Medical Marijuana and Transplant: What Do We Know?

  Download Speaker Slides  

Medical Marijuana and Transplant: What Do We Know?

Wednesday, May 4, 2022

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

Presentation is 38 minutes long with 18 minutes of Q & A.

Summary: Medical marijuana offers new options for managing problems arising from cancer treatment. This presentation reviews the potential benefits and risks of cannabis, who is most likely to benefit, and who should avoid using cannabis.

Highlights:

• Cannabis can treat pain, nausea, lack of appetite, seizures, and muscle spasms in multiple sclerosis patients. For cancer patients, it may be most helpful in treating side effects of chemotherapy including nausea, wasting illness, and chronic or neuropathic pain.
• Only a minority of people, however, experience measurable benefits from cannabis use. For transplant patients, this means that cannabis should only be used as an “add-on” treatment and never as a replacement for standard of care.
• From a health standpoint, smoking and vaping are more problematic than consuming oral cannabis products. The risk of pulmonary infections and various heart-related problems increases when cannabis is smoked or vaped.

Key Points:

(05:54): THC is the psychoactive component of cannabis that can produce a high.

(06:36): CBD is the non-psychoactive component although it can decrease anxiety.

(07:03): Some products contain a mixture of THC and CBD.

(08:21): Smoking cannabis is more potent and more fast acting than ingesting it.

(09:36): Cannabis can interact with other drugs and bodily systems in ways that increase or decrease its effects.

(16:46): Synthetic cannabinoids tend to be unsafe compounds that should be avoided.

(17:43): THC produces euphoria but also decreases bodily functioning and cognition.

(22:24): Medical use should start at a low dose of a non-inhaled product without THC.

(23:51): Cannabis is less addictive with no overdose risk compared to other recreational drugs.

(28:43): Cannabis use can harm young people

Transcript of Presentation:

(00:03): [Lynne Spina] Introduction. Hello, my name is Lynne Spina. 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. Dr. Bubalo is an oncology pharmacotherapy specialist with Oregon Health & Science University in Portland, Oregon. He is also an assistant professor of medicine in the division of hematology and medical oncology. Dr. Bubalo 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.

(01:04): [Joseph Bubalo] Overview of Talk. Thank you for that kind introduction and welcome everybody to our talk today. We're really going to explore what medical cannabis is and how it can possibly, when appropriate, be integrated into the care of someone who has had or is about to undergo a stem cell transplant. And on your screen now you can see the traditional ways that cannabis was referred to. This really comes a lot from the drug use culture, as cannabis continues at a federal level in the United States to be a prohibited medication, despite the fact that it's been legalized in multiple states. And we'll talk a little bit more about this. But those are historic terms that were used to describe cannabis products.

(01:58): We're going to really talk about how cannabis products may affect you as far as mood and/or physical symptoms, what the products themselves can look like, and how you may want to think about evaluating them; [we’ll] talk about potential benefits, if any, that are out there for a stem cell transplant survivors, and then focus also on potential adverse effects or interactions with other medications that you'd want to be aware of.

(02:27): Cannabis was widely prescribed in the U.S. in the 1800s. Cannabis, and actually marijuana, has a long history in the United States. It came over in the 1800s with immigrants and was one of the most prescribed agents through actually the 1800s. Major uses were things like labor pain, nausea, and rheumatism. After 1900, however, due to a variety of reasons, it became increasingly criminalized in the public eye. And in 1970, it was made Schedule I, meaning it had no medically acceptable use. However, in 2018, we now have our first non-synthetic cannabis product that was approved, a product called Epidiolex, which is approved for pediatric seizure disorders.

(03:17): Marijuana, or cannabis sativa, is a prolific flowering herb. Marijuana, or cannabis sativa as it's known, is a flowering herb. There are a variety of other species, mostly indica and ruderalis, that also have been used in medicinal ways. While it originated in Asia, it's literally an avid weed. It'll grow anywhere. So it's on all the continents except Antarctica, and it has kind of naturalized. So each continent has kind of a little different product.

(03:47): Different forms of cannabis have been legalized in over 30 U.S. states. In the United States it's now currently approved for medical use and sometimes recreational use in over 30 states. Every election cycle, one or two more seem to get added. And then states that actually don't allow medical cannabis or marijuana, a lot of them will allow low delta-9-tetrahydrocannabinol or THC, which is the major psychoactive component in marijuana to be used in some states, along with cannabidiol, which is a non-psychoactive cannabinoid that is in marijuana. So it's pretty available throughout the 50 states.

(04:27): The main component of the cannabis plant that is of interest to users is the phytocannabinoid which change the body’s response to different things. When we look at what's actually in a cannabis plant, the main one of interest has been these phytocannabinoids. These are found mainly in the female flowers. And we know now that they bind to cannabinoid receptors in the body and change the body's responses to different things, depending on what the person's state is at any point in time. And actually also it differs with age as the endocannabinoid system that these receptors belong to actually change as the body matures.

