Hi everybody. We're going to go ahead and get started. Thanks for being here. Timely topic to discuss today with an expert on it, and so I'll give a brief introduction for Dr. David Casarett. He's the chief of palliative medicine at Duke and serves as the director for the Duke Center for Palliative Care. He got his MBA at Case Western, did his internal medicine residency at Iowa, was an ethics fellow at the University of Chicago, and then came back to Iowa to complete a chief residency for the Department of Medicine. He did his palliative care fellowship at Penn, where he was on faculty for a while and has been at Duke since 2016. And he's also a faculty to the Duke Trent Center for Bioethics, and is concurrently a fellow at both the Center for Bioethics at the University of Pennsylvania, and also the university Pennsylvania Institute for aging. He has over 160 peer reviewed publications, and has written four books, and has many other academic accomplishments. 

And his talk today will center on the medical science of cannabis. At the conclusion of his topic, we have Andrew Miller, who's on the legal counsel with Piedmont Liability Trust who will talk about the legal implications of medical marijuana specifically in the state of Virginia. So should be a stimulating talk. Join me in welcoming Dr. Casarett. 

Thanks everyone. Thanks for the invitation, and thanks for being here. I know this is one of these topics that a lot of us physicians would like to avoid, and if there's one takeaway for this talk from me to you it's kind of this is one of these secular trends that you can't avoid. You don't have to recommend it. You don't have to believe in it. You don't have to suggest it or certify your patients, but your patients are using it, they will be using it. As it comes online in Virginia, they'll be using it a whole lot more. So at least understanding it enough to have a conversation with your patients really is essential. And that's kind of how I got into this deal. Not that I was a believer, still not entirely a believer, but I interested in this area because a patient came to me. I'll tell that story and second. 

Just a couple of conflicts to note. I do work with a couple of groups, companies in this space. I won't be talking about any of those here now. The other one, I'm just going to focus on medical cannabis use. There are lots of interesting issues related to recreational use. It strikes me that as physicians, there's enough to focus on just in terms of whether medical cannabis is really medical, whether it helps our patients, what the benefits are, what the risks are without getting into all of the moral, legal, political, sociology, justice issues of whether cannabis should be legalized. So different topic for another time. We'd be happy to talk about that over a beer sometime, but not here, not now. 

So I got interested in this topic, probably four or five years ago now, because of a patient who came to me. This is a 73-year-old retired English professor at the University of Pennsylvania. And I was running the program then, so I would get referred to me a lot of those the VIP's who were on the Penn board or Penn alumni or faculty. And she was referred to me in the palliative care clinic because she had advanced pancreatic cancer, neuropathic pain that persisted despite a celiac plexus block, and nausea, vomiting that we thought was related to chemotherapy but persisted. 

So she came to me for advice. And in the course of that first consultation, she asked me whether I thought cannabis could help her. And I told her what I had learned in medical school about cannabis, which is, A, that it's addictive, and, B, what I hadn't yet learned in my training as a palliative care physician, which is as far as I know, there's no evidence to support its use. 

And this is a retired, really tough, crusty English professor at Penn used to beating up undergrads, and she wasn't going to let that go easily. So she reached into her handbag, pulled out this big stack of randomized controlled trial articles about cannabis, flunked them down on my desk and said, really, there's no medical benefit, doctor? 

And you know when patients call you doctor, you're in trouble. It's sort of like when your mom uses your middle name. When I hear David Jonathan Kessler, I know I really, really screwed up. And she left those articles with me as we finished the consultation, and I promised that I would read them. And I did. I started looking through them. 

One surprise was, yeah, believe it or not, there actually are randomized controlled placebo-controlled trials of cannabis. You can create placebo cannabis that looks, smells, and tastes like cannabis but doesn't have THC or cannabinoids in it. So that was surprise number one. Surprise number two is that there actually are randomized controlled trials out there that are well designed by respected researchers, many of whom have been doing this stuff for 10, 15 years funded by NIH grants, not for the cannabis stuff, but for other trials-- really well-designed randomized parallel trials or crossover trials. 

And so I started getting interested in the field of cannabis and research, wound up writing a book, wound up doing some consulting, wound up doing some of my own research. And what I wanted to share with you in the next 45 minutes, because I want to give time to Andrew to talk about legal implications, is some of what I've learned along that road. 

And one question I haven't really been able to answer, which I'll pose to you, which is, what is this stuff? Is it really a medicine the way the cannabis industry would want us to believe? Or is it just a weed, complementary alternative medicine at best, or at worst just an opportunity for people to get high legally? And this is something that all of us, as health care providers, need to decide on our own. Whether or not it becomes legal in our states, our patients, as I said before, are using cannabis legally, illegally in a variety of forms. So I think we all need to figure out where we sit on the spectrum. 

And just out of curiosity-- show of hands-- how many people believe that there could be some benefit to medical cannabis? So about half. How many people believe that's absolute crap, not possible-- it's just an excuse to get stoned? 

And I'll pull up my hand, because that's kind of where I was. And how many people are undecided, not sure? So a few. So it seems like this is a crowd of believers more than I would have expected. But I'm not trying to convince you either way. I'm certainly not trying to convince you in the next 45 minutes that it works or that it works for specific indications. But I'll give you an outline of what we know about what it does, what we don't know yet about what it does, and then I'll speed you through some of the risks and = at least that we know about. 

And I want to do that in three categories. And these were three things that surprised me as I started looking into this field. One was actually the science of how this stuff works. I thought going in that it didn't really change our response to pain or nausea, for instance. It might make us euphoric enough so that we would forget we're in pain or nauseated, but it didn't actually have any effect. It turns out that's not true, or at least not entirely true. 

