Medical Marijuana and Stem Cell Transplant: What Do We Know?

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Medical Marijuana and Stem Cell Transplant: What Do We Know?

Monday, May 1, 2023

Presenter: Alison Carulli PharmD, BCOP, Hospital of the University of Pennsylvania

Presentation is 53 minutes long with 11 minutes of Q & A.

Summary: Medical marijuana has the potential to treat a number of problems associated with stem cell transplantation. More research is needed, however, to clarify its appropriate uses. This presentation reviews the currently known risks, benefits, and side effects of medical marijuana for transplant patients.

Highlights:

• Because of federal restrictions, there have been few good trials testing the efficacy and safety of medical marijuana. Along with ambiguities in how to dose various forms of medical marijuana, this makes it very difficult to make authoritative recommendations about its use.
• Medical marijuana is generally well-tolerated. But the potential side effects may include dizziness, tiredness, anxiety, short-term memory impairment, elevated heart rate, decreased blood pressure and, less commonly, paranoia and psychosis. To minimize these effects, patients should start with low doses and only increase them slowly, as needed.
• Medical marijuana is best used as an add-on medication in the third line setting. It may help with symptoms of nausea and vomiting, anorexia, cachexia, cancer-related pain, and potentially peripheral neuropathy.

Key Points:

(00:03:25): Medical marijuana can affect many part of the body and treat a variety of problems.

00:04:35): Medical marijuana has a long history in various cultures.

(00:09:17): Recreational marijuana remains illegal under federal law, which has limited efforts to scientifically study its effects.

(00:13:41): Palliative care and oncology practitioners tend to have a favorable opinion about the effectiveness of medical marijuana in managing various symptoms.

(00:16:58): Depending on the formulation and route of administration, medical marijuana's onset and duration can really vary widely.

(00:19:48): Inhaling, smoking or vaping marijuana can produce the quickest effects but carry risks of lung infections.

(00:21:07): Medical marijuana is pretty well-tolerated but does have some common side effects.

(00:25:40): Medical marijuana can interact with transplant medications including anti-infectives and certain drugs used to treat graft-versus-host disease (GVHD).

(00:31:57): Medical marijuana may decrease the metabolism of maintenance therapy medications and increase their toxicities and side effects.

(00:59:01): The big difference between medical marijuana and street marijuana is that medical marijuana is regulated, so we know it’s been tested to be sure there are no infectious agents contained in the product.

Transcript of Presentation:

(00:00:00): [Michala O’Brien]: Introduction: Good afternoon. My name is Michala O’Brien and I'll be your moderator for this workshop. Welcome to the workshop, Medical Marijuana and Transplant: What Do We Know?

(00:00:10): I'd like to introduce our speaker for this session, Dr. Allison Carulli. Dr. Carulli is a hematology/oncology pharmacy specialist at the Hospital of the University of Pennsylvania, where she participates in a daily monitoring of patients on the leukemia and allogeneic stem cell transplant inpatient oncology units. Her research includes a pilot program studying the safety and feasibility of using rescue therapies for CAR T-cell therapy patients who develop cytokine release syndrome and HLH like syndrome. Dr. Carulli is a member of the American Society for Transplantation and Cellular Therapy, the Hematology Oncology Pharmacy Association, and she is a peer reviewer for the Journal of Hematology Oncology Pharmacy. Please welcome Dr. Carulli.

(00:01:02): [Dr. Alison Carulli]: Overview of Presentation. Thank you very much for the introduction. I appreciate that. Today, as was just mentioned, we're going to be going through medical marijuana and stem cell transplant and what do we know. We're going to try to go through a big overview of marijuana, in general. We'll go through the legalization status in the United States, . We'll look at the available products, routes of administration, marijuana's place in therapy and use in symptom management, looking at those more relevant and long-term side effects in patients who have had transplants, and then look at drug interactions between medical marijuana and more commonly used post-transplant medication.

(00:01:53): Medical marijuana is an extract of the plant cannabis sativa. Just to get us on the same page with definitions, when we say medical marijuana, we're talking about the leaves, the stems, the flowers and seeds of all the species of the cannabis plant. This plant contains over 400 components, but the ones we are mostly concerned with are the cannabinoids.

(00:02:17): There are two main types of cannabinoids; phytocannabinoids and endocannabinoids. Endocannabinoids are produced by our own body. Phytocannabinoids are the ones that we're going to be focusing on today. They come from plants. There are two that are the most studied -tetrahydrocannabinol, aka THC, and cannabidiol aka CBD. THC is the psychoactive one, meaning that that's the one that's going to cause people to get that high feeling from medical marijuana and CBD doesn't really have that effect.

(00:02:58): Medical marijuana works by binding to cannabinoid receptors. There are two main cannabinoid receptors that we focus on: CB1 and CB2. Where these receptors are located is going to really help us understand the potential benefits and side effects of medical marijuana. Now, while there is some overlap, not everywhere has both receptors.

(00:03:25): Medical marijuana can affect many part of the body and treat a variety of problems. This picture is divided by three colors to show that. The purple lines are where CB1 receptors are located. I want to draw your attention to the fact that CB1 receptors are located in your brain. You can see why you might get some mood changes with medical marijuana.

(00:03:45): CB2 receptors are in red, and notice that your white blood cells have CB2 receptors on them. That's going to be really important to think about, with side effects and treatments, because we don't want anything suppressing people's white blood cells after a transplant.

(00:04:02): Then the green lines are pointing to parts of the body that contain both CB1 and CB1 receptors. As you can see, the stomach and the digestive tract have CB1 and CB2 receptors, which is why some people might find medical marijuana is helpful with nausea, vomiting or appetite. They're also in the heart. That's something that we're going to have to think about with potential side effects.

