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

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

Tuesday, April 20, 2021

Presenter: Joseph Bubalo PharmD, BCOP, BCPS, Pharmacotherapy Specialist, Oregon Health & Science University

Presentation is 33 minutes long with 21 minutes of Q & A.

Summary: Marijuana is used by many stem cell transplant recipients to manage a variety of side effects, but caution is advised. The potency and purity can vary, depending on the source, and marijuana can affect the effectiveness of some other medications the patient may be taking.

Highlights:

• Medical marijuana is used for pain, nausea, appetite, seizures, and muscle spasms. Studies of pain control, however, have not been inconclusive due to methodological limitations.
• Compared to other recreational drugs, cannabis is considered a “soft drug” in terms of lethality, dangers, and addictiveness. But there remain risks which vary with the method of delivery. For instance, oral preparations generally pose less risk than smoking cannabis.
• Transplant patients should consult with their care team before using medical marijuana, as it may cause serious side effects with medications such as Jakafi, tacrolimus or cyclosporine that are often prescribed before or after transplant.

Key Points:

(05:27) There are major differences between the cannabinoid THC and CBD. THC produces a psychoactive effect sought by recreational users while CBD does not produce those effects.

(07:43) The dose and response to cannabis can vary greatly depending on whether it is smoked or taken orally.

(09:15) Cannabis can interact with prescription medications and may alter their effects. Depending on the medication, it may intensify or cancel out the intended response to prescription medications.

(10:21) Pharmaceutical cannabis comes in synthetic form with varying blends and differing preparations of THC or CBD.

(12:18) Cannabis comes in different forms: plant, resin cake, tincture, oils infusions, and edibles.

(14:19) Cannabis has varying potency and labels can be misleading.  Commercially available synthetic compounds available on the internet are riskier than those from a dispensary using regularly sourced products.

(15:36) Commercially produced synthetic products, called cannabinoids are different than cannabis, and can cause serious side effects such as organ damage.

(21:52) Smoking cannabis delivers four times the particulates you get when smoking a cigarette,  and has a similar risk of causing cancer.

(24:32) Cannabis use in people under age 25 can cause long-term problems, including addiction, because their brains are still developing.  

(29:02) Cannabis is not a first line treatment. It’s most appropriate for debilitating conditions that have not responded to standard medications or therapies.

(34:47) Since cannabis can modulate the immune system, patients should refrain from using it for at least 100 days after a donor transplant (allogeneic) and 60 days after a transplant using your own stem cells (autologous).

Transcript of Presentation:

(00:01) [Michelle Kosik]      Introduction. Good afternoon. My name is Michelle Kosik, and welcome to the workshop Medical Marijuana and Stem Cell Transplant: What Do We Know? I'd like to introduce our speaker for this session, Dr. Joseph Bubalo.

(00:14) Dr. Bubalo is an oncology pharmacotherapy specialist with Oregon Health and Science University in Portland, Oregon. He is also an assistant professor of medicine in the division of hematology and medical oncology. He has been active in the clinical care of stem cell transplant and cellular therapy patients for over 25 years. He has received research grants to investigate ways to improve supportive care and decrease symptoms for transplant and other cellular therapy patients. Please welcome Dr. Joseph Bubalo.

(00:58) [Dr. Joseph Bubalo]      Overview of talk. Good morning, afternoon, or whatever time it is where you are. Medical Marijuana and Stem Cell Transplant: What DO we know? Depending how you look at it, cannabis has been around for a long time, over 100 years. And we're going to touch on that. It's been called lots of different things, and this first slide is just illustrating a lot of the culture around cannabis, which I was reminded right before the discussion today, it's 4/20, which is kind of a national cannabis day, or was at one point in time. I think it's still become a part of popular culture, that basically people on 4/20, they would congregate on Hippie Hill and smoke cannabis. Appropriate that we're talking about it today, no matter what it's called. The goal is to have a productive discussion.

(01:57) So after this workshop, I'd like you to have an idea of how cannabis probably works. We're still really working this out when it affects both either mood or physical discomfort. We'll talk about the products that are out there. As a pharmacist, I'm very interested in both quality and potency, and delivery methods if we're going to use it as a therapeutic intervention. Any potential benefits in how we might use those in stem cell transplant recipients, and then adverse effects and interactions that we would want to be aware of so we can actually integrate it successfully into overall care.

(02:39) Historical background of cannabis use in the U.S. So really in the 1800s, cannabis first came to the United States, and it came through a variety of different methods, via immigrants as they came into the country, but it was widely prescribed. And this is something that has been used for a long time. Common uses were things like labor pain, nausea, and rheumatism, which we don't use for labor pain, but certainly nausea and rheumatism are still looked at today. Over time, a lot of it, due to political activity, it was criminalized as a drug of abuse through the 1900s, and in 1970 it became schedule I federally, which means it has no accepted medical use. And then two years ago in 2018, the first non-synthetic cannabis product was approved, Epidiolex for seizure disorders.

(03:34) So we're talking really about cannabis sativa, which is a flowering herb. Also, the indicia and ruderalis species are less commonly used, but still have roles in how people use it therapeutically. Originated in Asia, but it grows avidly and can be found on every continent at this point, except maybe Antarctica.