There really are some benefits, and I'll walk you through some of those, along with some gaps in my knowledge of what we know and what we don't know. And then depending on how we're doing for time, I'll either walk you through some slides or maybe just allude to this last question, which is something I'll ask you to think about now, which is we're talking about something-- and I've been pretty open and honest about this-- that there probably are some benefits, probably not as many as a lot of people in the cannabis industry would like us to believe. But there probably are a few benefits. 

And yet it's turned into this multi-billion dollar business. CBD alone, like all of your patients probably are on some form of CBD, as well as probably half of your friends and family members, despite the fact that we have no idea what it does. So that's one puzzle to think about as we're talking about some of this evidence. There is some evidence, not a lot. And yet it's enormously popular. What's going on? 

And it's worth, if we have time, thinking about what the cannabis industry and what this cannabis trend, movement, whatever you want to call it tells us about health care. Because anytime you see patients flocking to any treatment way beyond the bounds of what's justified by the evidence, you've got to ask, well, what's the attraction? What's the appeal? Is it just the fun of getting stone? But then why is everybody using CBD, which doesn't get you high? What's going on? So as we go through the evidence, think about that question. If we have time, we'll come back to it. 

So surprise number one for me, there is a science of how this stuff works. Molecular structures of THC and CBD. THC, you probably all know, is that cannabinoid that gets you high. It makes you feel good, makes you feel euphoric-- not you, but people in general. It's also the cannabinoid that makes people feel anxious or paranoid, and it's the cannabinoid that's responsible for withdrawal syndrome and addiction and substance use disorder. 

It's also, by the way, the cannabinoid that's gotten all the attention. You look at studies of cannabis for a variety of conditions, it's not CBD, despite the fact that you can see CBD appearing on CVS drug shelves. Most of the studies are either on THC or some combination of THC and CBD. It's really the cannabinoid that's gotten all the attention. 

One other point in parentheses-- there are a lot of cannabinoids out there. There are probably at least two dozen cannabinoids that are called phytocannabinoids, but basically the cannabinoids that appear naturally in the cannabis plant, number one. And there are, at last count, probably 90-plus synthetic cannabinoids that are related in structure to THC or CBD or CBN that have been created in laboratories. There was a big cottage industry in the '70s and early '80s. A lot of drug companies were starting to manufacture synthetic cannabinoids. 

Most of those are still sitting on the shelves now. A few have made it into clinical trials. Nabilone is the synthetic analog of THC-- not THC, but related. Dronabinol. Marinol is used for nausea. That's a synthetic form of THC. But that's two or three out of more than 90 that have been created. So one thing to keep an eye out in the next couple of years for is I'm guessing that many companies will start taking those synthetics off the shelf and start putting them into clinical trials for a variety of indications. What do they do? I have no idea. 

A little bit of plant biology, just quickly. With sativa, that says that because it's the female plants, so they're male and female forms of the cannabis plant, which was another surprise to me, the lesson in horticulture. But it's female plants that have the buds, and therefore the female plants that have high concentrations of THC, CBD, other cannabinoids. And this close up, for those of you who can see it, is a close up of the bud. And these little nail head-like projections are called trichomes, and that's where all of the THC, CBD, other cannabinoids are concentrated. 

So when you hear about CBD or THC oil, for instance, how that's manufactured is scraping those trichomes off the bud, concentrating them. CBD naturally is an oil-like substance. It's very sticky. But you concentrate that up to 30% or 40%, and what you get is an oil that's made up of those trichomes after they've been purified. 

For any of you who have spent any time looking online at dispensary websites to try to get a sense of what your patients are being exposed to in terms of advertising for cannabis and medical uses, you've probably seen a bunch of ads for various strains. And if you haven't spent any time looking, I would encourage you to do that, because regardless of what you think about cannabis, it's important to know what our patients are hearing, what they're learning from the internet before, hopefully, they come in to us with questions that are often misguided and misinformed. 

But one common misconception you see on websites all the time is that there are two species of cannabis, sativa and indica. What patients often hear is that if you have an issue like neuropathic pain or nausea, something that's physiologic, you want a species-- I know how crazy this sounds, but just bear with me-- you want to use a species of cannabis, a strain from the sativa species because it's activating. Whereas if you want to have help with PTSD or anxiety or falling asleep, you want a strain from the indica species because that's more relaxing. 

So there's this conventional wisdom out there that it's almost a weird form of naturopathy, that you can select the strain and the species based on the symptom that you're having. In truth, what happens is the chemical composition of those strains and those species has no relationship with the strain name or the species name. 

Here's a graph for those of you who can see it. There are strains within the indica species which should be calming and relaxing but have really outrageously high percentages of THC. And then there are also strains within the sativa species that should be high in THC but are actually quite low. So just keep in mind, a lot of patients are making medical decisions about what to put into their bodies based on this overall idea that I'm really anxious, so I need to use an indica strain. 

Another reason, whether or not you believe in cannabis or not, it's important to figure out what patients believe, what they're using. So at very least you can tell them what not to do, whether or not you make recommendations. 

There's a lot of the science of cannabinoid receptors that we don't understand. Here's a little tip of the iceberg of what we do. THC generally binds to CB1 and CB2 receptors that are mostly in the brain, also in the reproductive system. With one caveat-- those receptors seem to be throughout the brain, except in the brainstem. So what you often hear, which I think is pretty much true, is that you can't overdose on cannabis. You can't fatally overdose. 