(00:04:35): Medical marijuana has a long history in various cultures. With that many potential places for marijuana to work in the body, it's kind of easy to imagine that it's had a lot of uses throughout the years. It's definitely been years. Marijuana has been around for tens of thousands of years. It's believed to have originated in the northeastern Tibetan plateau with the earliest reports of use in 10,000 BC. There are multiple reports of ancient cultures using marijuana in China, India, Africa, Greece, et cetera. They even found cannabis in an Egyptian mummy, which I think is just really cool. What they used medical marijuana for seems to vary between the regions and the cultures, but some are similar to what marijuana is being studied for today.

(00:05:23): For example, one of the most studied indications for marijuana in modern times has been for seizures or for epilepsy, but they figured that out thousands of years ago in India. The ancient cultures also knew of marijuana's potential effects for pain relief and really frequently used it for rheumatic pain, menstrual cramps and other types of pain. Now, they also recommended it for indications that we know it's not really useful for like rabies and malaria and tuberculosis, and as a pesticide. They weren't completely correct. As you can see, marijuana has been a really popular treatment for many years.

(00:06:08): Unfortunately, though, in the early 20th century, marijuana's place in therapy really became much more controversial in western world. This is partly due to the more effective medications being produced, inconsistency and efficacy between different marijuana plants and a concern that marijuana had high risks of intoxication and addiction.

(00:06:32): The United States restricted marijuana use throughout most of the 20^th century. Now, we will be focusing a little bit more on how the United States dealt with these concerns. Legally, they really started restricting cannabis in 1914 with the Harrison Narcotics Tax Act that regulated distribution of opiates and banned prescribing habituated drugs like medical marijuana. They really took things a lot further in 1937 by banning the use and sale of all cannabis in the US. People who wanted to use cannabis had to register and pay totally separate taxes. This was a law that made it really difficult for people to use and study marijuana in the United States. Use really declined significantly for a short time.

(00:07:20): In the 1950s, really, use actually started to really increase again in a more underground fashion, though, amongst young people. This didn't really change the course of federal regulations. It was categorized as a Schedule 1 drug in the 1970s, meaning that there's no accepted medical use based on federal standards. Since then it's really been very, very difficult to study marijuana for legitimate indications and has really stalled our ability to determine effectiveness in a variety of different diseases. However, there continued to be some interest, and a synthetic version of marijuana, called dronabinol, was approved in 1985 for nausea and vomiting.

(00:08:08): In the last three decades, public opinion changed and most states have legalized medical marijuana. In the last few years there has been a pretty much complete reversal of public opinion. California became the first state to legalize marijuana for medicinal purposes in 1996. Recreational use really wasn't approved until 2021 in Colorado and Washington. As you can see, since 1996, 37 states have legalized marijuana for medicinal use in the US. This graph depicts where marijuana is legalized, medicinally, in blue ,and where it's legalized recreationally and medicinally in purple. As you can see, it's now really only a minority of states that have not legalized marijuana in some form in the US.

(00:08:56): Now it's estimated that there are at least 35 million Americans who use marijuana on a monthly basis, and over 5 million patients have a medical marijuana card as of 2021. Use and public acceptance has really definitely exploded in the past few years.

(00:09:17): Recreational marijuana remains illegal under federal law which has limited efforts to scientifically study its effects. However, marijuana continues to be considered illegal under federal law and is still a Schedule 1 drug. Therefore, no one can really actually get a prescription for medical marijuana. Physicians use a loophole to recommend medical marijuana. Even with that loophole, federal restrictions still significantly limit our ability to study marijuana's effects, mostly because a lot of hospitals and research centers obtain grants from the federal government, and they can't perform research on a Schedule 1 drug because of that.

(00:09:57): As you'll see later, there really isn't enough data on medical marijuana's effects, and that's just one of the limitations that we're faced with. There's still a lot of education gaps because medical marijuana is dealt with so differently compared to other drugs. Physicians have to be certified, especially to prescribe medical marijuana, and the prescriptions aren't at all what they're used to. Healthcare professionals are really used to prescribing a specific dose of a medication and knowing exactly what the patient's going to be getting, but medical marijuana prescriptions don't contain doses or the contents or the type of medical marijuana that is being recommended. Those are very, very different.

(00:10:45): Dosing medical marijuana properly is a challenge compared to other medications. Because the potency varies from plant to plant, and product to product, it's really difficult to know exactly what you're getting. The THC and CBD content is going to vary in each product. Quite a few products don't actually even list the CBD content at all.

(00:11:03): The purity can also vary from dispensary to dispensary and isn't intensely regulated. That can make physicians and pharmacists like me, understandably, a little bit nervous. It makes it doubly important to try and make sure that everyone goes to a reputable dispensary and tries to stay consistent with what products they're using.

(00:11:24): Of course, dosing is completely different for each indication and person. [inaudible 00:11:32] marijuana plant, which makes my job so fun. Each plant has a different CBD and THC amount in it, meaning that people can't just say, "Okay, take this X amount," because it can really vary. The modes of administration can also really change how much is absorbed in the body and how quickly it is, which can really dramatically change the amount someone needs.

(00:11:57): This being said, we really don't know the optimal dosing. The general mantra is to start low and go slow, meaning start at the lowest dose and increase it slowly until you get symptom relief or side effects. That uncertainty really means that healthcare professionals are probably more likely to prescribe something that they're more familiar with and can titrate more consistently and really only think of medical marijuana as a second, or third, line agent.

(00:12:29): Lack of education probably plays a role in this. A group of researchers surveyed medical personnel that were still in training, so students, residents and fellows, and found their knowledge in medical marijuana to really be severely lacking. Only about 25% of trainees felt confident enough to answer questions about medical marijuana. Only 5% felt that they had enough education and training to prescribe it. Have you ever been to a hospital or discussed medical marijuana in detail with a physician in training? You might not have gotten the in-depth education that you really need, but I would definitely encourage you to ask your palliative care team or oncologist questions that you have.