(03:57) Over 30 states in the U. S. have medical cannabis programs. Currently we have over 30 states, and the number changes so much, I just have over 30 because with last November election, I think a couple more picked up medical marijuana programs, and I think it's 36 or 37, plus the District of Columbia, that allow use for specific medical conditions. Additionally, another 14 allow Low delta 9 THC, and high cannabidiol, what we'll call CBD during the talk, products for qualifying medical reasons. So some form of cannabis is available in all but I believe two states.

(04:37) There are three main cannabis compounds: terpenes, flavonoids and cannabinoids. The compounds that are actually in cannabis come in three main categories. The terpenes, which are what give plants, in general, their smells, whether it be pine, or citrus, or other plants that have an aroma, but they are responsible for both the unique aroma and the flavor of cannabis.

(04:58) Flavonoids are what are commonly considered to be anti-inflammatory or antioxidant compounds, and are one of the main reasons people are interested in the vegetarian diet, because they're in a lot of different plants.

(05:11) And then cannabinoids, or phytocannabinoids, as we call them, have the highest concentration in the female flowers of the cannabis plant, and these are compounds that actually bind to the cannabinoid receptors in the body and enact a response.

(05:27) The differences between THC and CBD. The two main cannabinoids in use are Delta-9-tetrahydrocannabinol or THC. This is the psychoactive component in cannabis and the one that has been widely used recreationally to cause people to have a high or a euphoric feeling. Originally it was found in relatively low, somewhere around 0.5% by weight, up to around 20%. It is not common to have greater than 30 or 35% THC concentration as people continue to refine the growth of these plants. CBD is really kind of the opposite.

(06:04) The cannabidiol lacks the psychoactive effects, so originally it wasn't really sought out in any way by cannabis users since it didn't cause them to get high. But we now know that even though it doesn't interact with any of the known cannabinoid receptors, it still has therapeutic effect, and we're trying to figure out what those are now and how they actually occur so that they can be better effected when someone needs care. Overall, there's over 140 different cannabinoids that are in the cannabis plant, just these two are what we'll focus on today, as they're the best characterized.

(06:43) The human body has two types of cannabis receptors. The human endocannabinoid system, we do have receptors, which THC latches onto that are called the CB1 receptors, that were discovered in the late '80s. And if you look in the body here, you notice these light blue receptors are clustered mostly through the nervous system, the spine and the brain, and so it makes sense that these are going to be causing changes to how we interpret things or appreciate things.

(07:13) CB2 receptors are found throughout the immune system. They're found in lymph nodes and in the thymus and other places in the body, and those are the little black dots. Cannabinol is your classic CB2 agonist, or activator of those receptors. And then once again, CBD kind of plays to the middle in this cartoon. It's just showing the fact that it really doesn't interact with either of these two receptors, yet we see therapeutic effects from it, and that's still being worked out exactly how that occurs.

(07:43) If you are eating cannabis, you need 3-5 more than the amount you receive when smoking it. When we think about what dosing means with cannabis, generally two to three milligrams are in the average cannabis cigarette, or joint as they're called, and that is what is used for the average kind of high. Some people need more, some people need less.

(08:00) If you're going to take that orally, whether it be a gummy or a cookie or a brownie, or soda or whatever, you need about three to five times as much as the inhaled dose because the stomach acid actually breaks it down before it gets into the system, and the liver also metabolizes part of it. So somewhere between six and nine grams orally, maybe even 10, would be normal.

(08:25) The thing about the smoked versus taken by mouth is that everybody has a faster or slower GI tract, depends on how acid your stomach is, various other things, whether you have food in it or not, so it's hard to predict the onset with eating something as opposed to when smoking, where usually it occurs within two to maybe 10 minutes. It's rare to see it take longer than 15 minutes.

(08:51) Each state can decide what a dose is, so in Oregon for example, a dose is five milligram increments. So if it's a square of chocolate, each square is five milligrams of THC content. Washington, which is just to the north, is 10 milligrams per dose, and then some states have multiple different doses that are available.

(09:15) Cannabis interacts with prescription medications and may alter their effects. These drugs do interact with prescription medications, and it's fairly common, actually. So it is important to let your physician know what you're taking, and actually what's in what you're taking, because they're going to work with the liver enzymes and other metabolic systems to potentially change the effect of another compound if you have prescription medications.

(09:36) There are dynamic interactions as well, so if you have something that is going to cause you to be sleepy, generally cannabis is going to add to that, especially THC-containing cannabis. So a sleeping pill or an antihistamine or antianxiety agent, you may be much sleepier if you're also taking cannabis.

(09:54) If you're taking a stimulant, something for fatigue or ADHD, possibly, it may make that not work quite as well because it's going to be opposing it dynamically. And then those that have history of depression or other psychiatric illness for which they take drugs, we can have kind of unpredictable effects, depending on what the compounds are in that particular cannabis product.