And that's because, unlike benzos or barbiturates or, of course, opioids, there are no receptors in the brainstem, so no risk, as far as we know, of respiratory depression. There are certainly instances of somebody taking large, large amounts of THC containing cannabis, developing an acute psychosis, and injuring themselves or others. That's certainly known to happen. But in terms of respiratory depression-mediated overdoses, as far as we know, that doesn't happen. 

CBD we know a whole lot less about where those receptors are what they do, except that there are a lot of them, and they seem to be all over. Probably G protein receptors in the brain that are likely to be mediators of some of CBD's effect, if there is an effect, on pediatric seizures. And then receptors are known and relatively well characterized in the immune system, so in the spleen, thymus and GI tract. What the function of those receptors is, I don't think anybody knows. 

But that association-- lots of CBD receptors on T cells, high concentrations in the spleen and the GI tract-- has led people to think about the role that CBD might have in autoimmune disorders or Crohn's disease, for instance. But as far as I know, those haven't even begun to prove out. So lots of theories around these receptors-- where they are, what they could do-- but not a whole lot of action yet. 

Another surprise for me is a way of thinking about these receptors. So you've got the cannabinoids in cannabis. You have these receptors in the body. And where the penny really dropped for me and I started to think about this in a new way is when I spent a week in the lab of a man named Raphael Mechoulam, who really has been very quiet. He's not a clinician. He's a biochemist at Jerusalem Hebrew University in Jerusalem. And he's been advancing, gradually, incrementally, the science of cannabis over the last probably 45 years. 

But he was the one who first described the structure of THC. He was the first person to synthesize it. And his lab made a discovery that was fascinating, that across many species, animals, people have receptors that bind to THC. And so his question was that that's too much of a coincidence that we all happen to have these receptors that bind to THC. So his hypothesis was there must be some endogenous molecule in all of our bodies that's evolutionarily highly conserved that these receptors are designed to bind to. 

And it turns out it's a class of molecules called endocannabinoids. Anandamide is one. 2-AG is another, and there are several others. And so it was Raphi's lab who first defined anandamide, figured out it blinded to THC receptors, or THC binds to anandamide receptors. And he was the one to flesh out this idea of an endocannabinoid system, that we have this neuroendocrine system in all of us that's, again, highly evolutionarily conserved across mammals and reptiles and insects, in which 2-AG anandamide bind to these receptors, modulating a lot of functions of the body we don't begin to understand. 

And when you take in THC or CBD into your body, what's happening is you're essentially hacking that endocannabinoid system and convincing your body that what's binding those receptors is anandamide, when what really is binding to those receptors is THC or CBD. In the same way we're not born with receptors for morphine, but we do have enkephalin receptors. And when you take a 30 milligram tablet of MS contin, you're tricking your body into thinking what's binding to those enkephalin receptors is one of the enkephalin class rather than morphine. Kind of a silly example, but that's exactly what's happening. 

And that's a lot of implications, both positive and negative, if you think about it. So you've got this elaborate endocannabinoid system that nobody yet really understands that spans all the cells, as near as we can tell, in our bodies. When people start using cannabis, they're putting those cannabinoids into those receptor notches in all of these receptors, in all of these cells, in all the organ systems of our bodies. 

And if you're an optimist, you would hear that admittedly not very scientific explanation of physiology. I forgot everything in medical school I learned about physiology, so I'm not the person to explain this. But you could hear that story and think, wow, there's all sorts of potential. And indeed, if you look at receptor polymorphisms, so how these receptors differ in structure among people, you can see receptor polymorphisms that are associated with conditions that range broadly from obesity to depression to anxiety disorders to problems with bone density. 

So the endocannabinoid system, those receptors have been implicated in a lot of these conditions. And that leads the optimists in the cannabis world to say, wow, THC, CBD, other cannabinoids could be cures for diabetes. They could be used to treat depression. They could be used to increase bone density. None of this is proven out, by the way, but these are things that optimists think about late at night. 

On the hand, just full disclosure, the negative side to that is you've got all these receptors throughout the body as part of the system that nobody really understands. And now you have, at a public health level, lots of people using cannabis containing cannabinoids that bind to these receptors. How do we know what we're messing with. What consequences could this have long term in terms of bone density, or the prevalence of depression, or any of these other things that seem to be linked to these receptors? 

So I think over the next three to five, probably 10 years, we'll understand a lot more about these receptors in the endocannabinoid system. And what we're seeing right now of the impact THC and CBD on these receptors, we'll talk in a minute about what we know about chronic pain and nausea and anxiety and other conditions. But it's probably just the tip of the iceberg, both in terms of benefits, but also potentially in terms of risks. 

So there are signs of how to use this stuff. One thing to know is that there are a variety of different formats. Oils will be coming online here in Virginia, but in other states you can get varying formats, ranging from flower, the actual bud, to oils, to vapes, to edibles, which we'll talk about in a second, with varying concentrations of THC and cannabinoids. Bioavailability, like morphine and other drugs, is limited when you take it orally. So it undergoes a first-pass effect. Some of those metabolites are active. Some of those are not. But in general, you lose somewhere between 30% and 50% of the active dose with oral administration versus buccal or inhalation. 

The other thing to know is that there's a wide inter-individual variability in serum levels, even for very precisely controlled inhalation experiments. So two people inhaling the same amount, same lung volume, for the same period of time will wind up with very, very different volumes. And that inter-individual variability expands dramatically when you start talking about gut transit speed and oral absorption or other formats. 