(00:13:23): As we can see on the right, surveys from 2017 to 2019 indicate that they are significantly more confident in the use and prescribing medical marijuana. 50 to 80% of physicians believe that medical marijuana should be legalized in general.

(00:13:41): Palliative care and oncology practitioners have a favorable opinion of the effectiveness of medical marijuana in managing various symptoms. As you can see, the numbers seem to be more consistent with the palliative care or oncology practitioners. 70% of palliative care workers believe medical marijuana is effective for symptom management and almost 70% of oncologists recommend it as an add-on medication for pain. Clearly physicians who are specialized in symptom management are seeing the benefit of medical marijuana, we just need more data and education.

(00:14:12): There is some data that has led to the FDA approval of a few agents. Dronabinol and nabilone were approved in the mid1980s and 2000s to target CB1 and CB2 receptors, which were on the picture that we discussed earlier. They are primarily approved in chemotherapy-induced nausea and vomiting and age-related anorexia or cachexia. They do have several studies in cancer-related anorexia and cachexia though, so we do use them fairly frequently. While they [dronabinol and nabilone] do work particularly well in patients who have found medical marijuana to be effective, most patients say that they're not quite as effective as their medical marijuana, but they are readily available oral options that can be trialed, so a good option for some patients.

(00:15:06): Epidiolex® is a purified cannabidiol that seems to act on those cannabinoid receptors that we discussed earlier. However, it has a very narrow indication for seizures related to a very severe form of epilepsy and is pretty strictly only used for that indication. We [in oncology] really have not had access to that medication at all.

(00:15:27): Sativex® (nabiximol) is an oral spray that can be given on the inside of the cheek or under the tongue. It's a really unique medication on this list because it's the only medication that actually has THC in it. There are equal parts of THC and CBD in it. It's approved in Europe and Canada, but not in the US, for multiple sclerosis related spasticity. The trials required for US approval are actually wrapping up, though, so we may see this agent in the US in the next few years, but for now we don't have access to it and medical marijuana is actually easier to get.

(00:16:10): There are quite a few medical marijuana options available, and they all have different modes of administration. This is helpful because there really is a way to get medical marijuana to everyone even if they can't swallow or if they can't take anything orally. Conversely, though, it can get really confusing and overwhelming, with all the options available, [to decide] which one's best to choose. Every time I turn around, there seems to be another dispensary popping up and different options, different types, different flavors, et cetera. This list is not nearly as all-inclusive, but I did try to include some of the more common routes of administration, or some of the more unique ones and a few pearls to keep in mind.

(00:16:58): Depending on the formulation and route of administration, medical marijuana's onset and duration can really vary widely. As you can see, using edibles or oral tablets can have a pretty variable onset. It also has a very variable bioavailability, meaning how much is actually absorbed in your body. It can take up to two hours to see an effect with it. That “start low and go” slow mantra, that I talked about earlier to find your ideal dose can be kind of hard to figure out with this. You need to be really careful to not just keep taking extra every few minutes until you see an effect. Make sure that you've waited the full two hours before taking any additional edibles to avoid overdoing it.

(00:17:51): Then, in patients who cannot swallow or want a more local effect, there are also quite a few options. Creams and lotions are great options for those who are looking for that more localized effect, like if you specifically have a knee or a foot pain or something and you want to target that area. There are some debates, though, with these about how much is actually absorbed in your body and how deeply these creams and lotions can penetrate, so keep that in mind if it's not working. You might need something that can penetrate a little bit deeper or that affects the entire body.

(00:18:29): Tinctures are also great options. They tend to have better systemic absorption, meaning that it goes into the whole body and it affects the entire body, [more] than the creams and lotions.

(00:18:42): If you're having trouble swallowing but want that more systemic effect going into the whole body, there are also different alternatives, but these are less studied. Transdermal, meaning a patch that can be absorbed through the skin and hit every part of the body is an option, but again, less studied and really variable absorption. It's really hard to titrate this up and down and find out your ideal dose.

(00:19:09): Suppositories are also available and can be used rectally, but there are limited studies on these, so we have less knowledge about dosing. The other thing, of course, to consider is your platelets and your white blood cells. We never want to increase the risk of infection or bleeding, and inserting something into the rectum can be associated with moving bacteria to other places or causing physical trauma. Suppositories are really not recommended if you have a low white blood cell count or a low platelet count.

(00:19:48): Inhaling, smoking or vaping marijuana can produce the quickest effects but carry risks of lung infections. If you can't take any of these, there is one other route of administration that people always think of, probably think of it first. I do want to spend some time on it as I think it's the most common route, which is inhaling, smoking or vaping marijuana. The onset of this one is probably one of the quickest, but unfortunately smoking or vaping is associated with an increased risk of both bacterial and fungal lung infections. This is because this method of administration deposits spores in 50% of individuals. People are three and a half times more likely to develop infections, as a result, particularly, if you're immunocompromised, like all people who have recently gotten a transplant or are on any therapy for graft-versus-host disease or on something to prevent cancer from coming back. We have case reports to prove that. The main takeaways from the last two slides are that there are lots of ways to administer medical marijuana, but smoking and vaping are the methods that pretty much every person in the cancer world is going to recommend against.

(00:21:07): Medical marijuana is pretty well-tolerated but does have some common side effects. To switch gears a little bit, I'd like to start discussing side effects. Fortunately, medical marijuana seems to be pretty well-tolerated, overall. Even though a lot of people actually use it to treat nausea and vomiting, if you take too much of it, then you can actually cause nausea and vomiting. That's one thing to watch out for and a really important side effect to note if you're trying to titrate your dose up.