(10:21) Pharmaceutical cannabis comes in synthetic form with varying blends of THC or CBD. So if we look at the pharmaceuticals that are out there, this would be non-natural things, Dronabinol and Nabilone are two synthetic THCs that are made by pharmaceutical companies that interact with both the CB1 and CB2 receptors to produce effects. And Dronabinol, we use it mainly for appetite stimulation and for nausea.

(10:44) Nabilone actually is used mainly for pain in other countries. We don't use it very much in the U.S. And then more recently, we had cannabidiol in the form of Epidiolex, which was a purified solution standardized to 100 mg/mL that is actually extracted from a single cultivar of cannabis plants, the sativa plants. And once again, we aren't exactly how that works, but it's clear that there's benefit, and now it's FDA approved in this case for seizure disorders in children, primarily.

(11:15) Cannabidiol is worth a little extra mention here because federally, it is any hemp plant that has a maximum of 0.3% THC or less. However, if you look at marijuana-derived CBD, it can have a lot of THC in it. So if you're someone who is not used to that, you may have a very different effect than if you got a hemp-derived THC. But those who use it medicinally often have strong opinions as to which is better.

(11:47) The pharmaceutically-derived, the Epidiolex, actually has a very low THC. The plants that it comes from have a less than 0.1%, so it is primarily CBD, though there are other compounds in it as well. As I mentioned, there's a lot of cannabinoids in a cannabis plant. And while there's many different forms of cannabis sativa, the actual cultivar, the actual... I have some names of products coming up at the end... has very different content.

(12:18) Cannabis comes in different forms including plant, resin cake, tincture, oils infusions, and edibles. So if we look at preparations that are out there, you have marijuana, which is dried leaves, stems, or flowers, and it's really flower or bud, as it's called in the dispensaries, that people are purchasing. Hashish is a resin cake that is a very concentrated form of THC.

(12:38) Tincture here is different from your average pharmaceutical tincture. If you go to a pharmacy and ask the pharmacist what a tincture is, they'll say it's something dissolved in alcohol. When we talk about cannabis, it's actually any liquid that has cannabis in it. So it could be anything from soda pop to some other beverage.

(12:59) Oils are generally going to be extracted from the plant with some type of solvent, and originally there were a lot of gas solvents used. Butane and ethanol, propane, and most of those have gone away and it's mainly CO2 extraction that is done now. A couple benefits of CO2, one, it does not leave any organics in the extracted product, so you don't have a butane contamination or something like that, and also it's not explosive. People would blow up things when they were working on extracting it sometimes, so it could be relatively dangerous.

(13:34) Infusions are going to be plant material that's often mixed with a cannabis oil, and then they're used to make oral edibles, so whether it be butter or cooking oil or whatever, you're going to have THC or whole cannabis that's been extracted and dissolved into one of these things to be able to cook with.

(13:54) The edibles themselves come in a wide variety. You can get almost any food. I think the only thing that you really can't get as an edible is alcoholic beverage. Most states have said that you can't add cannabis to an alcoholic beverage. And then, once again, if your edible is hemp-based, it's really you're getting mainly CBD, but the THC content can be quite variable.

(14:19) Cannabis has varying potency and labels can be  misleading.  Which kind of brings us to the fact that this is a natural product, so it's grown in fields, some of them are grown indoors, and we have really a wide variety of things out there. They are often tested for herbicides and pesticides, and it's important to know that these aren't there, hopefully.

(14:41) Dispensaries are safer than buying off the internet. The potency is going to really vary. In fact, multiple studies now have showed that over half of those products that are out there are going to be mislabeled. They'll either say they have more or less of the THC or CBD, for example, in them than the label has. So that has been relatively unreliable, so it is important to get them generally not off the internet, from a dispensary that is using regularly sourced products.

(15:11) Each batch, even though it's the same cultivar, depending on the growing conditions, and a lot of the growers work very hard actually to make their batch as reproducible as possible, but there's still some variation in what they actually turn out. And then the appropriate dose for any one medical condition is unknown. Everybody who does it is basically experimenting on themself.

(15:36) Commercially produced synthetic products, called cannabinoids are different than cannabis, and can cause serious side effects such as organ damage. There are things that are synthetic cannabinoids. Just as we were able to make Dronabinol and Nabilone, chemists have found that there are seven different structural groups that actually interact with the endocannabinoid system. And you'll see things like Spice or K2 or Fake Pot, et cetera. Sometimes these are even in gas stations or convenience stores. These are all now considered schedule I. One again, no medically acceptable use.

(16:05) And the problem with these as opposed to something which is extracted from a cannabis product is that you can actually get a lot of organ damage. There's been people who've lost kidney function and have had other problems when using these, so they are other chemicals that interact with the endocannabinoid system that really should not be used due to their really unknown toxicity profile, and unpredictable things happen when you take them.

(16:30) Medical use of THC can lead to euphoria, disorientation, drowsiness and cognitive lapses. So when we look at the medical use, there's a couple different things that happen. And these are mostly thinking about THC, but when you think about effective things, people are generally going to be euphoric and more likely to laugh when they're taking cannabis products, especially THC-predominant products.

(16:51) There's some changes in your time and space perception, and a little altered state and disorientation is common. As I mentioned earlier, drowsiness is a very common side effect, as well as dizziness and maybe some changes in your motor coordination.