 (04:59): Terpenoids in marijuana are being investigated to determine if they have medicinal benefit. Also, there are products called terpenes. These are aromatic chemicals that are found in almost all living plants, and they give each plant its unique scent. So the really strong, almost skunky flavor that is part of cannabis is mostly mediated by terpenes. And there's a variety of different terpenes or terpenoids as they're called. And they can give kind of a unique, both smell and flavor to different cultivars of the plant. And they're thought that they may have some medicinal benefit. And that's in a very experimental phase of being looked at. And then finally, like a lot of plants they have flavonoids. These are anti-inflammatory chemicals that are found throughout the plant world and may have antioxidants as well.

(05:54): THC is the psychoactive component of cannabis that can produce a high. The most common cannabinoids that are going to be in any product that you purchase are going to be either THC, which is the major psychoactive component, and this is what was originally used recreationally to give someone a euphoria or a high. Originally it was somewhere between a half to maybe six or 8% THC that was found in most cannabis that could be purchased. And this was all illegally purchased at that point in time. And through a lot of selective cultivation, 20% is actually now on the low side. You can easily find products that are up in the mid or upper 30% THC ratings.

(06:36): Cannabidiol or CBD is the non-psychoactive component of cannabis, although it can decrease anxiety. Cannabidiol is really quite different in that it doesn't have psychoactive effects. You don't get high or get euphoria from cannabidiol or CBD, as it's known. It may actually decrease anxiety, however. And though it doesn't interact with the cannabinoid receptors, there's a lot of other receptors in the body that are impacted by cannabinoids, and it's thought to probably work through a cluster of those, though they have not yet been identified.

(07:03): Some products contain a mixture of THC and CBD to reduce the psychoactive side effects of THC while providing medical benefit. We do know however that it does modulate the action of THC. So it is not uncommon that you may see a mix of THC and CBD in a particular cannabis product in an attempt to reduce the psychoactive effects of THC, but still give medical benefit. And there are actually a lot of different cannabinoids, over 140 that can be found in the cannabis plant.

(07:29): The human endocannabinoid system has, as I mentioned, receptors. The CB1 receptors are these bright blues. And they're found mainly in the central nervous system. And these are the ones that mediate euphoria or a high so to speak. The CB2 receptors, which were actually found about five years later... The CB1s were designated in 1988. In the early 1990s, they discovered the CB2s and these are scattered around the body. And interestingly enough, they're clustered in immune areas. So lymph nodes, the thymus, other areas of the body that are responsible for immune effects have a lot of endocannabinoid CB2 receptors. And as I mentioned, CBD actually does not impact either receptor, but does modulate the effects of other cannabinoids.

(08:21): Smoking cannabis is more potent and more fast acting than ingesting it. If someone is smoking cannabis or marijuana, generally two to three milligrams is what is found in the average marijuana cigarette. And that's enough to get someone into a euphoric state or high. The oral dose generally needs to be somewhere between three and five times that because when you take it by mouth, the stomach acid breaks down some of the cannabinoids, and then the liver also metabolizes some before they get to the rest of the body.

(08:50): With smoking, it's a very quick onset time, generally minutes. Whereas oral can take an hour to maybe even two hours, depending on how it's been taking, whether you have food in your stomach and a variety of other things to actually feel the onset. So it was a different pharmacologic timing to the effect. And the dose that's available, if you can purchase it in your state or country, is going to vary be by where you live in the United States. Most states are looking at five milligram increments of THC as a normal dose or a divisible portion.

(09:36): Cannabis can interact with other drugs to increase or decrease their effectiveness. As far as drug interactions, we know that it does interact with a variety of body metabolic systems. And so you have the potential to either reduce the effect of other drugs, or actually increase the effect of other drugs, depending on where the other medications you're taking are metabolized in the body. There's also what we call dynamic interactions. So since it can be kind of sedating to take a THC product, if you're taking a sleeping pill or an antihistamine or an anti-anxiety agent, you see additive sedation or sleepiness. If someone is taking a stimulant for maybe like for attention deficit disorder, you actually make get less benefit from that stimulant if you're using cannabis. And then if someone is on a drug for depression or psychiatric condition like schizophrenia or bipolar disorder, you can have pretty variable effects. And the concern there is that you may not have your normal level of control.

(10:41): Some prescription cannabinoids help with nausea, appetite, and neuropathic pain. There are some prescription cannabinoids that are available, dronabinol or Marinol as it's known. They're these synthetic THC in a sesame oil inside of a capsule. And this impacts both the CB1 and CB2 receptors. It's used mainly either for nausea or for appetite stimulation.

 (11:00): Nabilone or Cesamet as it's called, is another THC mimic that binds in a very similar fashion. That is used mainly for nausea. And actually in some countries it's used for neuropathic pain management as well.

(11:16): Epidiolex is approved for pediatric seizures. Cannabidiol is the product I referred to earlier as Epidiolex. This is a purified cannabidiol that comes from a single plant cultivar and has been standardized to a hundred milligrams per mil as an oral solution. This is approved for two pediatric seizure disorders. And as I mentioned, CBD doesn't bind to either of the cannabinoid receptors that we're aware of.

