This transcript has been edited for clarity.
Anne Cross, MD: Hello. I'm Anne Cross. Welcome to Medscape's InDiscussion series on multiple sclerosis. And today we're going to take on the somewhat controversial topic of the use of cannabis and cannabinoids in the treatment of symptoms in patients with multiple sclerosis. We have an expert to speak to us today about this, Dr Jacquelyn Bainbridge, who is a professor in the Department of Clinical Pharmacy at Skaggs School of Pharmacy and Pharmaceutical Sciences and the Department of Neurology at the University of Colorado Anschutz Medical Campus in Aurora, Colorado, outside Denver. Welcome, Dr Bainbridge. I'd like to start out by asking you a little bit about how you came to this career in pharmacy and related to neurology. If you could, give us a little bit of your background.
Jacquelyn Bainbridge, PharmD: Sure. And thank you, Dr Cross. I was an undergrad in medical technology and combined science and working in the critical care unit, watching telemetry. I was fascinated by medicines working very quickly to bring some of these heart rates from 10 or 20 up to a normal heart rate using atropine. I loved the chemistry behind all of that, and I was good at chemistry. My father was a chemist, my mother was a fashion person, and I decided I didn't want to spend my life in the lab. I decided to go to pharmacy school and from there I moved to Colorado. My husband has a medical practice here, so we moved together for his residency, and I decided to get my doctorate. I was in the first post-BS PharmD program here at the University of Colorado, and I loved the program. I liked working with the physicians that I worked with and I liked critical care and neurology. I decided to further my career after my doctorate and do a residency specifically focused in neurology. I spent time at UCSF and in Madison, learning from people that had a PharmD who were working in neurology. I subsequently created a faculty position here at the University of Colorado, specifically in neurology and research in the School of Medicine, in the Department of Neurology. So here I am.
Cross: Well, we're glad you're here. And that's quite a unique one-of-a-kind story, I think. We'll get right into the topic of discussion, which is what is marijuana, what are cannabinoids, and what do they do in the body? I'm wondering if you could take on those questions for me.
Bainbridge: Certainly. And one thing that I will point out to begin with, when you talk to consumer groups that are using marijuana or cannabis for medicinal purposes, they don't like the term "marijuana" because they feel that that is more of a recreational-type slang word. They prefer to talk about "cannabis" or "medical cannabis." Of course, I found that out very quickly when I was talking to a consumer group, and they stopped me in the middle of my presentation. Cannabis is really fascinating. We know the plant has more than 400 chemicals or compounds in it, closer to 500. More than 100 of those chemicals or compounds are cannabinoids; we've identified about 100. We don't know what all the cannabinoids do. Some of them may have medicinal purposes and some may not. And many we just don't know. The two main cannabinoids that we talk about are THC [tetrahydrocannabinol], which is in the most abundance or an abundance in the cannabis plant, and then cannabidiol or CBD. We'll talk a lot about those two compounds. There are also a few other cannabinoids that are being looked at for medicinal purposes now, like CBN [cannabinol], more for sleep, CBG [cannabigerol], etc. But we don't know exactly where those compounds will find their way to medicinal uses. There are also terpenes in the cannabis plant. Terpenes give the "nose" to the plants but they may also have medicinal purposes, positive or negative. You find the cannabinoids in the entirety of the plant, which is very interesting. Cannabis has been used since 400 AD. Cannabis used to be in the USP in 1850, but then it was removed with the Substance Act. We'll talk mostly about THC, or delta-9 tetrahydrocannabinol, and cannabidiol.
So how do they work in the body? THC will directly bind to CB1 and CB2 receptors, whereas CBD or cannabidiol indirectly influences the CB1 receptor, generally by working through the endocannabinoid system and increasing endocannabinoids or cannabinoids such as anandamide, etc. that are found naturally in the body and produce homeostasis in the body. Their whole goal naturally in our body is to produce balance, which is very interesting. We know that the CBD works indirectly, as I mentioned. The mechanism for different disease states or conditions, or symptomatology, is unknown. However, it's believed that CBD will influence receptors so it potentially will block a GPR55 receptor. We also see that it desensitizes TRPV1 channels. All of this really inhibits adenosine reuptake pumps and will decrease calcium in the body and increase extracellular adenosine, producing a decreasing neuro-excitability. That's where we see most of the mechanism coming from, when we talk about neurologic conditions such as patients with multiple sclerosis.
Cross: Wow, that's fascinating and very complex. How many of the almost 500 compounds in cannabis are psychoactive?
Bainbridge: Great question. We find that THC or delta-9 tetrahydrocannabinol will actually produce the most psychotropic or euphoric feelings. Since we're mainly talking about CBD and THC, both are psychoactive because they work in the brain. But THC has that euphoric component, so it makes people feel high. CBD, however, does not give patients that euphoric feeling or does not make them feel high. They may have other feelings, such as sedation, which is often wanted with CBD, but they should not get that high feeling from CBD.