(17:07) Cognition, nobody actually thinks more clearly on THC-based cannabis, anyhow, and there's similar research coming out with CBD that you can have memory lapses and a little more challenged concentration, and your short-term memory appears to suffer a bit when you're using a cannabis product.

(17:27) Medical marijuana is used for pain, nausea, appetite, seizures and muscle spasms. The potential uses for medical marijuana or cannabis, really pain, nausea, appetite. We now have an FDA approval for seizures, and this is a specific type of seizures, two pediatric disorders that are out there. And then muscle spasms is the other one with an approved product in other countries that is in phase III trials here for muscle spasms. And those are really the main uses that are likely to come out, at least in the short-term, meaning the next five years or so for medical cannabis. While there's looks into these other disorders, I think the research is much less far along.

(18:11) Studies of pain control have major limitations. Probably the most interesting for many people is pain relief, and can we do a better job of controlling pain? And while there are more and more publications coming out all the time, this is still low quality evidence. I think if there's one thing that's happened with the COVID is we've all become clinical trial experts as we look at these vaccines that come out. And the bottom line is things that are most well-established as beneficial tend to be pharmaceutical products, and while there's moderate quality evidence for benefit against pain, it's mostly nerve caused pain, and possibly cancer pain. And so far, the smoked THC and the product called Nabiximols, which is a one-to-one THC to CBD ratio product have had been what's looked at.

(19:07) The problem is that these are short lengths of time that they're studied. Weeks, really. Different outcomes measures that are not reproducible across trials, there's no blindings, so everybody knows what they're on, and often then don't cross over from the one placebo to the other and see whether there's a placebo effect or not. So we can't really say a lot, currently, about the efficacy, and it's interesting.

(19:37) In 2015, there was what we call a meta-analysis, and they looked at how many articles were out there about the use of cannabis. And at that point, there were about 6,000 articles. Last year in 2020, there was actually three of these meta-analysis, and there's now over 13,000 articles in the medical literature about cannabis. So while the evidence is proliferating rapidly, it's still not coming out in a form that we're able to use. And until it's legalized in some manner, it's unlikely that we'll have great research, at least in the U.S. There are other countries that are actually looking at it much more thoroughly and in a much more scientific way than the United States is.

(20:23)  Cannabis is a soft drug in terms of lethality, dangers and addictiveness. So if we talk about potential harm, and this is where we talk about how we would integrate it in with standard care, it's almost impossible to overdose on cannabis, certainly with plant material. If you have something that's synthetic, it's certainly more possible. But it's considered a soft drug. It's less addictive, less dangerous, both side effects and lethality, than a lot of other recreational drugs. However, there are pretty reproducible side effects, and if you look at what's available with the pharmaceuticals versus standard natural marijuana, things can be quite different.

(21:04) If you look at appetite increase, Dronabinol, Nabilone help that. Regular marijuana does, but cannabidiol at the doses that are used in pediatric seizure disorders, about up to a quarter of those individuals had appetite decrease. And so if you look at these, we do see differences between different cannabinoids that are in a product. As these slides are available, I would encourage you to look at them. But the bottom line is that as we learn more and as the products are more and more targeted to product different cannabinoids, THC, CBD, and so on, each one's going to be different in the side effects and the effects that you can see from it.

(21:52) Smoking cannabis deliver four times the particulates you get when smoking a cigarette,  and has a similar risk of causing cancer. It has traditionally been a smoked product, and smoked without a filter, and people when they smoke cannabis tend to take very large breaths, hold their breath, and so on. And it turns out that if you do that, you get about four times the particulates with smoking cannabis than you do when you're smoking the same amount of tobacco. So these things are tars, hydrocarbons, carbon monoxide, ammonia, very similar to what we see when someone smokes a cigarette.

(22:20) If you're using a vaporizer, and this is not a vape pen but a vaporizer, you have less carbon monoxides, but you still get hydrocarbons and lower amounts of particulates. So if somebody is going to aerosolize this by smoking a vaporizer, once again, not a vape pen where these oils can actually cause what we call lipoid pneumonia and cause harm to your lungs, would be the way to do it. So if there is going to be a less harmful way of smoking, and I actually don't recommend any smoking process, is the vaporizer would be the way to do it because there are other respiratory effect.

(23:01) Wheezing, sputum production, chronic cough are common. It turns out that in cannabis leaf and buds, the most common bacteria is enterobacteriaceae, and then the most common mold, which is aspergillus, which is a pretty pathogenic mold, especially those that are immunocompromised. And the dry buds are going to be more dangerous than an oil form, but there's been a lot of case reports of fungal cases, especially with smoking cannabis. You can sterilize the leaves and buds, but this is not done routinely in the United States.

(23:38) About the risk for lung cancer, as I mentioned, your particulates and stuff, it's about the same as a cigarette, so about 8% for each joint-year versus 7% for each pack-year of cigarette smoking, joint year being one joint per day per year.