(00:21:32): Dizziness and tiredness are common; anxiety, panic and paranoia may also occur with higher THC products. I would say that the most common side effects that everyone thinks of are the ones that affect the brain. The more THC in medical marijuana, the more likely you are to experience some of these side effects, but you can still see them to a smaller degree in products that only target CBD. They are good to keep in mind, regardless. The most commonly reported ones are dizziness and tiredness. Anxiety, panic, paranoia and psychosis are seen more commonly with those higher THC products.

(00:22:13): Short-term memory impairment is also an issue with medical marijuana, particularly with long-term use. We don't recommend driving while taking medical marijuana. There have been studies that have shown that people have less motor coordination, meaning that they have slower reaction times in cars and take longer to perform important functions like stopping a car, which is a really important function. Definitely don't drive while you're taking medical marijuana.

(00:22:46): Addiction is also reported in up to 9% of people on medical marijuana, which is actually a lower percent than other medications such as opioids, but something to keep in mind.

(00:22:57): Other side effects that can occur include elevated heart rates and decreased blood pressure. There is some concern, and it's really an evolving concern, that there's an increased risk of heart attacks and strokes with medical marijuana. This is still being studied, but that's something to really discuss with your doctor if you have any sort of heart problem or a history of strokes or anything like that.

(00:23:24): Then the other side effect is coughing and wheezing, which mostly happens when you're smoking medical marijuana, so, again, don't smoke it.

(00:23:36): Now, I wouldn't be a pharmacist if I didn't want to talk about drug interactions. Unfortunately, I don't have a lot of great data to draw upon for drug interactions with medical marijuana. There are generally several ways that we determine drug interactions in the healthcare world. They can make models of the metabolism and the functions of the human body and use Petri dishes to see what happens when medical marijuana is introduced to different modes of metabolism. Those are just models, and not a person. Human beings are infinitely more complex than those models. Our genetics, our own metabolism, the way our organs work all determine the true relevance of an interaction. Those types of tests using models and Petri dishes tend to be the first steps when looking at a drug to give us an idea of what should be happening when we're studying it.

(00:24:42): Afterwards most drugs are then tested by giving them to an actual human being and looking at the levels of the drugs in the body, when you're looking at something that would inhibit them. These are really helpful studies and, really, the studies that we really need to see to know what the true interaction is, and how concerned we should be. But we don't have those, due to the legal restraints; differences in CBD and THC contents, because as you can see, they inhibit little different things in the liver; administration routes, and a host of other things. We really don't have these studies yet. Because THC and CBD inhibit those different parts of the metabolism pathways, the true impact of the interactions are likely really individualized based on the product, the dose and the person.

(00:25:40): Due to legal restraints on research, we know very little about how medical marijuana interacts with other medications. All that means that it's really hard to know what interactions we should be worried about with medical marijuana. We really don't know the clinical impact of any of these interactions. Therefore, I want you to take these next slides with a grain of salt. They should only be used to instigate a discussion with your doctor about using medical marijuana so that you both know what to monitor and keep an eye out for.

(00:26:11): Medical marijuana can interact with transplant medications in several ways. In general, with interaction for these different agents, we're concerned with three different things. If medical marijuana increases the level of a transplant medication, then you can get an increase in toxicity or side effects of that transplant medication. A lot of these transplant medications have a pretty narrow dose range, meaning that they only work at a certain dose and giving any more can cause really bad side effects. Higher levels can be concerning.

(00:26:47): Conversely, if the levels of the transplant medication are decreased, by an interaction with medical marijuana, then there's a higher risk of the medication not working. Depending on the medication, that can mean higher rates of graft-versus-host disease, that can mean cancer coming back if you were looking to use that medication to prevent cancer.

(00:27:11): On the flip side of both of those, some transplant medications can actually increase the levels of medical marijuana and increase the risk of marijuana side effects.

(00:27:24): What I did was I tried to list the most commonly used medications used to treat graft-versus-host disease and the theoretical risk. Again, these concerns are still theoretical, because of everything we just discussed on the last few slides.

(00:27:45): Unfortunately, medical marijuana does seem to have an impact on most of the medications used in transplant to treat GVHD. The main concern is that medical marijuana decreases the metabolism of the transplant medication. That means that there's more hanging around in the body for longer, and you might get increased levels of that transplant medication, increasing your toxicity and your side effects. We can actually monitor levels for some of those like tacrolimus or the cyclosporine or the sirolimus, but I would definitely still recommend frequent monitoring when on those medications.

(00:28:28): I would pay special attention to monitoring with tacrolimus, because this interaction really does seem to be important. There are multiple reports of people starting medical marijuana and seeing their tacrolimus levels shoot up. That can cause side effects like kidney problems and can cause some confusion and neurotoxicity. This interaction seems to be very real from the literature, not something that you want to ignore.

(00:29:01): There's less data on the other medications, but prednisone, ruxolitinib (Jakafi®), belumosudil (Rezurock®), ibrutinib (Imbruvica®) are very important medications used to treat GVHD and can have some concerning side effects if you get too high of a dose. Talking with your doctor is going to be really important if you want to start medical marijuana while you're on one of these medications.

(00:29:32): Medical marijuana can also interact with anti-infective drugs. In terms of anti-infectives, which I'm sure everyone's familiar with after getting a transplant, there are two main drugs that might interact with marijuana. Those are posaconazole (Noxafil) and voriconazole (Vfend). Actually, posaconazole and voriconazole actually may decrease medical marijuana's metabolism. You actually might have more medical marijuana hanging around your body for longer, increasing your risk of marijuana side effects. Definitely something to note and monitor. If you start one of these agents, you might actually need less medical marijuana in the long run or you might get more side effects if you haven't changed your dose after starting these.