So whenever people talk about dosing of cannabis, which we're not going to talk about now because it's really a guessing game. The best advice usually is to start low and go slow, like dosing antipsychotics in older adults, because you never know what's going to happen. And that doesn't sound very scientific, and I admit that. And I think that's a turnoff to a lot of us who are clinicians who want to know, this is the dose for that group of patients. This is the dose for that group of patients. Start here and go to there. But starting low, going slow, and letting patients titrate up is something we do occasionally, like for opioids. But for the most part, it doesn't sound very medical. 

In this slide, very briefly is why people love smoking and vaping. This is a graph of serum concentrations of THC and its metabolites from a vaping study done by, again, Donald Abrams, who's based at UCSF, really one of the first researches in the space. And if you can't see the legend, what you'll see is a series of arrows on that upsloping shoulder, and those arrows correspond to inhalations. 

So even without being able to read the legend, what you can see is that for every puff somebody takes on that vape device, serum concentrations go up. People stop inhaling, and the serum concentrations go down. There's a huge amount of control over serum levels that you really can't get for other sorts of drug delivery devices that are patient administered, except for maybe a PCA pump is probably the best example in a hospital setting. And that's why patients really love smoking and vaping. 

And gradually there's becoming a trend, I think, toward other forms. But a lot of people really like that, because particularly for neuropathic pain, anxiety, PTSD, especially for chemotherapy-induced nausea and vomiting, being able to have some feeling of relief immediately is really important to a lot of patients. 

And the last point about routes of administration, briefly, William O'Shaughnessy was a surgeon in Calcutta in the 19th century, who became interested in researching cannabis. And he was the one who came up with the idea of making tinctures of cannabis, so large amounts of cannabis resin dissolved in small amounts of alcohol, which wasn't a new idea. Laudanum is a tincture of opium. He was familiar as a physician with using laudanum. He just made a tincture of cannabis. 

But I mention this for two reasons, or three. One, it allowed him to experiment on goats. And frankly the idea of cannabis experiments on goats I still find hilariously amusing. Number two, he was really the first person to realize that the same exact dose, so two people given exactly the same thing-- three drops of the same exact tincture from the same bottle-- would have very, very different effects. So even back then, we didn't know why, but we knew people respond very, very differently. 

And it's partly a combination of metabolism as well as genetic makeup. We have different receptors. We metabolize differently. And some people are more likely to get paranoid. Some people are more likely to develop addiction than others, for instance. And number three, because I think we're going to see that increasingly used in our patients. 

Again, it's just oils, as far as I know, in Virginia. But those parameters have a way of expanding over time as state laws grow. And there's a lot of interest and a lot of patients in using tinctures. It avoids the first-pass effect, so it's a more efficient mode of administration. It's quicker, not as quick as vaping, but still pretty quick. It's discreet. It's easy to use. And it's easy to dose. So especially given a lot of concern about vaping lately, I think we'll probably see patients using tinctures more and more. 

Edibles, the only point there is that people have managed to figure out how to get cannabis, cannabinoids into pretty much any product you could find on a grocery store shelf, which I think is mostly useful for the recreational market, although I've certainly taken care of patients who, for reasons of increasing appetite or improving sleep, will take a part of a brownie or part of a piece of chocolate. And the main risk here-- again, not so much in Virginia, but certainly in states where cannabis is legal recreationally-- there are patients who use these sorts of things or people who use them for fun. 

And when you've got things like cannabinoid-infused waffles in the house and you've got kids in the house, that's a public health crisis waiting to happen. So that's also something to be aware of when you have patients who are using cannabis for any reason, making sure we keep those out of reach of kids. Again, there's no risk of a fatal overdose, but if you look around the country at reasons for emergency room visits among kids, you see a gradual year-over-year increase in the number of ER visits for kids for cannabis-related exposures. Again, no fatal overdose, but it's not something you want to give to your kids. 

Future of vaping, I thought it was really bright. Recent events suggest it may not be. Honestly, I think some of these issues will play out. The industry will clean itself up. But right now if I have questions with people, and I get emailed these questions on an almost daily basis, my general advice right now is if you are vaping, you're probably OK, but be careful. If you're thinking about starting, probably don't until we figure out where all of these illnesses and deaths are coming from. 

There are some medical benefits, not, though, as many benefits as the cannabis industry wants our patients to believe. And this is a chronic theme. And I think increasingly health care providers are going to find themselves in between patients on the one hand and the cannabis industry on the other that stands to make billions of dollars off of patients spending money on cannabis and beginning to mediate that, and advising on whether and how cannabis could be effective, but also tamping down expectations that people are going to hear about online and from ads. 

If you look at potential uses in state laws-- and I know Virginia is a little bit interesting in which I think it's the only state that I'm aware of that doesn't specify qualifying conditions, which on one hand I love, because I don't like the legislature telling health care providers whether and when to use any medication, whether it's lovastatin or cannabis. On the other hand, it puts you guys in a slightly awkward position because there's no guidance, and you have to look for guidance elsewhere. But honestly, I'd rather have physicians look to national guidelines than to state legislatures. 

But many other states do have qualifying conditions. This is a partial list. The one thing I'll say about this that I find both fascinating and really frustrating is that if you look at one state's qualifying conditions, you've seen one state's qualifying conditions. PTSD is a great example. PTSD will get you access to cannabis in California, but not in Colorado or Wisconsin, which makes no sense. It's like saying simvastatin will work if you have high cholesterol in Vermont, but if you cross the border to New Hampshire, then it doesn't work anymore. It makes no sense. 

And the process of establishing these laws is driven by a lot of really, really messy factors, not driven by medical science, which is why I'm glad in Virginia, the legislature has decided to leave it up to health care providers to make these decisions. Overall I think it will be difficult initially, but I think it's the right way to go. 