(11:41): Cannabidiol can be derived from hemp or marijuana with differing potency. Cannabidiol since it's becoming so prevalent, I think is kind of worthy of its own slide here. So at a federal level, it is considered a low THC, less than 0.3% content by weight type of hemp plant or marijuana plant. However, if you look in the community, you'll see whole cannabis-derived CBD, and that may have somewhere between five and actually 30% of THC in it, despite the fact that it may be rated just for its CBD content. Interestingly enough, the cultivar that they use for the Epidiolex, the FDA approved product, has less than 0.1 per percent THC. So it is really pretty much a pure CBD compound, as opposed to one that's modified in some way. So while all these cannabis plants that are out there are sativa or indica, it's really the cultivar that predicts whether it's going to have a lot of CBD or a lot of THC content.

(12:48): Cannabis comes in many different forms including marijuana and hashish. Preparations that if you're looking into purchasing that you may see available... Certainly there's marijuana. Primarily what's sold today is flowers, the female flower, but you may see some leaves or stems which have a lesser amount of THC or CBD in a lot of them.

(13:06): There's a product called hashish, which is a concentrated resin, which may come as kind of a dark-colored cake that can be pieces pinched off of it.

(13:17): Tinctures are liquid forms of cannabis. Tinctures in cannabis-speak are any liquid form of cannabis. So from a pharmacy standpoint, usually a tincture is an alcoholic mixture, but actually it could be soda pop. Anything that has cannabis infused into it may be considered a tincture.

(13:35): There are a lot of oils that are being extracted from this plant as an attempt to capture the cannabinoids that people want to use therapeutically. And originally in the last five years, you saw a lot of different extraction methods, butane ethanol, propane, CO2, et cetera. And a lot of these are actually dangerous to use. Butane, propane, for example, both are flammable and can explode. And occasionally the extracting... People who are doing it in their homes would literally cause a fire or an explosion. CO2 is now probably the standard extraction method that is out there. And that's partly because it's less dangerous to use, but also because it is thought to leave less organic residue in any cannabis that is extracted. So it's probably a safer product from that standpoint.

(14:29): Cannabis is available in edible form. Infusions are when cannabis plant material are actually mixed with a non-volatile solvent, so it could be butter, cooking oil, et cetera, as you're getting ready to make the ingredients for a cannabis edible. And these edibles come in all kinds of solid and liquid forms from snacks to drinks, to things that could be on a main dish, actually, for a meal. And then once again, a hemp product is mainly aimed at providing CBD, but depending on what cultivar it comes from, there may be THC present as well.

(15:03): When you think about natural products, these are quite variable as they're grown in nature. And there's also a concern about how they've been treated, whether there's been herbicides or pesticides that have been used in their growth to make them grow better, much as you would in your garden, and that some states are testing for these, but it may or may not be completely consistent with every batch.

(15:30): Products can differ significantly in potency. They'll also be looked at for potency. And generally they're rated on THC content without a lot of regard for the other cannabinoids that may be present. So there may be a lot of variability except for THC. And there are some products that'll actually have a whole list of the cannabinoids that are present. And some consumers are very interested in these other ones other than THC.

(15:57): Cannabis products often have food-like labels, but they are often mislabeled or inaccurate. However, when we actually look at the labeling, which is very similar to a food label. If you look at the side of a food can, it'll tell you the ingredients from the most, to the least, as well as preservatives or whatever. Over half of these products are going to be mislabeled. So there's not good quality control between the label and what you're actually getting. And sometimes that's a challenge just because even with the same cultivar, depending what time of year it's harvested, what the sun, rain, soil contents, and exposure have been, you can end up with a fairly different batch from the cannabinoid content. And we're still actually trying to figure out what appropriate medical dose is. So anytime I give you a dose, that is an educated guess.

(16:46): Synthetic cannabinoids tend to be unsafe compounds that should be avoided. Synthetic cannabinoids are out there. They emerged in the early 2000s, and it was found that there were other chemical compounds that could actually cause people to get euphoria or high. There are seven major groups. And you'll see them mostly in convenient stores, gas stations, etcetera, under a variety of names, such as spice or K2 or fake pot, et cetera. These are all now Schedule I. And even more than regular cannabis, they have no acceptable medical use and a lot of toxicity associated with them. There's been cases of kidney injury, heart attacks, all kinds of contamination, including even poisons. There was a big contamination of product with a rat poison a few years ago. So these are really unsafe compounds, and I would recommend avoiding them.

(17:43): THC produces euphoria but also decreases bodily functioning and cognition. So let's look at the medical use of cannabis. When we think about the effects, we really are usually directing them at whatever the effects of THC are. So if we think out about what people expect to see, the psychological aspects, changes in behavior, so you're going to be more buoyant, laugh easy. You may have sensory changes, and this is usually some kind of time and space perception alteration. And disorientation is actually fairly common. When you're thinking about how functional you are, it's really common to be drowsy. You may get dizzy. You may be less coordinated. And then when you're thinking... Nobody thinks better on cannabis, especially THC. So you're more likely to be confused. Especially, short-term memory lapses are common, and concentration is difficult. So this isn't something that improves your testing skills.