Cross: Thank you. I'm going to do my best not to use the "M word" that you mentioned that I should not use, especially not in front of anybody who knows about cannabinoids in cannabis and it's use for medical purposes. Speaking of medical purposes, can you speak to the use of cannabinoids for symptoms of MS? I've read various papers and it seems to be controversial as well there.
Bainbridge: Yes. The University of Colorado will start a clinical trial coming up here in the next couple of months, which will be looking at Sativex (the generic name is nabiximols). So, nabiximols are really a combination of cannabinoids. We find that there's about a one-to-one ratio of THC to CBD. We also know that in that mixture of nabiximols, there are other cannabinoids in that mixture as well and terpenes. This particular product, nabiximols, is actually approved in 29 other countries. However, it is not yet FDA approved here in the United States. It's an oral mucosal spray, and patients use it to relieve spasticity or spastic movements. The indication is for spasticity in patients who have tried other medications prior to moving on to nabiximols. There are other — as you know, Dr Cross — conditions that come along with spasticity, such as pain or a central pain component and also some bladder discomfort. Patients in other countries have recognized that Sativex may help alleviate some of the other symptomatology in addition to the spasticity. And basically, we should talk about the fact that cannabis has not been shown or proven to cure any disease states — it helps relieve symptomatology.
Cross: So you're saying that nabiximols are going to be considered perhaps for approval in the US, but that they're available in many other places and are approved for primarily spasticity and pain. What about what I hear about using these for seizures? Is there any good evidence for using cannabinoids for seizure, or other cannabis compounds?
Bainbridge: Great question. We also know that there is a CBD product on the market. It is FDA approved and it is again cannabidiol or CBD, and it falls under the brand name of Epidiolex. That particular product is an oral solution and it is purified. Both Sativex and Epidiolex are purified from the cannabis plant, much different than our other FDA-approved medications. So Epidiolex — and I use that brand name, although I know we usually fall back on the generic name, because I think it's important to point out the difference between Epidiolex CBD and CBD that you can purchase online or in a dispensary; they are much different. The FDA-approved product is purified. We know exactly what's in it and so the patient knows exactly what they're getting. It's easier to dose. We know from lot to lot, batch to batch, it's going to produce the same effects or have the same consistency and cannabidiol in it. I think is important because people get that confused. That particular product is approved for a rare type of catastrophic seizures. So, [for] Dravet syndrome, tuberous sclerosis complex, and Lennox-Gastaut syndrome, and we used that CBD product Epidiolex in conjunction with other medications.
I don't foresee in the near future that we'll be using Epidiolex for patients with multiple sclerosis who also have seizures, at least not as the first medication. There are many other medications that can be used for those focal-type seizures or whatever seizures. And the patient with multiple sclerosis generally has a focal-type pattern. There are many other medications that would be tried prior to that product, but as you move down the line, that may be an option for those patients, provided you could get it approved for the specific seizure type.
Cross: Okay, thank you. And what about sleep? I have seen a few commentaries about use of cannabinoids for sleep in MS patients with insomnia or sleep difficulty.
Bainbridge: Very commonly used for sleep is CBD. We know that that's a side effect of the medication. We always counsel patients on that particular side effect, but often that's why they're taking the CBD — for sleep. It does help very much for sleep. I would say that watching the dose is going to be important. Depending on which product you're talking about, we're not going to be using Epidiolex for sleep, at least not now, or that particular CBD. The CBD products that patients would be consuming would be from a dispensary or online. I would recommend that people, when they're purchasing something from a dispensary, that they ask for a certificate of analysis. They should be able to provide that at least online or with the product. Very importantly, it'll talk about heavy metals that could be in the product. And we'll also talk about exactly what's in the product because, you know, this is a very unregulated field. Often what you find labeled on the bottle is not necessarily what's in the bottle. I can give you a brief example of that. Someone went into a grocery store, all the CBD products were behind lock and key, not behind the pharmacy, but behind lock and key, and the person purchased a very expensive bottle of CBD, took it home, looked at the lot number or batch number, went to the website and found out that there were about 81 milligrams of THC in that bottle of CBD. It's really important for consumers to do their homework and find out exactly what's in the product that they purchased. You can also ask your health care provider or your pharmacist to help sort some of that out. And many of us do help patients with trying to find that information and push them in the right direction. It’s important to find a good distributor as well.
Cross: Great. What about safety? Do people develop tolerance or dependency on cannabinoids or any specific ones?
Bainbridge: Cannabis, in general, can produce a tolerance effect. So basically, that results in "we need more, we need more, we need more." That is very important when we talk about THC and sleep. Because people fall asleep quickly, but then they wake back up, kind of like alcohol and the metabolism of alcohol. You'd need to go back and repeat the dose. You need more and more and more or a bigger dose. We also do see people who use cannabis frequently and we're talking more the THC component, not the CBD component. More is known about THC, where people will develop a physical dependence and experience withdrawal symptoms. That is more of a dependence-type pattern that we see with THC, not so much with CBD. We do see that habitual use and dependence, which is important for consumers to be aware of and that's with THC.