(23:58) Smoking cannabis can also poses cardiac and cerebrovascular risks. There are some cardiac and cerebrovascular, so stroke events, when you smoke a high THC cigarette. And this is with smoking, not with eating cannabis products. You see increased heart rate, increased blood pressure, cardiac output, and if somebody has the right or wrong risk factors, you can have a sudden cardiac or a stroke even. And it happens, once again, mostly with smoked product. So once again, it's a reason we would suggest staying away from an inhaled cannabis product.

(24:32) Cannabis use in people under age 25 can cause long-term problems because their brains are still developing.  In young people, it's clear that the endocannabinoid system is critical for brain development and maturation. Adolescent exposures tend to have more long-lasting alterations in the endocannabinoid system, and some other systems. And this has been linked to behavioral changes, cognitive changes, and things that probably last into adulthood, as far as the consequences. And while legal sales go to the age of 21 and older, brain development goes until around the age of 25. So if you're thinking about it, when was it best to use it, it would actually be after the age of 25 to do the least harm.

(25:12) Reproduction studies show that in animals, it causes some growth retardation and it can cause fetal malformations. Human studies are very challenging because most everybody who's using it and is pregnant is often using other products, including illicit drugs. In general, those babies that are born to someone who is using cannabis regularly, they tend to be a lower birth rate. They can have some delays in their eye development and their visual development, and they tend to have increased tremors at birth, similar to the way that babies who are born addicted to opioids are when they are first born. And changes in memory, generally lower memory and verbal outcomes have been seen in children who have been exposed in utero, but it's hard to tell with kids what that means. And so prenatal exposure is potentially a harmful thing, but it's unclear exactly what that is.

(26:20) Addiction risks are greatest for adolescents. There is a risk for addiction. There is a cannabis use disorder. It develops in about nine to 10%. It is more likely to occur in the developing brain, so it is more common in young people. If you compare that to nicotine, nicotine about a third of people who use it become addicted to it, and heroin is around a quarter, alcohol's around 15%. So sedatives and cocaine are a very similar addiction potential to cannabis, and there is some withdrawal symptoms if you've been using it long-term.

(26:52) Cannabis can impair driving ability. Driving, so today is 4/20, and we know that there's a 125 increase in fatal car crashes on 4/20 versus either a week before or after. So there is a risk for more accidents with cannabis if you're driving while impaired, and it's not overt. It's not like someone who's drunk a bunch of alcohol and is visibly staggering or having trouble. What happens is you lose the automatic functions of driving, so you're less likely to turn on a turn signal when you turn. If you see brake lights in front of you, you are less likely to hit the brakes right away. Somehow your automatic helpful systems have been somewhat disengaged. So in some states now, especially those with recreational cannabis, if somebody rear ends another person, they're automatically going to be checked for cannabis.

(27:47) Risks of fungal infections, bacteria and mold. Fungal infections, as I mentioned earlier, are a particular concern in those who have cancers, especially the hematologic malignancies, or after a bone marrow transplant. There are certainly case reports in others as well, and so we know that smoking cannabis deposits spores, fungal spores, in about half of those people. And while you can sterilize it, currently there's not a commercial delivery device that sterilizes cannabis, so once again, a reason to stay away from that.

(28:21) As I mentioned, whether it's smoke, which is highest, but the vaporized products also have some inhalation of both bacteria and molds from the plant surfaces. If you sterilize with plasma peroxide, you can autoclave it, or ethylene oxide, and this is done actually in Israel and some other places. It works, but you have a lower THC. Those that want to do it on their own, if you bake it for 300 degrees in the oven for 50 minutes, you're going to probably lose a quarter to a third of the THC content, but that will kill most of the spores that are on a product.

(29:02) Cannabis is not a first line treatment; it’s best used when other standard therapies are ineffective. So in general, this is the advice that has come from a medical journal recently, that cannabis is currently not a first line thing. It's probably third line or later, and it's used for those that have a debilitating condition that is not being helped by standard medications or standard therapies that you hopefully would have already tried, and unfortunately not been successful with the first line therapies. So a failed trial of Dronabinol or something like that is often considered important before you would get a medical cannabis card.

(29:38):Since it's recreationally available, a lot of people don't have to get cards anymore in order to have access to it. If you have a mood disorder, and anxiety disorder or other psychiatric condition, you really shouldn't use cannabis. It tends to result in poor control of most psychiatric illness. And then depending on the laws in your state, you would have to follow up to see about using it, or if there's recreation available, obviously you don't have to get a cannabis card.

(30:10) Cannabis poses lung, cardiac, psychiatric and dependency risks while the true medical benefits remain unclear.  So take home points, risk. I think we know that lung cancer risk is really unclear, just because folks are often smoking cigarettes and other things at the same time, and that if you're going to use it, vaping, not a vape pen, is the best way to go about it.

(30:27) You really have to be concerned if you have any cardiac risk factors and you're going to use a smoked product because there is risk for both heart attacks and strokes.

(30:36) Psychiatric concerns are real. Those that have schizophrenia or bipolar disorder especially are more likely to lose control of that illness if they're using cannabis. And there's been pretty strong links in it, especially if a young person is using cannabis in that way.

(30:56) It's less habit-forming than nicotine and the hard rugs, but there is a real dependence, especially in young people, of around nine to 10%.