(18:42): Cannabis can have beneficial effects on pain, nausea, appetite, seizures and muscle spasms. When we think about the potential uses, there are many. And as I mentioned in that first slide, it's been used since the 1800s in the US. So it's not surprising that there's a lot of interest here. And as noted in that slide, pain and nausea are the top two. Then the other things that have been looked at are certainly appetite. We now have an approved product, the Epidiolex for seizures. And there's actually another one out there that is in phase 3 testing for muscle spasms in multiple sclerosis patients. So there is evidence of potential benefit, and we're just trying to figure out where it fits in.

(19:20): Pain management, this is a new guideline that came out last year. Canada legalized cannabis nationwide about three years ago now, and this is their first attempt at actually putting out a guideline. So I'm actually going to use their guideline this year because the US has nothing as advanced as this.

New Speaker (19:41): Adults with cancer pain or nerve pain may benefit from cannabis. So who might be helped? Who out there could consider using it and maybe getting benefit? So if you have moderate to severe either cancer or non-cancer pain, or if you have nerve type pain. And these guidelines are strictly from a pain standpoint. Those are the two types that are more likely to be helped.

(20:01): Some people, including children and people with mental illness should not use cannabis. Who should not be using it, or may not be helped? It's not advised to be used in children. Canada suggests not using it in veterans. And it's unclear why that is. People with mental illness. As I mentioned earlier, you can lose control of your illness control. And then people with disability benefits are involved in litigation. I think that's some kind of medical legal thing. The guideline does not recommend either inhaled cannabis, that recreational use has any application to management of pain, and then they actually don't suggest it in end-of-life care.

(20:44): One in five people experience reduction in pain, and one in seven have improved physical functioning after using cannabis. So, what are the potential benefits and how likely is someone to get benefit? And this is the first time I've seen this. So I thought it was really interesting to look at. One in five people actually have a reduction in pain. So not everybody, clearly. With that reduction in pain, one in seven actually had improved physical functioning. There was no change in emotional function, so it was no different than placebo. So if someone has an emotional condition, anxiety, or whatever, it doesn't appear to really benefit that when used for pain. It's no different than placebo in most roles. So whether it be your work role, your life role, social functioning, it does not change. And about one in six people had improved sleep quality. And whether that was from better pain management or from the cannabis itself, it's unclear.

(21:39): One in three people have impaired attention or disorientation when taking cannabis. The potential harm that they found was that one in three people had impaired attention, and it's that kind of disorientation I was mentioning. Four out of five people had more drowsiness. So it's a quite sleepy time drug. And then one out of two had some cognitive impairment. So as I mentioned, people are not thinking clearer when they're using this. So the recommendations that they are saying is that to use cannabis only if standard treatments have been tried and are not working. If using, they want you to use a non-inhaled form of cannabis. And we'll talk a little bit more about why that is. And then generally this is an add-on therapy. You're not going to replace your standard therapy. You're going to add this on if you meet all these criteria.

(22:24): Medical use should start at a low dose of a non-inhaled cannabidiol product without THC. So, their key recommendations are it should be started at a low dose, non-inhaled product, and they want to use cannabidiol products, not THC. And then you can gradually increase the dose and then add THC, depending on both your response and whether or not you tolerate it. Prior cannabis experience should be considered. So if you're someone who's used before and you would want to monitor for side effects, you'll have more likely an expectation of whether or not you're going to get benefit and whether you can tolerate the side effects.

(23:01): THC can affect neurocognitive development and should not be used in people under 21 years of age. Young people, cannabidiol is preferred as THC appears to change neurocognitive development. And so there's really concern about exposing anybody under the age of 21, and maybe under the age of 25, as you may not reach your full mental potential if you use it early. And then you should avoid driving or operating machinery when you're using this, when you're changing doses. And there's a recent paper that suggests that you should not use it until at least four hours after taking a dose. And then those that are pregnant or considering becoming pregnant or are breastfeeding should discontinue the use because it will be passed on to their fetus, born or not.

So is there harm from cannabis? As a drug, it is generally less addictive, considered less dangerous because unlike fentanyl or heroin or something, you really can't overdose on it. So the overdose risk is relatively small, which makes it kind of a soft drug when we think about other recreational drugs.

(24:16): Side effects depend on the specific type of cannabis being used. The side effects, if we were to compare the two prescription products, dronabinol and nabilone, and then cannabidiol as it's now used in seizures, and then regular marijuana or medical marijuana, you could see that as we kind of break out these different cannabinoids, there are differences that are seen. Cannabidiol, for example, tends to decrease appetite, whereas we see increases with medical marijuana and nabilone, and dronabinol is actually FDA approved for that. And you can look through this table and see that there are changes based on... and you would expect to see changes based on the cannabinoid content that is in your product that you purchase.

(25:01): Smoking cannabis deposits four times more particles into your respiratory system than smoking tobacco.  So, we've talked about using only orals. Smoking and vaping are problematic from a medical point of view because you're delivering particles when you burn that cannabis into your respiratory tract. And you get about four times actually the number of particles when smoking marijuana than you do from the smoking a tobacco cigarette. And that's mostly because of the way people inhale and hold their breath when they're smoking marijuana in an attempt to absorb more THC. When smoking, the combustion is actually really hot, 600 to 900 degrees Celsius. And this produces a lot of toxic byproducts, tars, hydrocarbons, carbon monoxide and ammonia. When you vaporize, the combustions at a lower temperature and you generally see less carbon monoxide, but you're still getting absorption of other things.