(00:30:23): Medical marijuana can also interact with maintenance medications after cancer treatment. Then, as I'm sure you are aware, a lot of people are on medications to keep their cancer from coming back after transplant. We call these maintenance medications. I wanted to include the potential interactions with marijuana and the agents that are more commonly seen in ALL or acute lymphoblastic leukemia and CML, or chronic myelogenous leukemia. These include imatinib (Gleevec), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), ponatinib (Iclusig®), and asciminib (Scemblix®). With these agents, the main concern is that the medical marijuana may decrease the metabolism of the maintenance medication. That means that there's more hanging around the body for longer and you might get increased levels of the maintenance medication, which can increase your side effects and your toxicity.

(00:31:29): A lot of these medications can have a really narrow window where they're effective but don't cause very concerning or life-threatening side effects. It’s very important to discuss starting medical marijuana with your doctor if you're on any one of these. They'll probably want to monitor you a lot more closely, and they can tell you which of those side effects to specifically look out for, so that you're more aware when you're starting.

(00:31:57): Medical marijuana may decrease the metabolism of maintenance medication and increase their toxicities and side effects. These medications are the ones that are commonly used after transplant for maintenance in acute myeloid leukemia or AML. They include venetoclax (Venclexta®), gilteritinib (Xospata®), sorafenib (Nexavar®), azacitidine (Onureg®), enasidenib (Idhifa®), and ivosidenib (Tibsovo®). Similar to the ones that are used in CML or ALL, the main concern is that medical marijuana may decrease the metabolism of the maintenance medication. That means that there's more hanging around the body for longer, and you might get increased levels of the maintenance medication, increasing the risk of toxicities and side effects. This is a concern for all of these agents except for azacitidine (Onureg®). Marijuana really doesn't seem to affect that medication.

(00:32:57): Similar to before, some of these medications can have really narrow windows where they're effective but they don't cause these really concerning side effects. Very important, again, to discuss starting medical marijuana with your doctor if you're on any of these because again, these are theoretical, but they're what we have right now. We definitely, at the very least, will want to monitor very closely if anyone starts these.

(00:33:24): Now, whether to start medical marijuana is one of the questions that people are asking most. I wanted to go through that and the current recommendations about medical marijuana's place in therapy. These guidelines are actually from outside of the US. Canada and Australia have both developed medical marijuana guidelines that I'm going to be referencing. Unfortunately, there's really very little data in transplant specifically. We're going to be mostly discussing data about using medical marijuana to treat symptoms that people who have undergone a transplant have, but not really studies specifically in patients who have undergone transplant.

(00:34:11): As of right now, medical marijuana is not recommended first line in any setting. It's generally recommended as an add-on agent in the third line setting. These recommendations really go back to the lack of data that we have. As I said before, marijuana's lack of federal legalization makes it very difficult for hospitals and physicians to conduct really large, robust, good clinical trials that would tell us if marijuana works in different diseases or symptoms. Most of the studies that we have use the FDA-approved products such as dronabinol. As a result, we really only have smaller trials that aren't of high quality, for actual medical marijuana.

(00:35:05): Even the few trials with medical marijuana have serious limitations. There are some concerns about using those types of trials. The less patients that you have in a trial, the higher risk of false positives, meaning that marijuana can look like it's effective when it's really not, when it's tested in a larger patient population.

(00:35:25): Most of these trials are also not blinded, meaning that people know exactly what they're getting and if they're getting medical marijuana or not. The concern with that is that people experience what we can call the placebo effect, meaning that a person's mind actually believes that treatment is beneficial simply because they believe that that treatment should work, but it's not really due to the properties of the drug. Essentially, it's another risk of a false positive, where we think marijuana works, but truthfully it doesn't. These trials also don't have long follow-up times, so it's not really possible to determine the long-term efficacy or side effects of medical marijuana, when taking it for these different indications.

(00:36:21): Correct dosing of medical marijuana remains a challenge; users should start low and slow and slowly increase as needed.  One of the largest, and last issue, that I want to talk about is the variety of doses and preparations that are used in these trials. They all use different products and doses, making it impossible to know whether a lack of effect, or a side effect, in a study is due to too low or too high of a dose. It also means that we really don't know what dose is best for anyone. That's really why we haven't discussed dosing throughout the presentation. That's also one of the main reasons that we hesitate to recommend marijuana in a lot of cases. The only advice is to start low and slowly increase your dose based on symptoms and side effects.

(00:37:07): In terms of symptoms that studies have shown medical marijuana can help, the first is nausea and vomiting. I would say that this is probably one of the best studied areas, but most of the studies are looking at the FDA-products, dronabinol and nabilone. Remember, those work on CBD only, and have no THC. These studies have actually seen a benefit in using dronabinol and nabilone, but not as a first line agent. While they have seen a benefit compared to some other agents like chlorpromazine, which I think people are fairly familiar with, and they've also seen a benefit compared to placebo, there's really not data to suggest that it's better than initial therapy. It tends to be recommended as an add-on agent in a third-line setting.

(00:38:04): I particularly like to use it in patients who have found medical marijuana to be effective in the past but are unable to use the medical marijuana right now for whatever reason, they're in the hospital or something else. These patients seem to have the best benefit. The summary of this is that your dronabinol and nabilone are good options for nausea and vomiting symptoms if the initial agents don't work, but you won't see them really in the frontline setting.

