing to research, that's probably the most direct way they can do that. It would be to contact individuals who are doing the research and make donations directly to them.
I know there are some trials that are happening, including the one in Colorado, which I think is still recruiting. There are other trials that are undoubtedly going to be getting off the ground looking at different products, but those would be great places to start.
James Beck 01:01:10
Great. Thank you very much, Dr. Kluger. Benzi, I know you need to go, so I'll keep talking a little bit more with our community. Thank you very much for your time and for a wonderful presentation you've given us today.
Benzi Kluger 01:01:22
Yeah, thanks so much for inviting me, and thanks to everyone who's been present for this webinar. Take care.
James Beck 01:01:29
Take care. For those of you who are still with us, I just want to let you know we will be posting an archive of this in about a week. You can go to our website and find some more information about that. For those of you who still have some persistent questions, I know we haven't been able to answer everyone that's come in. We'll work for that, but we also have our 800 number, which you can call. It's 1-800-4PD-INFO. That's 1-800-4PD-INFO.
I would like to thank everyone for their time today and look forward to having a chance to interact with you again with our next Expert Briefing. If we can bring the slide up for that, it's going to be coming up in a couple months. Just pulling up the date, it will be June 5, Tuesday, same time, same place, 1:00 p.m., and we'll talk about home safety and management in PD. Thank you very much. Have a good day.