(31:06) We worry about anybody who's thinking about getting pregnant or possibly could get pregnant and being exposed to it.

(31:13) And then we're still really figuring out as those that were born or active in the '60s become older adults and they have all the older adult illnesses and stuff, what do we do with the older folks who have experience with cannabis and decide to use it medicinally, or recreationally, actually? So the benefits, the true medical benefits are unclear.

(31:36) Cannabis can provide pain relief, manage seizures, and help with appetite and nausea, but most people take it mood enhancement. We have lots of reports of people who have had, for example, pain relief when they use it, especially neuropathic pain. And we know that muscle disorders, as I mentioned in the Nabiximols product, is in phase III trials with FDA right now, and is approved in eight other countries currently. We have these pediatric seizure disorders, where they take children who have 50 or 60 seizures a day, and they bring it down to where they're having often less than 20, less than 10. They don't actually completely go away, but they really improve the quality of life for these individuals. And appetite and nausea have been a primary use, and when we talk to people, the main thing they tend to use them for is actually mood. They just report they feel better when they're using a cannabis product.

(32:25) So I think that while we really have to do a lot of work clinically to characterize this, we want to understand more of it before anybody is going to actually prescribe it once it becomes legal. And it's thought that at some point, it will become legal in the U.S., as it has in many other U.S. countries. So while the names have changed, and the products are clearly different than those that were available certainly in the 1800s and the early 1900s, and even from the '60s and '70s, from the last century. So just be aware that whatever it's called, that things have changed and you have to really do more or less an experiment on yourself to figure out what is right for you.

(33:19) When used as a medical therapy, patients should have clear medical goals they are seeking to accomplish. And it kind of depends on what your goals are. As with any other medical therapy, you want to think about it as you go forward to decide whether or not it actually did achieve your goal, whatever your medical goal was for taking it. And I know there's a lot of interest because whether it's just mood or something else, it is not uncommon to be unhappy with our medical therapies at this point in time. With that, I'd like to go ahead and open it up to questions. We thought that there would probably be a lot of discussion around this topic, and we're looking forward to that.

(34:03) [Michelle Kosik]      Q & A. Thank you, Dr. Bubalo, for this excellent presentation. Let's go ahead and look at all of the incredible questions that our audience has come up with. I do believe you addressed this one, but there are a couple of questions, so I think it's worth hearing directly from you. On what method of consumption is preferable, knowing post-transplant risks of liver and lung concerns occur? Do you think tincture, smoking, vaping, or some topical application is best for this group of individuals?

(34:47) [Dr. Joseph Bubalo]     I think smoking and vaping would be my least desired routes of administration. I think an oral product would be best. Once again, it depends on what the goals are, but usually we would say take something by mouth. We really don't want you to take it in anything at all, at least in the first 100 days after an allogeneic transplant, and at least probably 60 days after an autologous transplant, because as the immune system is getting used to you and you're getting used to it, we know that cannabis does modulate the immune system. We're just still trying to figure out how.

(35:33) We wouldn't want to change your risks to be a stable chimera and have disease control, which the transplant is providing. So preferred would be oral. Topical is a challenging question, in that there are actually no pharmacokinetic studies currently that have told us how well topical is absorbed, and what kind of dose you're getting. Topical does go past the liver metabolism initially, so it's absorbed right through the skin. Cannabinoids are very lipid-soluble and they go right through the skin, but we don't know really what the delivery is like. So if I was going to do this, I would go with an oral product. Sorry, long answer. I'll try to be shorter.

(36:29) [Michelle Kosik]      No, I think that's excellent, and I think you allow us to really think about all of our options in that answer. The next question is, I take Jakafi for my chronic graft-versus-host disease, and I'm not supposed to eat grapefruit due to the interaction. I've heard that CBD oil has the same effect as grapefruit with certain drugs. Is that true, and how does that work with THC?

(36:56) [Dr. Joseph Bubalo]      Yeah. That is absolutely correct. Jakafi is a liver modified drug, and if you're taking a high CBD product with the Jakafi, you would be increasing your Jakafi levels, so there's a chance that you could become myelosuppressive. It could affect your white counts, and it could affect... Often if you're on Jakafi, you're on an antifungal and some other drugs. Maybe Tacrolimus or cyclosporine, and it could affect the levels of those as well. If it's a THC product, it's going to have less of an effect on Jakafi than if it is a high CBD product. The CBD is a stronger metabolic interactor than THC is for the enzyme that metabolizes Jakafi.

(37:49) [Michelle Kosik]      I sure hope everyone was listening to that. That's critical information. It does have a strong impact on multiple levels, which really could impact overall well-being. And of course, important to share with their physician if they are utilizing these products.

(38:07) The next question is I'm seven years post-transplant with severe GVHD with the lungs. I have neuropathy, and at times I have severe cramping in my upper body. Arms, fingers, shoulders, and internally in my esophagus and stomach muscles. Do you think cannabinoids could be helpful with these cramps?