(00:38:36): Medical marijuana can reduce cancer-related pain compared to placebos but may not be as effective as opioids. Cancer-related pain is probably one of the other most common symptoms that I get asked about. Not to sound like I'm repeating myself, but medical marijuana is not recommended as a first- or second-line therapy for cancer-related pain. There are multiple trials out there looking at various medical marijuana products, comparing them to placebos or opioids, like oxycodone or dilaudid. Unfortunately, a lot of these studies aren't designed as well as we would like. They have a high risk of both false positives and false negatives, and they all use different pain scales, or comparisons, making it really difficult to compare them and draw conclusions for all of medical marijuana. Of course, pain is subjective, so it's hard to objectively assess pain in any trial. All in all, the trials need to be taken with a grain of salt.

(00:39:45): That being said, though, quite a few studies have shown a reduction in pain scales when compared to placebo. I do think medical marijuana does have some efficacy in cancer-related pain, but the benefit's less clear when medical marijuana is compared to other opioids. Opioids do seem to work similar to, or better than, medical marijuana in these studies. Medical marijuana is unlikely to replace opioids in the long run but given the higher rate of addiction with opioids and the side effect profile of opioids, I do think that medical marijuana will be a key medication for pain in the future. But we need those studies, first, to be able to recommend medical marijuana as a first- or a second-line agent. For now, it's going to continue to be recommended as a third line agent and as an add-on.

(00:40:44): In terms of which products to recommend, Canada's guidelines on medical marijuana recommend nabilone or a nabiximol over other agents, but of course nabiximol is not approved in the US, so don't forget that part.

(00:41:03): Medical marijuana is not recommended for peripheral neuropathy but can be considered as an add-on agent in third line treatment. To get more specific on different types of pain, I want to discuss peripheral neuropathy. Peripheral neuropathy is nerve pain that causes tingling or burning that's commonly seen in the hands and feet. It can be really severe  and can make walking difficult or doing things such as buttoning your shirts or anything like that difficult. This is a type of pain for which we have very limited treatment options, right now. I would love it if we could use medical marijuana and if it was found to be effective.

Right now, medical marijuana is not recommended for peripheral neuropathy caused by cancer agents, but it can be considered as an add-on agent in the third line, thanks to studies in HIV-related neuropathy. There are not strong agent-related peripheral neuropathy trials out there right now, but there are those few trials in HIV that have shown lower pain scores when compared to placebo.

(00:42:13): A few things to keep in mind though. These trials are very short in duration and peripheral neuropathy can really be a lifelong issue. Long-term follow up to make sure that medical marijuana continues to be effective is essential before this can be recommended in the frontline setting.

Something else to consider is that the trial showing efficacy used strains that had a lot of THC, and results were less consistent with cannabis extracts, increasing the risk of side effects such as anxiety, paranoia and panic, and clearly showing that we need to get the dose right and the product right before we can recommend it more consistently. For now, it will continue to be an add-on agent in the third line. You can consider it there.

(00:43:07): Medical marijuana can help with anorexia and cachexia in the third line setting. Anorexia, or loss of appetite, and cachexia - a really marked weight loss with muscle loss, as well – is common after a transplant. It's probably one of the other more studied indications for medical marijuana. Most of the studies are looking at the FDA-approved products, dronabinol and nabilone that work on CBD only and have no THC. Keep that in mind when you're trying medical marijuana for this indication. The side effects you experience may be really very different than what we saw in the trials using CBD only agents, like dronabinol.

(00:43:54): In terms of where medical marijuana is recommended here in the U.S., it's not recommended as a first line agent, but it may be beneficial for some patients in the third line setting. This is mostly because the majority of studies in AIDS-related anorexia show trends towards increased weight, but there's a probability that this is actually just due to chance, alone, since it wasn't statistically significant. Some of those false positives are a big risk in these studies. The study using cannabis extract and THC combo didn't show any benefits compared to placebo. That might have been the dosing or the product.

(00:44:41): There's several studies in cancer, but I want to draw your attention to one which looked at a first line agent called megestrol (Megace®) which was studied and compared to dronabinol in cancer patients. The patients who were taking Megace® actually had more of an appetite and weight gain when compared to patients taking dronabinol. Patients on the dronabinol arm did gain some weight and have an increased appetite, as well, so dronabinol probably does also help with the anorexia and cachexia. But we can't recommend it as the frontline agent, based on this data, when we see that Megace® actually working a little bit better. Again, it's a third line agent for certain patients.

(00:45:28): Medical marijuana is not recommended for depression or anxiety, although it might have some efficacy in the latter. Then the last symptom that I wanted to talk about was depression and anxiety. At the moment, medical marijuana is not recommended for either of them. There are limited trials in depression, and the few that we have are in chronic pain, so not really patients who have cancer, and they're looking at the chronic pain part. The depression is kind of an add-on thing to see afterwards. The studies aren't as focused on depression as we would like. These studies, which have used nabiximol or nabilone, also didn't find a difference in depression symptoms when compared to placebo. One study actually found that patients had less symptoms of depression when receiving placebos compared to nabiximol. I never really recommend medical marijuana for depression, based on that information.

(00:46:29): There might be some efficacy in anxiety. A small trial in social anxiety disorder did report improvement in symptoms. There are several studies looking at chronic pain that also have reported symptom improvement in anxiety. However, these studies really didn't report any baseline anxiety levels, so it's hard to draw any conclusions. We really need larger, more robust trials to confirm the efficacy of medical marijuana before it's recommended for anxiety.

(00:47:06): Medical marijuana may help with insomnia but is only recommended as an add-on in the third line. I didn't have a slide on this, but I also wanted to talk very briefly about insomnia, because I heard that there were quite a few questions at another one of the lectures about this. Medical marijuana has been studied in insomnia, but very similar to what I've been saying throughout this talk, it's really not recommended as a frontline agent. It's really recommended as an add-on, in the third line. There have been several studies that have shown that patients are reporting subjective improvements in sleep quality, but most of these studies are in patients who are in pain. It's kind of a question of whether the medical marijuana reduced the pain levels, which then made it easier to sleep, or if it's more of a change in the biological sleep patterns.