(25:53): While vaping is probably safer than smoking, it's still not a recommended way to deliver cannabis. And you do probably get more THC out of vaping than you do out of smoking it. But whether that's truly less harmful either from the byproducts or decreased pulmonary symptoms, it probably is, but it's hard to know what the long-term effects are.

(26:23): As far as the effects on lungs and breathing when someone chooses to smoke, you see a fair amount of wheezing. There's increased sputum production, and there's a chronic cough, but you don't actually see chronic obstructive pulmonary disease as you do with long-term cigarette smoking. And we don't know if that's because people haven't been doing it long enough, or it's truly going to be different as far as the long-term impact on the lungs.

(26:49): Pulmonary infections in immune-compromised individuals are a major concern with smoking or vaping cannabis. We're most worried, actually, about the risk for pulmonary infections, and especially in those who are immune compromised, like somewhat after a stem cell transplant. From a bacteria standpoint, enterobacter is the most common bacteria that we see contaminated.

(27:03): Aspergillus infections from smoking cannabis can be lethal for immunocompromised people. And then the most common mold is aspergillus, which is a pretty aggressive pathogen in the stem cell transplant population. The dry buds actually are more dangerous than the oil. The processing of the oil actually reduces spore content but does not eliminate them. There's a lot of case reports with certainly people who have died from aspergillus infections. And there are some other countries, Israel actually for one, has looked at sterilizing cannabis, but it's not routinely done, and certainly not in the US.

(27:39): There has been questions about smoking cannabis and lung cancer. There's a single study, what we call a case control study from New Zealand, where they look back at people who smoked a lot of cannabis, and they found that there was a similar risk of lung cancer based on what they called joint years, which was a joint a day for a year versus pack years of cigarette smoking. But most of these people who smoked cannabis also smoked cigarettes, so this is pretty confounded at this point, but it's certainly not a zero risk.

(28:12): Smoking cannabis can also cause heart problems. We do know that it does, when you smoke it, that it changes the blood flow through the heart. You get increased rate, increased blood pressure, and in some people, that can cause problems as either sudden cardiac death or stroke has been seen. You can also see some changes in heart rhythms or arrhythmias, which can be problematic. So this is another reason that we try to stay away from inhaled cannabis products.

 (28:43): Cannabis use can affect brain development in young people. Young people, as I mentioned, the endocannabinoid system is critical for brain development and maturation, both physical and mental. So those that have a lot of adolescent exposure tend to have long-lasting alterations. We know that genes get turned on and off at different times in life, as you're supposed to grow at certain times and maybe not grow at other times, but we know that early use of cannabis products can result in changed behavior and cognition that lasts into the adulthood. And as I mentioned, brain development probably goes until the age of 25, while we have legalized this for 21 and older. So we try to stay away from it in anybody who's younger, certainly younger than 21.

(29:33): Maternal use of cannabis may harm fetal development and may be linked to behavioral and mental health problems as children develop. With animals, we do know that young animals show some fetal malformations and risk for growth retardation. We have a fair number of babies that have been born to people who are using a variety of substances. And those with cannabis tend to be a little lower birth weight, and they may have some delayed visual symptom development. And then they kind of also, sometimes these babies will be kind of tremulous and have some lack of muscle control, which may be a form of withdrawal from cannabis. It's hard to see. As you follow these children into their adolescent years, they tend to have more delinquency and some problem behaviors, but this is very hard to tell just because adolescents are so variable anyhow. There is concern, however, that it is a going to predispose them to mental health conditions.

(30:29): Cannabis is not highly addictive but can create dependence on the drug. While it's not considered as addictive as some drugs, there is a dependence that can form to cannabis. And this happens in about one in 10 people. It's certainly less than nicotine, than regular cigarettes or heroin or alcohol. And it's about the same... As I said, it is like a benzodiazepine like Ativan or something on that order and cocaine addiction. The risk is greater for smoke versus eaten, it's thought, but that's not been proven. And we now do see that some people who use orals do become dependent upon them. And if you use them long enough, there will be some physiologic withdrawal symptoms if you stop suddenly.

(31:09): Cannabis use while driving doubles the rate of accidents. In general with driving, it doubles the rate of auto accidents. And these tend to be not like you've been drinking alcohol and you have that profound loss of coordination and kind of thought that alcohol can do to you. This tends to be a loss of autonomic reflexes. So you forget to turn on your turn signals when you're going to make a turn. You are less likely to hit the brakes in response to a brake light in front of you. Things like that. And April 20th is this national kind of pot holiday. And if you look at one week before or after around April 20th, you have a 12% increase in fatal car crashes.

 (31:50): And then there's a recent study where they took almost 200 people, these were experienced cannabis users, and they would have them drive a track in a parking lot. And then they would have them go ahead and take cannabis and then try to repeat that. And actually out to about four hours after a dose, even though these were experienced users, they had poor scores on their driving course. So it's thought that probably at least four hours should elapse between taking a cannabis dose and driving.