Cross: Oh, okay. So could someone die of overdosing if they became very tolerant and had to use higher and higher doses?
Bainbridge: We know that at least in the wild, wild west here in Colorado, you can get very high THC-containing products. When you're talking about more "dabs" or "waxes" or "shatter," we're talking about a very high THC component. Cannabis can cause problems when we are talking about the heart. THC, as you notice … when somebody consumes THC, their heart rate goes up, their blood pressure goes up. There are objective measures that someone has consumed the product. So you also see that it will change heart rate variability. And when you're changing heart rate variability, that can lead to causing arrhythmias. We've also seen that there is morbidity/mortality information in patients who have suffered an acute myocardial infarction and THC being problematic in that group of patients. It's not exactly as safe as people initially would have thought.
Cross: Okay. Thank you for that. What is known about the long-term safety if someone is using or people are using cannabinoids or even nabiximols for long periods of time, is there any safety data on that?
Bainbridge: Well, the safety data, if people are consuming the product as recommended; that is, not using super-high doses very frequently, more of that recreational habitual side, it really hasn't produced a lot of problems. There are side effects. We see side effects with CBD. We see some liver function tests increasing. We monitor for that. We also see some GI upset, which is probably due to the CBD. I initially thought it was due to the carrier or what we were mixing the product in, but I think it's most likely due to the CBD. With THC, when people have been using it habitually, that's when we get into problems with psychosis, especially with edibles, because people tend to want the effect quickly. When you're consuming something orally, especially when we're talking about cannabis, you see a one in four change in the way it's going to produce a response in a patient. That means in the same person taking the same product one in four times, you're going to get a change in your bioavailability when you're consuming the product orally. With that being said, with the higher doses of THC, you can see a psychosis and that does take people to the emergency department. There's also something called hyperemesis syndrome, which is also very bad and hard to treat. A lot of our typical medications that we use for nausea and vomiting don't work on that hyperemesis syndrome. So that can be quite frightening. It often takes people to the emergency room as well.
But as long as people are using their CBD, if we're talking about the nabiximols or if they're using their FDA-approved product, there shouldn't be a lot of problems. That FDA-approved product is no longer scheduled by the DEA [Drug Enforcement Agency]. We do have a concern about drug-drug interactions, and so it's obviously a really good idea to check all medications that a patient is on when they're adding either a CBD product or a THC or a combo product.
Cross: Thank you. So, many of our patients with MS are women and many are in their childbearing years. I'm just wondering if you know anything or can tell us anything about women who might get pregnant while using cannabinoids or who breastfeed while using them?
Bainbridge: Yeah, both of those are no-nos with cannabinoids, at least at this point in time. We do know that there's transfer into the placenta. If it's a THC product, especially with high doses, you can see a withdrawal effect in the newborn and then you will see transfer into breast milk. We generally have our patients stop using cannabis if they're trying to get pregnant or if they happen to get pregnant.
Cross: Right. Thank you. You had mentioned, with nabiximols, some randomized controlled trials looking at its use in MS and spasticity. At least their first study was negative. Do you have any thoughts on that? Do you expect the other two studies to have a better outcome?
Bainbridge: I'm hoping for a better outcome. So, that RELEASE trial, which was in MSS1 and then I think the other two [trials] are MSS3 and MSS5 and I'm going to go back and look and see which one we are going to be enrolling patients in. But there was one component of the Ashworth scale that was negative, which is a commonly used scale when you're measuring spasticity in patients with multiple sclerosis. I'm hopeful that the next two trials will be positive trials as opposed to a negative trial. We are using it in 29 other countries.
Cross: Yes, right. And it would certainly be nice to have a controlled compound that we can offer to our patients that is as safe as possible, like other pharmaceuticals. I think we are about out of time. Thank you so much, Dr Jacqueline Bainbridge, for being with us today. I appreciate hearing all this information and I'm sure the listeners do too. This is a very complex topic. I particularly appreciate your information on safety issues, drug-drug interactions that may cause a problem, potential liver toxicity, tolerance, and possibly dependency, particularly from the THC component of cannabinoids. Good luck with your future studies on nabiximols and others in our MS population. I hope that we end up with a good pharmaceutical-grade product that we can offer to our patients. Thank you so much.
Bainbridge: Thank you.
Resources
Cannabinoids in Medicine: Limitless Hope or Hype?
Medicinal Cannabis: History, Pharmacology, and Implications for the Acute Care Setting
Sativex Prescribing Information
Epidiolex Prescribing Information
Cannabis and Psychosis: Recent Epidemiological Findings Continuing the "Causality Debate"
Cannabinoid Hyperemesis Syndrome
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Cite this: Can Cannabis Help Patients With MS? - Medscape - Dec 01, 2022.
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