(00:48:03): Most of these studies were also looking at nabiximol, which is that agent that's approved in Canada but not in the US yet. It's that spray that has both THC and CBD in it. It was promising data but not enough to recommend its use in the frontline setting.

Then the other thing to keep in mind with insomnia is that there are some reports that if you stop cannabis abruptly, you can actually exacerbate insomnia. Keep that in mind when you're looking at it for this indication or for other ones.

(00:48:47): There have been some promising but small trials suggesting that medical marijuana may reduce the incidence of graft-versus-host-disease (GVHD). Now to switch gears a little bit and finally talk about something specifically related to transplants…Medical marijuana has been studied in one trial to prevent graft-versus-host disease or GVHD. They gave 48 patients cannabidiol for 38 days, in addition to the standard graft-versus-host disease prophylaxis [preventative medicine] that people normally get. They compared this to historical patients who had previously undergone transplant but didn't receive cannabidiol for prophylaxis. What they found was that the incidence of graft-versus-host disease was low, at 12%, and severe graft-versus-host disease was even lower, at 5%. These results, along with the fact that there were no severe side effects reported, are really promising. There are several ongoing trials looking at this more closely.

(00:49:48): Trials looking at medical marijuana to prevent GVHD found that certain white blood cells did not come back when exposed to cannabis, which dramatically increased the risk of infection. However, until we have these trials, medical marijuana is really not recommended for GVHD prophylaxis, because in these animal models that they looked at, they found was that certain white blood cells didn't come back after transplant when exposed to THC, CBD and cannabis extracts. So lymphocytes, and T-cells. This is one of the biggest concerns in transplant, because no white blood cells or certain ones really dramatically increases your risk of infections. It also increases your risk of the stem cells being rejected by your body. We take that very, very seriously.

(00:50:38): Now, these are only animal models and there are no human studies available. I would categorize this as more of a theoretical concern, but one that might not be worth the risk right after transplant. Those animal models are really the reason that we generally recommend avoiding medical marijuana for the first few months after transplant, to ensure that your white blood cells completely recover. After that, adding on medical marijuana in the third line setting is very reasonable, but needs to be discussed with your doctor, because of the side effects and those drug interaction that I discussed earlier.

(00:51:26): I wish I had more to say on dosing, but we really still don't know the best dose or even products for these symptoms. Always start with the lowest possible dose and increase it, based on side effects and symptoms. Of course, don't smoke it, whatever you do. We definitely don't want any fungus in the lungs after transplant.

(00:51:51): In terms of the future, I'm hopeful that we will have more data to guide our recommendations, and that we may see medical marijuana recommended more consistently. There are over 200 ongoing trials using medical marijuana in a lot of different disease states. Hopefully, that can shed some light on this.

The FDA was directed to review the scheduling of cannabis in the last few years. If it's rescheduled, then those clinical trials will be a lot easier to conduct and will likely help a lot in determining the best place for medical marijuana.

(00:52:30): Thank you so much for listening to me. That concludes the presentation. I'm happy to take any questions that anyone has.

Question and Answer Session

(00:52:39): [Michala O’Brien]: Thank you, Dr. Carulli, for this presentation. Our first question is can you discuss any current research on medical marijuana for the BMT or SCT survivor?

(00:53:01): [Dr. Alison Carulli]: Yeah. Unfortunately, there's not a lot of data specifically for transplant survivors. There's just a lot of data about the side effects that we might see. That's what I was trying to go over a little bit. There's some data in pain, cancer-related pain, and there's some data in nausea and vomiting that can commonly happen, sleep and those types of things, but not really much specifically for what patients after transplant should do. I wish I had more.

(00:53:33): [Michala O’Brien]: Okay. Can medical marijuana reduce the inflammatory sclerotic effects of GVHD of the skin and nerves leading to sclerosis and peripheral neuropathy?

(00:53:46): [Dr. Alison Carulli]: That's a really good question. We've never studied it for GVHD treatment specifically. It does seem to inhibit T-cells, which are really one of the big things that are causing graft-versus-host disease. That can be a good thing to think about. Right now, we don't know.

(00:54:09): At this point I probably wouldn't recommend it, but there is some data in peripheral neuropathy, mostly HIV, that it does actually seem to be a benefit in the third line or as an add-on. That might be a good option to try, but just be really careful with those other graft-versus-host disease medications that you're on. You want to talk about it with your doctor, about the interactions that might happen, before starting it.

(00:54:38): [Michala O’Brien]: Do you suggest edible or inhaled marijuana for better sleep issues after a transplant?

(00:54:46): [Dr. Alison Carulli]: That's a good question. The studies have been all over the place, so really technically, you can do any of them. What I would say is that the edibles and the orals do tend to last longer, so they have a longer duration of effect. If staying asleep is the issue, I would probably use an edible or an oral option because that way you can stay asleep the entire time. Whereas some of the other ones, like the lotions, the tinctures, sometimes the inhalers and smoking it, they don't necessarily last as long. That's why I would probably personally err on the side of using an oral or edible. Again, theoretically, you can trial any of them.

(00:55:35): [Michala O’Brien]: Okay. Another sleep question, is it safe to use CBD for long-term insomnia?

(00:55:42): [Dr. Alison Carulli]: There's no data to suggest it's not safe, aside from what we just talked about with the different interactions to think about. I think it's definitely a reasonable option.