(32:25): Fungal infections from inhaled products are a serious concern. As I mentioned with the fungal infections, these are really worrisome from an inhaled product. And all types of cancers and transplant patients have experienced this, even in the non-oncology setting. It tends to be associated with longer use and with smoking cannabis thus far. And we know that smoking it deposits the spores in the lungs of at least half the people who use it. As I mentioned, there is not really a process to sterilize it currently. In the immune compromised, the aspergillus is most concerning. And whether you smoke it or vaporize, it does not kill these spores and molds, bacteria that are on the plant surfaces. And I just threw in how it is sterilized in other countries. So you could bake it yourself if you wanted, but this is going to also change the THC content, which is sensitive to heat.

(33:25): For transplant recipients, cannabis may be appropriate in addition to standard of care but not as a substitute for it. So when we look at cannabis, this is really framed as a third line use, not first line. So you want to look at it and see, have you tried the standard of care, and is it working for you or not? If it's not, often they'll have you use a second product if there is one available before they consider adding something like cannabis to that.

(33:51): Cannabis can be helpful with side effects of chemotherapy such as nausea, appetite loss and pain. The areas where it's been beneficial are nausea control, especially around time of chemotherapy, certainly appetite like wasting illnesses, chronic pain, especially neuropathic pain. And then as I mentioned earlier, there's a trial looking at muscle spasms associated with multiple sclerosis, which looks quite promising.

(34:13): People with substance abuse problems may see those problems worsen with medical use of THC based products. And generally, you want, you're going to use it after the first-and second-line approved products are going to be used. You would want to actually consider using an FDA approved cannabinoid like dronabinol, if that's clinically appropriate for your use. Anybody who has a history of either substance use problems or has a psychiatric diagnosis, any kind of unstable mood, is probably going to have that worsened if you're using THC-based cannabis products. And then you're going to have to be in a state with a medical provider practice act or medical marijuana law that allows you to meet that. Anytime you buy it and take it across state lines, you are doing a federal crime.

 (35:01): In summary, there are a number of risk factors with cannabis use. So kind of our take home points, from a risk standpoint, smoking it, even with vaping, you're at risk for lung cancer and other kind of side effects. If you smoke it, you're going to increase your risk for heart attack or a stroke, especially in the elderly, meaning 60 and older. And anyone who has a psychiatric disorder, especially schizophrenia or bipolar, is probably not going to have as good a control over that disorder if they decide to use cannabis. And it's particularly concerning if they're a young person, whether they have a psychiatric disorder or not. It is certainly less habit-forming than nicotine and other hard drugs, but there is a real risk of dependence, especially in young people. We worry a lot about prenatal exposure, so when the mom is pregnant or is breastfeeding. And then once again, older adults with chronic illnesses, we don't have great history with that, and we're concerned.

(36:01): In summary, there are some measurable benefits. So benefits, your take-home points. We really are still figuring out the medical benefits and where, where it is a benefit. Clearly, we have an FDA approved product and seizure disorders are an area of promise. These are people in these disorders who have many, many seizures a day, sometimes 40 to 60 a day. And with the use of the cannabinol CBD product, they will have reduced numbers, but they usually don't go completely away.

(36:31): The greatest benefits of cannabis involve treating pain, nausea, appetite and mood, though not all people experience these benefits. Pain relief, especially neuropathic pain. We know now that somewhere around one in five or one in six people can get benefit. Muscle disorders, especially spasticity is of interest. Certainly, appetite and nausea are of interest. And actually, mood is kind of what a lot of people report benefit of. They just feel better. And that is still hard to characterize. But currently this is... And I need to emphasize this, it's not recommended first-line for any of these. It's going to be an add-on therapy.

(37:08): So while we started out looking at the names that have been historically used for cannabis, if you go into a dispensary now, and if you're going to buy this, you should buy it from a dispensary, you'll be able to get a certificate of analysis that's it's been looked at for fungus, for pesticides, for herbicides, all these things. But the names have clearly changed. These are all kind of fun names for the most part, as opposed to those that were more associated with the drug culture. And with that, I would be happy to open it up for questions.

Question and Answer Session

(37:48): [Lynne Spina] Thank you, Dr. Bubalo, for your very excellent presentation and comprehensive. We'll now take questions. So our first question is, this patient writes, "As a young patient going through the physical and psychological effects of cancer, I have consumed marijuana, mainly food, in order to calm my anxiety, reduce pain, et cetera. However, I have felt fear that it might negatively interfere with my treatment after three years of transplant. Can marijuana cause leukemia relapses or negatively interfere with the bone marrow?"

(38:37): [Joseph Bubalo] That's an excellent question. The bottom line is we don't know. But there is a new class of cancer therapies called immune checkpoint inhibitors. And we have seen now, it was first a case report and then now there's a second series that has been published, where individuals who used immune checkpoint inhibitors and are consuming cannabis at the same time actually have a decreased response rate to these checkpoint inhibitors. So how does that apply to transplant? We know that when we do your bone marrow transplant, your stem cell transplant, that we are giving you a new immune system, and this new immune system then seeks out the cancer cells and eradicates them and prevents relapse. And we know that the CB2 receptors of the endocannabinoid system are scattered throughout the body, mainly in areas of immune activity, thymus and lymph nodes and whatnot.