(38:33) [Dr. Joseph Bubalo]     We've never... When we use it as a muscle relaxer, it's used in multiple sclerosis primarily and conditions like that, and the Nabiximols product is a one-to-one ratio of THC to CBD, so it's basically one milligram per one milligram of THC to CBD. It is a spray that goes under the tongue, but that's for skeletal muscle, so those are the cramps in your arms or legs, or other parts of the body. Your esophagus and all of your GI tract is smooth muscle. It's a different type of muscle, and as a result, is relaxed or gets crampy from different signals than that.

(39:17) I have never seen a cannabis product that has been studied even for that type of crampiness or muscle spasm, as opposed to there is clearly use for THC-based products in the nerve and muscle pain that you're describing, but not for the esophageal or abdominal stuff. So there's potential, I think. You're seven years out. I'm assuming you have stable bone marrow function, though clearly significant graft versus host disease. I think an oral product could be tried, and I figured at some point there would be a dosing question that came up, and I'm going to just hop to a slide that is after that other slide.

(40:14) And this is actually now Canada doses cannabis. Basically, the guideline is you start low and you go slow. We know that it has what's called a U shaped curve, so with low doses some people see quite a bit of benefit, and then as the doses get bigger they kind of don't see any more benefit, and then as they get bigger still, as they are chasing some type of effect, they tend to start getting a lot of side effects. So what Canada does is they base on THC content because they're still trying to figure out CBD like everybody else, and they start at 2.5 milligrams, and they'll dose it and you don't take anything else for at least six to eight hours, and this is all oral dosing, and you see whether or not there's benefit.

(41:00) If you maybe got some benefit, depending once again on what your goal was, but it wasn't so great, then you can think about stepping up to five milligrams, which is considered a moderate dose, or even 10, which is considered a strong dose. But if you go over 10, you really start to see increased side effects at that point. And still, as I mentioned earlier, CBD has no threshold dose currently. We don't know where to start with the dosing on it. So I think at seven years out it could potentially help with the aches and pains that you're seeing, but I don't have any actual evidence to that at this point.

(41:40) [Michelle Kosik]      That's a great, great response. I'm sure a lot of folks really appreciated that. The next question is, are there long-term cognitive effects using CBD long-term?

(41:57) [Dr. Joseph Bubalo]      We don't know about CBD at this point long-term because it hasn't been used that much, interestingly enough. We know that long-term THC has lasting effects. If you look at people who start using cannabis in their 20s and they continue to use cannabis, there was a survey that looked at people in their mid to late 40s and early 50s, and it was common that those folks had memory problems, and were a little worse at math type things. So there appear to be some long-term effects cognitively, but that's with THC-based products, and we don't know if that's going to turn out to be true with CBD as well.

(42:43) [Michelle Kosik]     Great. The next question is my cannabis use has been so helpful throughout my life, especially post-bone marrow transplant, but I ran into a big problem after my triple bypass valve replacement. It seemed the interaction between my blood pressure meds and THC caused blood pressure to go ballistic, over 200. I had to discontinue its use. Do you have any information that could help me return to its use safely?

(43:15) [Dr. Joseph Bubalo]      That would be one to solve with your doctor, because it's clear that there's an interaction between the particular anti-hypertensive, the blood pressure medicine that they're using. So it would be a discussion with your physician to see if there is another blood pressure medicine that would not be as sensitive to the type of cannabis that you were using that could be interchanged. After a triple bypass, and depending on whether or not you have heart arrhythmias and are on a pretty specialized protocol, there may or may not be another alternative. But that's worth... Once again, if this has been providing you that kind of benefit and you want to try to recapture that, that would be a great discussion to have with your cardiologist, and they may need to call a pharmacist or somebody to help them figure out the drug interaction stuff.

(44:12) [Michelle Kosik]      Absolutely. The next question is, is medical cannabis safer than recreational because of the manner in which it is tested and processed?

(44:24) [Dr. Joseph Bubalo]     No, would be the answer to that. Medical cannabis and recreational cannabis are really interchanged anymore, and it depends on what state you're in and where you're getting it from. Those that are bootleg products, or if you live in a state where there is no recreational laws, it is really the wild west, so to speak. There's no real trust on what you're getting with that product. If you go to a state that has recreational cannabis, while they are tested and they are labeled, much as a food product is labeled, you'll actually see the milligrams or percent of THC, percent CBD, and so on, about half of those labels are incorrect.

(45:18) And with regard to fungal spores and pesticides and that type of thing, while pesticides and herbicides are tested for and those lots are supposed to be thrown out, I'm not sure that it always happens. And the fungal spore testing is really variable. In Oregon, for example, they test the cannabis for water content, and that is a surrogate for fungal spores, whereas a wetter product is more likely to be fungal contaminated, but it's not ruling out for spores. So that's why we, once again, go with oral as the safest way to take something, because your stomach acid helps to kill fungal spores and is likely to be a safer product if you decide that cannabis is really something that you want to use.

(46:13) [Michelle Kosik]      Yet another very informative response. Thank you. The next question. Our BMT and CAR-T team require all patients to cease smoking marijuana. Some providers allow edibles. When you covered oral forms, tinctures, are you also speaking to edibles, butter, brownies, candies?