Also what's present in California, where this comes from, or other places is a lot of direct-to-consumer advertising. So hopefully in Virginia, you can tamp that down or avoid it entirely because it's a bit of a problem. 

So one of the most authoritative set of guidelines that I'm aware of, Donald Abrams, who I mentioned before, chaired this committee with the National Academy of Sciences. It's a pretty thorough list of what we know and what we don't know. So good evidence they found for chronic pain, chemo-induced nausea, vomiting, spasticity in multiple sclerosis, moderate evidence for sleep in the setting of other conditions, probably not a primary sleep disorder, although we don't really know that for sure yet. Limited evidence for some other conditions. 

So I won't go back to that slide, but think back to what was on that slide of the state indications, some things like PTSD. Again, qualifying condition in California, no evidence whatsoever. There are a few clinical trials that should be published soon, but right now we really don't know. 

And I highlighted chronic pain because I wanted to walk you through, if we have time, a couple of studies to show you how messy some of this evidence is. So remember, National Academy of Sciences says there's conclusive or substantial evidence for the use of cannabis in treating chronic pain. That sounds great. That's probably enough for me to go into a patient's exam room and say, yeah, you should give it a try, because the National Academy of Sciences found that level of evidence. 

So that was their take on it. There was another meta analysis that had a slightly different take. Yes, it's beneficial, but probably the number needed to treat is about five. So 20% of patients will benefit. That's not inconsistent, but when I see 20% of [AUDIO OUT] 

--CNS malignancies and other conditions as well, as well as long-term survivals, like long-term survivors of breast cancer and prostate cancer. I'm really interested in using THC, CBD oil as a cure. And just to be clear, I think what we've talked about so far is using cannabinoids to treat symptoms of conditions. There are some really interesting theoretical reasons to think that cannabinoids might be useful as one part of cancer therapy sometime. 

THC, for instance, turns out in cell culture experiments to be very effective at reducing angiogenesis. So in theory, it could prevent or at least slow the formation of new blood vessels that tumors need to grow. But to take that cell culture work and to say, great, I'm going to stop chemotherapy. I'm going to stop radiation therapy. I'm not going to go for a bone marrow transplant, as one of the people I met writing this book told me, and I'm going to put all my trust in this concentrated cannabinoid oil is really not wise. 

And that's another reason to have these conversations with patients, not because we're trying to talk them into using cannabis, but to make sure we help them to have realistic expectations for what cannabis can and can't do. And that woman, by the way, was 34-year-old, had a diffuse large cell B-cell lymphoma and was just had a really, really tough time with chemotherapy and everything else she had to do-- single mom, two kids at home. And heard about this cannabis oil and thought, this is great. I just take a couple of drops morning, night. I'll feel better, and it'll cure my cancer. 

And she wound up dying about three or four months before the book went to press. So I think about that story whenever anybody asks me about using cannabis for cancer treatment. I often tell them that story and say, look, we can do a lot to try to manage your symptoms, but you really need to rely on your oncologist, your surgical oncologist, your radiation therapy doctor to give you the best chance of survival. Don't put those hopes in cannabis. 

The other thing that patients will learn from websites and from each other is that cannabis is safe. It's a plant. It's a flower. It's organic, increasingly. There's this is new phase of outdoor, natural-grown cannabis, like somehow cannabis that's outdoors is healthier for you than cannabis that's grown in a greenhouse. This is what patients are exposed to. And I love this quote, because many of you are chuckling as well. 

Last time I checked, morphine is an opioid. Opioid is derived from poppies. Poppies, last time I checked, are also flowers. And yet this is what patients are exposed to. Put away all your other drugs, because cannabis is safe. And to be fair, it is pretty safe, honestly. But there are some risks. Although not as much in the way of risks as many people think. 

I got a nasty email a couple of months ago from somebody asking why I'm talking about cannabis publicly. I'm engaged in the cannabis industry, but I've written that marijuana is acutely and probably chronically toxic in the Hawaii Medical Journal. And I thought, that's weird. I don't think I said that, and I hadn't written anything in the Hawaii Medical Journal. And I certainly hadn't written anything in 1971, when I wasn't really writing for the peer-reviewed literature back then. 

And I looked more closely, and I realized this is something my father, who was a toxicologist, wrote quite a long time ago. So fortunately I didn't have to apologize to that person, but that's another way of saying, this has been a concern-- risk of cannabis has been a concern for a long time. Even my dad 50 years ago was thinking and writing about the risks of cannabis. So there is something there that we should all at least pay attention to. 

So what do we know? Driving impairment is real. There's no question in my mind that somebody who is using cannabis, recently used, who has significant serum levels probably is as impaired to drive as somebody who's using alcohol. I'll tell you this story now in case we don't have enough time. So when I was in Pennsylvania practicing, a patient came to me telling me he had a peripheral nerve cell tumor that would usually go for surgery, but there was some PT rehab he had to do before that. So he was in kind of a waiting period. 

He was having a lot of neuropathic pain, and his gabapentin and methadone weren't working, so he started using cannabis. I said, OK, fine. But he told me one morning at a clinic visit that his strategy for using cannabis was to smoke a joint in the morning, and then midday, and then in the evening. And I knew that he was a single dad and drove his kid to school every morning. And so I just asked him about how those events were related. And he said, yeah, I would spoke about half a joint, and then drive Jamie to school. 

And I tried to impress on him that that was really not a good idea. And I couldn't convince him of that. So we staged a little intervention experiment and went to a deserted middle school parking lot on a Sunday morning. And I created an improvised obstacle course for him. I didn't have traffic cones, so I stopped at the local Safeway and got a couple pounds of bananas and spread the bananas out in the parking lot. He smoked his normal half joint, and then I had him drive through the obstacle course. 