(39:41): And the concern is that if you are going to use cannabis regularly, that you may actually be putting yourself into a state of immune suppression, which would then maybe increase your risk for relapse if you have residual leukemia. So I actually share your concern. We do not have evidence that it does that, but this hint from these other cancer agents make us a little more concerned than we had been previously.

(40:14): [Lynne Spina] Important to know, thank you. Can medical marijuana help with ongoing digestive issues after an allogeneic bone marrow transplant which can contribute to an inability to gain weight and sort of wasting away syndrome?

(40:34): [Joseph Bubalo] So the use of cannabis is really to increase appetite, and then it's kind of up to you what you can do with that appetite. So it's an increased desire for food and an increased desire to take in maybe certain types of food. If you had a graft-versus-host disease of the GI tract and you're having impaired absorption right now, it actually won't improve absorption of the food, though it will improve your appetite. So the hope would be that with the increased volume of eating, that you would actually end up getting in more calories and better calories, but it actually will not... It won't heal the GI tract. That's only going to happen with time.

(41:22): [Lynne Spina] Thank you. Here's another GVHD-related question. Any data on CBD in chronic lung GVHD? What would be the recommended dose of CBD to help with lung GVHD? I read a study where CBD was used to prevent acute GVHD after allogeneic transplant, and the dose was quite high.

(41:48): [Joseph Bubalo] Yeah. I have no advice actually on CBD dosing. The dose goes all over the place, and certainly the seizure dosing is quite high. It's like 20 milligram per kilo. So that's maybe as high... Depending on how large you are, it's 500 milligrams and higher in most people per day. So those are big doses. And as you can see from that one slide, you are going to see side effects, decreased appetite and other things. The study you're referring to where it looks like CBD might decrease the incidence of graft versus host disease was interesting and I think food for thought as to maybe a way, once we're able to get good products, that would be worth looking at in a larger number of people.

(42:41): The concern is preventing it is much different from treating it after it's happened. And I have not seen good evidence at this point that it will help GVHD. And I actually don't know what the dose would be at this point in time. That would be the next part, would be a kind of a dose finding study to figure out where, if benefit is going to be found, we would have to start the dosing.

(43:12): [Lynne Spina] Thank you. I'm going to throw out another GVHD question for you, see if there's studies that can help answer this. Can medical marijuana reduce the inflammatory sclerotic effects of GVHD on the skin and nerves leading to sclerosis and peripheral neuropathy?

(43:35): [Joseph Bubalo] So potentially it could, in that as we know, it has these flavonoids, which are anti-inflammatories, and then we were talking earlier, will it change the immune system? So if it actually does, down-regulate the immune system while it increases your risk for relapse, it might decrease the effects of GVHD, including sclerotic, which tends to be more responsive sometimes than other types of GVHD. Once again, the answer is I don't know, but there's certainly a possibility. This would remain to be seen. At this point I have not seen any evidence, however, that it will do that. Nobody has done that study.

(44:30): [Lynne Spina] Okay. Thank you. You mentioned it a little bit about this question, but maybe you can elaborate on it. Can it help with musculoskeletal pain and muscle spasms?

(44:47): [Joseph Bubalo] Yeah. So the product that is out there is a one-to-one ratio of CBD to THC, and it is used as a nasal spray, much like you use a steroid spray for seasonal allergies. And for multiple sclerosis, they will spray up to... I have not actually seen the prescription labeling, but it's multiple times per day, and they will use it to reduce spasticity. So it doesn't help with muscle pain, but it appears to help to relax muscles. And this is the first product that is at a prescribed ratio. So it's a one-to-one CBD to THC. So you have less of the psych effects, less high, less euphoria, less changes in your thinking. And it appears to relax the muscle rigidity which can come from multiple sclerosis. So this is not yet FDA approved, but it could be available actually within a year or so. It's approved in other countries at this time.

(45:57): [Lynne Spina] Great. This next question is a two-part question. Are edibles safe with elevated liver panels? Are they safe while on Tasigna?

(46:11): [Joseph Bubalo] So all of the cannabinoids we've seen so far are liver-metabolized. And at high doses, they do appear to increase the liver function test assays. So we don't know if they're actually causing harm, or this is just some part of their metabolism. So if you have decreased liver function, and the high liver panels are a symptom of that, or a measurement of that, you may not metabolize it normally and it could irritate that. We do know that the cannabinoids, especially cannabidiol, are dose-dependent inhibitors of drug metabolism. What that means is that the higher your dose of CBD, the more likely you are to actually interfere with your Tasigna. So I would actually not recommend taking a CBD product with, Tasigna because it will change the metabolism. You may get unexpectedly high Tasigna levels and side effects related to that.

(47:23): [Lynne Spina] Thank you. Do you recommend smoking marijuana after transplant? Perhaps you can elaborate, Doctor, on the whole aspergillus issue.