(46:36) [Dr. Joseph Bubalo]     Yeah, and actually, tinctures I don't necessarily recommend. Tinctures can be super concentrated and very high potency, and we have had a number of individuals try those, where they're putting a dropper or part of a dropper under their tongue or on the tongue, or on a cracker or something, and have had really unexpected psychiatric effects. We've had a couple people that have had to have MRIs because we thought they had strokes or head bleeds or something, so I don't go very much with tinctures. You have to have a lot of experience to use them safely. I am actually referring to gummies or brownies or cookies, or other things, and those I would treat as any other food.

(47:25) Make sure that they're relatively fresh, and you store them and buy them frequently, not in big lots. When I'm talking about edibles, that is what I'm talking about. Anything that is a high fat content product is going to increase the absorption of your cannabis, and that's why they put it in butter and oils and things like that, because a nice fatty brownie or whatever is actually going to give you better absorption than just a lollipop or something on that order, which is going to be more water-based as opposed to a fat-based foot. So actually, something that is more fat-based will give you better absorption and more reliable absorption, actually.

(48:18) [Michelle Kosik]      Wonderful. We are now running out of time, so this will be our last question, and I'm not quite sure how to take this question, so bear with me. Please talk about the different strains, indica, sativa, hybrids, and how patients use the different strains.

(48:37) [Dr. Joseph Bubalo]     Okay. So indica, many growers will put a color scheme. So you have the sativa, which is your standard product, and then indica, which is thought to be, for lack of a better term, a mellower product. It is less likely to make you high, it's less likely to give you hallucinations, less likely to make you really uncomfortable or feel like you're jumping out of your skin or something, whereas a high potency sativa can give you sometimes some pretty drastic side effects. And I would point out once again that any time you decide to use these, you're kind of experimenting on yourself, not the way we normally look at a prescription drug.

(49:28) So indica generally is a milder product, and is more sought after for its medicinal properties, whereas sativa products tend to be more highly sought after for recreational use. And we don't actually know what modifies the indica THC blend versus the sativa THC blend, whether it's the terpenes, whether it is some of the flavonoids, or whether it's just the CBD to THC mix that results in a product which has less psychoactive activity. But in general, indica is sought by medicinal users, where sativa is sought more by recreational users. And we have not really delved into the components and the general proportions of cannabinoids in those different cultivars to understand why one works the way it does versus the other.

(50:32) [Michelle Kosik]      Wonderful. We do have time for one more question. I'm just quickly looking through the chat. And I think you did speak to this already, but again, a lot of questions about the various types of taking in the cannabinoids. So this question is, does vaping dry flower present a risk for infection? In other words, can a dirty vape device support spores that can infect the lungs?

(51:06) [Dr. Joseph Bubalo]     Absolutely. Even if you're vaping, which is a safer form than smoking it in a cigarette, there is going to be some aerosolization. So as the product turns into smoke, you are still taking some fungal spores and some bacteria with it. The other thing I mentioned several times, and it's probably worth just going into a little more, is that there are vape pens out there. Much as people who smoke cigarettes have these vape devices that heat up a liquid and then they puff on it and you see these big puffs of smoke.

(51:39) Those are oil-based cannabis vape pens. The problem is, those pens in the cannabis products that are out there tend to, for whatever reason, result in delivery of oil globs to the lungs as well. And those oil globs tend to, over time, change your ability to exchange oxygen, as far as we can tell. So we don't recommend a vape pen, and if you do a vape device as a way of smoking, you are still potentially giving yourself bacteria and/or mold.

(52:19) [Michelle Kosik]      Wonderful. And then finally, CBD drops for sleep. What strength and dosage have been shown to help? How long does it last for? Does it last all night, or do you need a repeat in the middle of the night?

(52:33) [Dr. Joseph Bubalo]     When I talk to patients, sleep help is probably one of the most common uses. They may not be using it for pain or for other things, but they want something to help them sleep. And as I mentioned, we actually have no idea how to dose CBD. If you look at the children who are getting it for seizures who get very high doses, they're using hundreds of milligrams per day, and so they use very large doses. And nobody has done a dose finding on this yet. My guess is somewhere around 25 to 50 milligrams would be a reasonable starting point, but I don't know. Really, that is simply a guess.

(53:19) I have no evidence to base that on, but I believe it would not be a harmful dose if you tried to use it. Will CBD help you sleep? That would be you're experimenting on yourself. Most people who do use cannabis to sleep use a THC product, and usually an indica product, actually, as a blend that is more likely to give them a reasonable night's sleep. They tend to mostly be something to help you go to sleep.

(53:49) They don't necessarily keep you asleep, so if you're someone who has trouble falling asleep, that is how most people do it. The other thing is we don't know if they give you normal sleep. The problem with a lot of sleep aids is that you get sleepy and you fall asleep, but you don't get the right amount of deep sleep versus REM sleep, and so some people wake up and they really don't feel that much rested, despite the fact they were sleeping. So I can't actually recommend it as a sleep aid because I don't know what it's going to do to the quality of your sleep, even if you are asleep.

(54:29) [Michelle Kosik]    Closing. Dr. Bubalo, I am just thrilled to have been a part of this presentation. On behalf of BMT InfoNet and our partners, thank you for your very helpful remarks, and thank you the audience for your excellent questions.