And he failed miserably-- lots of squashed bananas. And we agreed after that that he would, if he really, really needed to use cannabis, he wouldn't drive within six hours. Nobody really knows what the safe time period was, but I was trying to be conservative. But he exhibited all of the elements that you see in driving simulators. There have been lots of studies of driving simulator cannabis dysfunction, as well as a couple of studies of cannabis use in flight simulators. 

Why anybody thought it would be a good idea to get stoned and then fly, I have no idea, but same impairment, not surprisingly. But people tend to be really slow. They react slowly. Unlike alcohol impairment, where people don't realize they're drunk and get really aggressive, patients who are stoned, people who are stoned know they're stoned, and they back off, and they're very, very slow, which can be also dangerous, but in a different way. 

They also have a hard time paying attention to the right details. So this guy was really focused on some seagulls that were off in the distance, and he rolled over three or four bananas. But it really is a problem. The other problem, just quickly as we're wrapping up, as we think about driving impairment, is there really isn't a good test for it. We have breathalyzer tests. We have serum alcohol levels. There's really no equivalent for THC intoxication. There's no clear association between serum levels and impairment. 

And some of the roadside sobriety tests that are typically used, like the heel-to-toe walk and the finger-to-nose test, they don't work for cannabis impairment. Because mostly people who are impaired know that they're impaired. And whereas somebody who's impaired due to alcohol won't realize it, and they'll just flop a finger in an ear, up a nose, patients, people who are impaired due to cannabis realize that, and they'll take extra long to make sure that that finger hits their nose. 

And it's comical to watch, but it's really concerning to a lot of public health experts and traffic safety experts because there's no way, when you pull somebody over, to say you're too impaired to drive. There's no test. And there's some interest now in behavioral tests related to trails speed, where you match one to A to 2 to B on a smartphone screen. And I think those are probably two or three years away from being implemented in a legal setting. Right now, we've got nothing. And the best indicator of whether somebody is too impaired to drive is whether they think they're too impaired to drive. 

Addiction is a real issue. People don't think of cannabis addiction, but it is real. We don't know a lot about impact on brain development in adolescents and young adults, but it seems to be real. Hyperemesis syndrome is also real. People who use cannabis, usually regularly, will develop nausea, vomiting that's refractory. Stop using cannabis, it goes away. Often can restart cannabis use safely. Nobody quite knows what causes it. Maybe it's up regulation of 5-HT receptors. Nobody really knows. 

But somebody comes into the ER with intractable nausea and vomiting, one of the first questions really should be, have you used cannabis? When was the last time you used it? Psychotic episodes due to acute intoxication, and then increased risk over time are definitely real. Many of these other risks, I think, are still hypothetical, and we just don't know. And I'll stop with this last slide and hand it over to Andrew. 

Pulmonary risks, even from smoking and vaping, as far as we know, aren't real. And I'm not sure why that is. The best hypothesis probably is that most people who develop chronic lung disease, COPD, or lung cancer, head and neck cancer often-- at least my patients-- have a 40, 50 pack a year smoking history. 

And it may be that if people smoked cannabis that much, they would also have those sorts of problems. But imagine what kind of shape you'd be in if you smoked the equivalent of 20, 30 joints a day for 20 or 30 years. You might wind up with COPD or lung cancer, but you probably wouldn't care. 

So I promised I would stop right at 1:00. There's still some things that we didn't talk about, but I think to make time for the legal discussion, I think that makes sense. Maybe the last piece, as I hand it off to Andrew, is this is a kind of field that's changing really, really quickly. And I think all of us, both in terms of science, in terms of evidence, in terms of what patients see and bring to us, but also in terms of state laws. There are a lot of physicians, I think, in various states who are trying to play catch up. 

It's low THC. Now it's high THC. It starts out with CBD. Now it's CBD plus THC. Having some source of evidence that you rely on and trust for updates and guidelines is really going to be important. Because we all, as clinicians, have a lot to keep up with. Especially in palliative care, I need to keep up with palliative care, plus oncology, plus heart failure, plus all these other disciplines. This is just one more. So thinking about how to keep up with that over time I think is a big struggle. Because, again-- last point, probably the most important, even if you don't believe cannabis is useful-- being able to talk to patients about it openly is probably the most important contribution you can make to patients' care. So I'm going to stop there, hand it over to Andrew, and then we'll do questions at the end. 

[APPLAUSE] 

So in true legal fashion, I'm not your attorney-- my disclaimer. If you do need an attorney once you leave the University of Virginia, please contact your risk manager. This is more of an educational series. So one thing they don't teach you in law school are marijuana laws. You are about common law, contracts, torts but there's no elective on legalization of marijuana. 

So the first place that you look to, if you're in the state of Virginia as a lawyer, is the Virginia code. And to my surprise, since 1979, physicians have been able to prescribe medicinal marijuana for glaucoma and cancer. The problem with that law is it's a hollow law because we all know under federal law you can't prescribe a Schedule 1 substance. 

So what was the General Assembly thinking at the time? Well, the thought process at the time was hopefully we can at least get the pendulum swinging in the direction of folks starting to talk about this. Unfortunately, or not unfortunately, that pendulum didn't swing until about 40 years later, in 2015. 

But before we get there, I think it's important to talk about the interplay between federal law and state law. Under the Supremacy Clause, federal law preempts state law when there's a conflict in the law. So what we're going to talk about are acts of Congress and state statutes. In particular, it's the Controlled Substance Act. So this basically says that marijuana is a Schedule 1 substance. It's illegal to prescribe, possess, dispense, or distribute. 