(47:39): [Joseph Bubalo] Yeah. So at least when they looked at crops of marijuana, they found that at least half of them had fungal spores on them. Interestingly enough, it's at least a quarter of the cigarette tobacco that out there also has the same fungal spores. But we have many case reports and case series of people who use cannabis by smoking and actually ended up giving themself a fungal pneumonia, some of which were actually fatal. So that is truly the concern with any type of inhaled cannabis product, that currently there is no way we can prevent you from contaminating your lungs with fungal spores. And as long as you're immune compromised, you are at increased risk for infection as those spores deposit there. We see less bacterial pneumonia, but the Enterobacter or Enterobacteriaceae, a species that is commonly there, is a risk for bacterial pneumonia. But those are usually treatable with antibiotics. The aspergillus unfortunately is not always treatable. Sometimes they have to actually surgically remove a lung. And depending on how much lung space you have, that may or may not be an option for you as well.

(49:08): [Lynne Spina] Okay. Thank you. Does marijuana interfere with medication, especially sirolimus and acyclovir?

(49:23): [Joseph Bubalo] The acyclovir? So it does not interfere with acyclovir. Acyclovir is just cleared by the kidneys, and that's actually not interfered with. None of the cannabinoids are cleared by the kidneys. The sirolimus, actually it would increase and prolong sirolimus levels. So we would not recommend taking the cannabis along with sirolimus. The same would go for cyclosporine or tacrolimus. Those two agents you wouldn't want to take along with cannabis. It will change your levels. And once again, since the products are kind of unpredictable, the change in the level would be unpredictable as well.

(50:12): [Lynne Spina] Good to know. And can you talk about synthetic marijuana?

(50:18): [Joseph Bubalo] Yeah. Synthetic marijuana, so this is just a chemical. And as I mentioned in that slide, there's seven different chemical classes. And all it does is make people high, basically. It has no medicinal value whatsoever. And in fact, it causes harm. The worst is it causes kidney failure, but we've also seen some other effects from it. And so these are just chemicals that folks have found by experimentation that cause them to get high. And they're dangerous. They're not really meant for human consumption. They have no medical testing whatsoever. So if somebody's selling you a synthetic marijuana, that has a higher harm rate than actually marijuana itself.

(51:05): [Lynne Spina] Okay. How do I find a dispensary?

(51:09): [Joseph Bubalo] So dispensaries are only available in states that sell medical cannabis. And interestingly enough, every state is different. You'll have some that are actually run by pharmacists, which is something that we have to learn after pharmacy school because they don't usually teach it in pharmacy school. And there are other states that are completely run... Oregon, where I live for example, they have an education program that is not really official, but the people who sell it in Oregon dispensers are called budtenders. And they have a broad experience from a variety of ways with cannabis products. And you go in and you discuss with them what your goals are, medical or recreational, and they can direct you towards a product that you can then experiment on yourself with. Because once again, each of us perceive it a little different. So each state has a different way of selling it, and it would depend on where you live. If you don't live in the US, I have even less knowledge about that. You would have to see what your local regulations are.

(52:22): Well, we do recommend that if you are going to use it, you do get it from a dispensary. They'll be able to give you assay records to look at purity, pesticide, or herbicide exposure, whether or not it's been tested for fungus, and what the rate of spores are, that kind of thing. The fungal testing is not great. What Oregon does, for example, is they test the moisture content, and the moister it is, they give it a higher rating of fungal contamination.

(52:51): [Lynne Spina] Thank you. Do you recommend a CBD cream?

(52:57): [Joseph Bubalo] We are still trying to figure out what to do with the CBD cream. So they are absorbed, but it's so variable we have not been able to actually figure out a percent absorption. And the other thing is a lot of CBD creams are being added to other stuff like a Bengay or other topical muscle pain type of cream, and then massaged in. And I have never, at this point, seen a placebo-controlled cream study to say that it's actually better than placebo. So there's a lot of activity around it. I'm a hiker. I get Backpacker Magazine, and there's all kinds of CBD creams in there if I want to rub them on at the end of the day. But yeah, I've not actually seen evidence as to what type of pain it's beneficial for, and then how much to apply and how often.

(53:55): [Lynne Spina] Thank you. And this will have to be our last question. And it states, "What is a recommended THC level in medical marijuana for anxiety and also nausea?"

(54:14): [Joseph Bubalo] Yeah. So for anxiety, there is actually not a recommended product at this point. Most people, if you are going to use cannabis for anxiety, they would recommend that probably an indica variety rather than a sativa variety. And there looks to be maybe better evidence for CBD for anxiety than there is for whole plant marijuana-based cannabinoid. So if you're going to try something for anxiety, I would recommend a CBD product after you've, once again, gone through the normal medical channels for the first, second, maybe even third-line products to consider. For nausea, Marinol actually is a well-tested product. It's pretty widely available in the US, and I would recommend you try that.

(55:11): And the dose of Marinol that works for you or doesn't work for you might give you insight into the cannabinoid dose that would work for you. For THC for nausea, somewhere between two and a half and five milligrams would be your starting dose. We know that most people, once you go over 15 milligrams of THC, you tend to see more side effects and less benefit. And unfortunately everybody has to kind of experiment on themselves. Outside of the Marinol, we don't have good dosing recommendations at this time.

(55:54): [Lynne Spina]    Closing. Thank you very much. And this will have to conclude our Q and A session. On behalf of BMT InfoNet and our partners, I'd like to thank you, Dr. Bubalo, for your very helpful remarks, and thank you, the audience, for your excellent questions.