(00:55:54): There are some side effects that do happen with long-term use. We're worried about those impending heart issues that we're starting to see in patients that have used marijuana long term, so those heart attack and stroke risks. We haven't quite figured out exactly how common that is, or how long you can use CBD before you get worried about that. Always think about that, and think about your own heart history, before using it for a really long time. Aside from that, I would say that it's definitely a reasonable option to consider for long-term.

(00:56:30): [Michala O’Brien]: Do you have a preferred method for taking marijuana for patients with stomach or GI issues that have graft-versus-host disease?

(00:56:40): [Dr. Alison Carulli]: That’s a really good question. I think it depends a little bit. I don't have a preferred method, but if people can't eat or take something by mouth, if you're throwing it up or something like that, then those tinctures or those patches might actually be a better option than trying to take some sort of edible. It's really what you can tolerate.

(00:57:07):  If you're having lots of diarrhea, sometimes medications don't get absorbed as well because they move through the GI tract so quickly. In those cases, it might make more sense to use something like a patch to make sure that it's not really going through the stomach and that you can definitely get that onset, and try to avoid any sort of nausea, vomiting or anything like that, that these can cause too, if you take too much. That might help.

(00:57:39): [Michala O’Brien]: Okay. This person's asking about sativa strains of marijuana that give the person energy to overcome fatigue and increase activity as he rehabs. He’s two years post-bone marrow transplant. What should he be concerned about with the daily dose usage?

(00:57:57): [Dr. Alison Carulli]: I wish I could talk with any sort of intelligence on dosing. It's very, very person-specific and we really don't know. What I would say is always start low and go slow. If you're going to try an edible, take a quarter of it first, see how it works. Wait about one-to- two hours and try and take a little bit more and see how you're doing, from a pep in your step type of thing, before trying a little bit more. I wish I had more than that, but it's so different, depending on the different products and the different marijuana plants that everyone uses. I really can't give anything more specific than that.

(00:58:48): [Michala O’Brien]: Okay. Does medical marijuana or street marijuana decrease your overall immunity? Is there a difference?

(00:59:01): [Dr. Alison Carulli]: There's not a difference between medical marijuana and street marijuana, in terms of immunity or acting on your white blood cells. The real big difference, probably, is that medical marijuana is regulated, so we know exactly what's going on there and what's in there. We know there's not fungus or those kinds of things that we always get really concerned about, especially for people who don't have an immune system. That's the big benefit of medical marijuana. It's very, very regulated and you're not going to get anything else in it. That might happen with street marijuana, but there’s no difference in its effect on white blood cells or immune response.

(00:59:51): [Michala O’Brien]: Do different forms of the THC marijuana pose different risks to transplant patients?

(00:59:59): [Dr. Alison Carulli]: That's a really good question. Technically, we don't know. It does look like both THC and CBD inhibit the white blood cells. I think that that's an equal concern no matter what strain or anything that you do. I would say that that's going to be consistent, but your side effects and your own toleration are going to be a little bit different, depending on how much THC is in a product versus CBD. That's going to be something to factor in.

(01:00:30): The drug interactions are also going to be a little bit different, depending on what strains you use, because THC and CBD act on different parts of the metabolism pathways. So you can have more concerns of certain drug interactions, depending on which ones you're using, from a THC to a CBD standpoint. I can't give huge specifics, because it's going to really, really depend on the different drug, but that's one thing to consider.

(01:01:05): [Michala O’Brien]: Can you get just as much clinical benefit from using marijuana that does not have the chemicals that cause you to feel high?

(01:01:14): [Dr. Alison Carulli]: It depends. As I, unfortunately, feel like I keep saying, I'm sorry I'm not able to get specific. A lot of the studies using agents, such as dronabinol and nabilone, don't have any THC in them, which is that high feeling, and have shown benefits in nausea, vomiting, anorexia and cachexia. You definitely can have a benefit with less or no THC in them. We don't really know what the perfect ratio is yet. I would say that it's definitely a really good first step to see how you do, from a symptom management standpoint, and see if it works with just CBD, or less. Then look at the THC components, adding in more of that afterwards, if you haven't gotten a good effect.

(01:02:12): [Michala O’Brien]: Here's another THC question. How does THC affect the immune system rebuilding after a transplant, specifically a T-cell depleted transplant?

(01:02:22): [Dr. Alison Carulli]: All of the agents, CBD, THC and cannabis extracts, all prevented white blood cells from reconstituting, or coming back, in those animal models. All of them are going to be a concern, theoretically. Again, it's all theoretical. We don't have the human studies available, but nobody really wants to mess with anyone's grafts or your stem cells. I'd still say it could be a concern for at least the first few months after transplant, just while those are coming back.

(01:03:01): [Michala O’Brien]: Is there a clean way to smoke marijuana? I once had a nurse tell me it can be baked to kill bacteria.

(01:03:15): [Dr. Alison Carulli]: There's no clean way to definitively get rid of every single bacteria that we have. Baking it or not inhaling it are good options, but certain fungi and certain bacteria can survive even those temperatures. It's not going to be a definite. That's one of the reasons why we like medical marijuana the most, because they test for those bacteria and fungus to make sure that those aren't there, at least not those concerning level. [But in answer to your question], it would work for certain bacteria but not all.

(01:03:53): [Michala O’Brien]: We have time for one more question. Are edibles safe for people with elevated liver panels?

(01:04:03): [Dr. Alison Carulli]: That's a really good question. Medical marijuana is metabolized by the liver. The liver is doing the work. If your liver isn't working that well, you might have more marijuana and it might not metabolize as quickly, and you might get more side effects. Marijuana, itself, doesn't seem to really cause elevated liver panels, or anything like that, so it's more that you'll probably need less and it might last a little bit longer, if you're going to take it with an elevated liver panel.

(01:04:36): [Michala O’Brien]: Well, thank you. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Carulli for her very helpful remarks and an excellent presentation. Thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way.