The crime that's associated if you're a practitioner and you do do that is the crime of aiding and abetting. And essentially that means you've helped somebody else, a patient, commit a crime, the crime being that patient actually went out and obtained the illegal substance-- CBD, THC-A oil, or marijuana, in the state of Virginia. 

So in California, we all know that it's been illegal since the early 2000s. And during that time frame, when the state passed the legalization for medicinal purposes, the Department of Justice, they weren't too happy with that because that's a law that's in direct conflict with federal statute. So the Department of Justice issued a memorandum. And in that memorandum, they basically said that if you recommend, orally, just having a conversation with the patient, taking marijuana, you're subject to criminal prosecution. You can be excluded from Medicaid and Medicare programs, and you'll have your DEA prescription authority revoked. 

So, naturally, the lawsuit was filed by a group of physicians. And the ultimate issue with the Ninth Circuit Court was whether or not we can have a conversation with patients about medicinal marijuana. And it came down to whether or not that's a crime, whether or not it's a crime of aiding and abetting. The Ninth Circuit Court ruled that it's a violation of the First Amendment for the government, for the Department of Justice to issue these threats of criminal prosecution, violation of the First Amendment being freedom of speech. 

So conversation should be allowed between a physician and a patient. We shouldn't intrude on that relationship. And so they ruled in favor of the physicians. And so in California, in the Ninth Circuit, at least, physicians can recommend medicinal marijuana. 

The problem with that is the Ninth Circuit, the Western Seaboard is only one circuit out of 12 different circuits, including the District of Columbia. Virginia are in the Fourth Circuit. So a Ninth Circuit Court opinion is not binding on the Fourth Circuit. The Fourth Circuit can look to the Ninth Circuit as persuasive authority, but they're not required to do so. The Fourth Circuit, if the exact same fact pattern made its way up the chain, could rule, you know what? A recommendation is exactly the same thing as helping somebody obtain an illegal substance, and that is a violation of federal statute. 

A lot of money, at that point, was thrown into the medical marijuana industry. The framework had been established. People started to lobby their lawmakers congressionally. As a result, a rider amendment was attached to an annual appropriations bill about 10 years ago. So each year, the government allocate money through this annual appropriations bill. This rider amendment has to be renewed every year, so it's not a standing law that's on the books. It has to be renewed every year. 

But with that rider amendment said was that it directed the Department of Justice, you can't use any money prosecuting physicians, practitioners in states where it's legal at the state level. So basically, essentially, it's still illegal, but it dried up the funding. So the federal prosecutors could not criminally prosecute people that were recommending marijuana in any state. 

So that brings us to the 2015, 2017 legislation. There's legislation between 2015 and 2017. In Virginia, first being this notion of providing for an affirmative defense for the possession of CBD or THC oil pursuant to a written certification to alleviate epilepsy. And just to unpack that a little bit, an affirmative defense-- what is an affirmative defense? 

Think of self-defense to murder. Somebody is coming at you. It's an imminent threat. Shoot. Kill that person. You can't be convicted of murder because you have an affirmative defense. Same thing applies with this written certification. If a patient's pulled over, it's still illegal to have marijuana-- and not marijuana, anything derived from the marijuana plant. So CBD oil, THC-A oil, those are derived from marijuana. If a patient has this written certification, that's kind of a get-out-of-jail-free card. It's an affirmative defense. 

Practically speaking, the way that it would work out in the court system, mom and daughter are driving down the road. It's late at night. Mom has a busted tail light in her car. She gets pulled over by an officer. Officer says license and registration. She presents those, rolls down her window. I guess people don't roll down their windows anymore. You push the button. The window goes down. 

And he smells something [INAUDIBLE] alcohol. Maybe it's smoke. He thinks there's some sort of illegal drugs in the car. That's enough for probable cause. He searches the car. It turns out there's nothing there, except for this little vial of CBD oil. Mom can't just present this written certification to the officer and she's scot free. Mom's going to have to go to court with a lawyer. Once they go to court, they'll present it to a judge. 

Your honor, I did have the CBD oil, but I had this written certification that I obtained from a licensed practitioner in the state of Virginia, who was registered with the Board of Pharmacy. And so that's the affirmative defense to the crime. 

In 2016 and 2017, the regulatory framework was established to start to build these processing plants in Virginia. There are going to be five different processing-- 

And so the framework had not been established. It just codified that for another day. 2018 legislation broadened the horizon. So no longer is it just for epileptic patients, but for any diagnosed condition. It doesn't matter what it is. As long as there could be some perceived benefit, a physician could issue this written certification. 

The definition was further expanded not only for just physicians licensed with the Board of Medicine, but also physicians assistants and nurse practitioners. And the safe harbor for a physician is you can't be prosecuted at the state level for dispensing, distributing, recommending CBD or THC-A oil. 

It's important to be aware of what the Board of Pharmacy regulations are because they are really granular. There's a lot of detail. It's kind of akin to the emergency opioid regulations that came out. So it's important to be able to go back and look at those regulations, understand those regulations if you do decide to write your written certifications. I'm not going to get into the granular detail. If you do decide, if you do leave UVA, it's certainly something worth asking your risk manager or legal counsel. 

Implementation-- both the physician and the patient have to be registered with the Board of Pharmacy. Once the physician is registered, they'll receive a link that allows them to fill out this written certification that they, then, can in turn provide to the patient. Five processors in Virginia, geographically distributed in different areas. It's supposed to be available in the spring and summer of 2020. It was supposed to be available in the spring and summer of 2019, so your guess is about as good as mine. 

There has been one CBD oil product that is legal under the eyes of the federal government. It was rescheduled. It's Epidiolex. It was rescheduled from Class I to a Class V. So this is actually something you can prescribe. And I think that the pharmacy here at UVA has actually started, or they released it at some point if they don't already have it stocked. 

So I know that's a lot in a couple of minutes. We talked about constitutional law, criminal law, state law, and federal law. But at the end of the day, it is technically illegal under the eyes of the federal government. But the risk of prosecution is pretty darn low. A federal prosecutor, the DEA, they have better things to do than go after a physician or a patient who has C-- I'm not talking about marijuana. We're talking about CBD oil. 

Better things to do-- trafficking, child trafficking, racketeering, hard-core drugs. So technically speaking, yes, it's illegal. But I hate to say they're safe harbor in Congress, but there is a congressional act that provides protection if somebody wants to issue a written certification. I know that at UVA they're still working through this issue to try to get a consistent policy. There isn't a policy out right now, so that's been brought to the attention of the administration at UVA. 

But at the end of the day, low risk. Being a lawyer, there is risk, but the threat of prosecution is probably pretty low. And I've heard that from the executive director of pharmacy who's talked to her colleagues in the DEA. So that's all I have. And I'm happy to stick around for some questions. 

[APPLAUSE] 

We do have some time for just a few questions. And we can try to pass a mike. 

Thank you very much for those wonderful presentations. It's great to end the week on a high note. 

[LAUGHS] 

So, seriously, since we will have CBD oil available in our pharmacy and these state dispensaries, what is the evidence for pure CBD and chronic pain relief, since that's what we often deal with in general term medicine as the main reason to prescribe, if we're going to prescribe it? As opposed to CBD plus THC or THC alone? 

Was that a question for me or for the lawyer? 

That sounds like a question for you. 

Sure. So as far as I know, zero, honestly. To be fair, there's one guy, Barth Wilsey, who's a longtime funded NIH funded researcher at UC Davis who started out doing trials of 10 to 1 THC CBD for neuropathic pain, has gradually been ramping those down. And he's now doing some trials that are almost negligible THC, so maybe 1% THC, 10% CBD. And he's seeing great results. 

So that points in the direction of, yeah, maybe CBD could be effective. But if you want actual evidence, no. In fact, there really haven't been any studies of CBD only, despite the fact that you can go into CVS and buy a couple pounds of it, nobody really knows what it does. Everybody thinks it does everything, but we don't know. 

Hello. Thank you. That was an excellent presentation. Is the federal government funding research in THC or related compounds yet? And are we in this boat that we are because the federal government didn't and precluded it for such a long period of time? 

No and yes-- not really funding it. Funding a lot of research on risks. May start to fund some research on cannabis substitution for opioids, maybe. Are we in this boat because of that? Yeah, partly. And other countries have some blame too. It's been legal in Canada for a while, but Canada is just starting to fund research. Israel has really been ahead of the crowd, but even then, they haven't done a lot. 

And I think we're in this [INAUDIBLE] in a couple of ways. One, we don't have as much research as we need. Number two, a lot of the best research that's coming out of other countries and so a lot of big academic institutions are looking up to Canada looking over to Israel thinking we should really be leading in this space, but we're relying on data that's generated in other countries. So I think we're going to try to catch up, probably. It's going to be a while, I think, before NIH funds therapeutic trials of cannabis. 

Hi. Thank you for the presentations. I'm curious-- so you can walk down the street and buy CBD oil right now. And I've been hearing about UVA starting to sell it. What's different with the stuff that's available out there on the street right now, here in Virginia, than the stuff that we are supposed to be waiting for from the dispensaries? Do you know? 

All I know is that it's going to be heavily regulated through the dispensaries in Virginia. I don't know the compounds and how they're going be different from what's out there. I know that there's a lot of [INAUDIBLE] problems with some of the products because folks just don't know what's in it right now. And so, for instance, in Utah in 2017, there were some people who ended up in a hospital because they thought they were receiving the CBD oil. 

But is the CBD oil that's being bought right there from Rachel's Nature whatever-- Whole Foods, is that illegal? 

Yes, kind of, because it falls under the farm bill, which is-- that CBD oil is being derived from hemp. It's not being derived from marijuana. The manufacturers in Virginia, those facilities are deriving their oil from marijuana. So there's a farm bill that Congress passed that allows for actually CBD oil. [AUDIO OUT] haven't done that with the medicinal marijuana. 

I could take a non-legal answer to that question, which is either going to throw you off or be helpful, not sure which, which is that-- again, I'm not a legal scholar. This isn't legal advice. As far as I'm concerned, CBD oil is essentially legal, as legal as echinacea for a cold. It's just out there. Everybody's using it. Everybody is selling it. 

I'm not familiar with the Virginia law. My sense is that what the Virginia law allows is the addition of THC to that mix, which is not covered by the farm bill, which is not legal and is not something you can get in Whole Foods. So quick summary-- I'm guessing if your patients want CBD only, isolates, there are plenty of good sources to get that from. If what you want to prescribe is a mix of THC and CBD, then they would have to go through that program. Again, that's a physician's answer, not a legal one. 

And if the patient is going to have this written certification, that written certification is for stuff being produced in these five facilities, not anything else. That's where the certification is supposed to go. A patient has [AUDIO OUT] 90-day supply, I think. 

Thank you all so much for being here. 

Thanks. 

[APPLAUSE] 

That was awesome, man. Sorry for the sound difficulties.