Thank you very much. Welcome to this APA session, Medical Cannabis, What Psychiatrists Should Know. I'm the chair, Dr. David Gorelick of the University of Maryland School of Medicine. My fellow speakers are Dr. Kevin Hill of Beth Israel Deaconess Medical Center and Harvard Medical School, and Dr. Arthur Williams of Columbia University and the New York State Psychiatric Institute. Our program today has four components. I'll begin with a brief history of the current legal status of medical cannabis in the U.S. and the various states, and then a brief review of potential public health consequences of legalized medical cannabis. Then Dr. Hill will give an overview of the medical indications for medical cannabis, comparing the scientific evidence with current state laws. And finally, Dr. Williams will review the practical clinical pharmacology of medical cannabis, including doses, strains, routes of administration, and drug interactions. Before I begin, here are the speaker disclosures for the program, and Dr. Williams has no interest to report. So let's turn now to the history and current legal status of medical cannabis. Medical cannabis goes back almost 5,000 years, beginning in ancient China and continuing right up to the present. But it was introduced to Western medicine in the 1830s, initially by Dr. William O'Shaughnessy, a British Army surgeon serving in India, who saw medical cannabis being used in India and brought it back home with him when he returned to Britain. In fact, medical cannabis was widely used in the U.S. and Europe. In fact, it was mentioned in the U.S. pharmacopoeia. But this ended in the United States in 1937 with the Marijuana Tax Act. This placed a high tax on the prescribing, dispensing, or sale of cannabis, making it effectively illegal. It became explicitly illegal in 1970 with the Controlled Substances Act. The cannabis plant and all cannabinoids were put in Schedule I, making them illegal to possess, sell, or dispense. The legal definition was that there is no currently accepted medical use in treatment, there's a lack of accepted safety for use under medical supervision, and there's a high potential for abuse. Note these are legal definitions, not necessarily scientific definitions. Synthetic cannabinoids such as spice and K2 are also illegal under Schedule I and are also illegal in most of the states. But one of the prominent cannabinoids, cannabidiol or CBD, is in an ambivalent legal status. So it's illegal if derived from the cannabis plant, as noted under Schedule I. But the 2018 Farm Act created a new class of hemp, which is the cannabis plant with less than 0.3% THC content. Hemp and hemp-derived products were removed from jurisdiction of the Department of Justice, that is from the Drug Enforcement Administration or the CSA. Therefore cannabidiol is legal if derived from hemp, although it remains illegal if derived from other cannabis plants. There are also some administrative rules that govern medical cannabis. Until 2018, the Department of Justice had a policy of not prosecuting for possession of dispensing of cannabis in states with an appropriately strict regulatory system. But still existing are riders in the annual U.S. budget appropriations bills, which prohibit the Department of Justice from using funds to prosecute state-authorized medical cannabis entities. Now under the CSA, physicians cannot prescribe medical cannabis because that's regulated under that law. But under state laws, physicians can recommend or certify for medical cannabis or discuss it with their patients. And this is protected under the First Amendment based on a 2002 U.S. Court of Appeals ruling, Conant v. Walters. Another complication is that there are actually several cannabinoids currently legal under federal law because they've gone through the standard FDA review process. One of these is synthetic THC, known as dronabinol, which is in CSA Schedule 3, and a THC analog, also synthetic, nabalone, which is CSA Schedule 2. There's also a plant extract of pure cannabidiol, which is not scheduled at all. This was approved a few years ago for the treatment of intractable childhood seizures. Dronabinol and nabalone are FDA approved primarily for the treatment of nausea and vomiting associated with cancer chemotherapy and to stimulate appetite and weight gain in cases of cachexia. There's also an extract that's one-to-one ratio of THC and CBD, known as an abiximols. This is not currently approved in the United States, but is approved in Canada and several European countries for the treatment of pain and muscle spasticity associated with multiple sclerosis. Part of the complexity in discussing medical cannabis is there's no single uniformly recognized definition. The cannabis plant contains hundreds of possibly active compounds, not only the cannabinoids themselves, but also terpenes and flavonoids, which are types of compounds found throughout the plant kingdom. It is thought that the terpenes primarily contribute to the unique scent and flavor of the cannabis plant. The two major cannabinoids involved in medical cannabis are THC and CBD. THC causes the subjective effects, euphoria, sedation, anxiety, and analgesia. CBD is not euphorogenic, does not cause a high, and does not have abuse liability. However, it does have anxiolytic, analgesic, and anticonvulsant effects. And when CBD and THC are given together, the CBD tends to ameliorate the THC subjective effects, especially anxiety and psychosis. Although this is not found in all studies. So legalization of medical cannabis has expanded dramatically over the past two decades in the United States. This map illustrates the current legal status as of March 1st of this year. The dark green and the medium green indicate the states with legalized medical cannabis programs, which is 36 states currently. The dark green states, which are 15 currently, also have legalized recreational cannabis programs. The medium green states have only the medical cannabis programs. The light green states, 11 primarily in the South, have what are termed low THC programs. That is, they've legalized high CBD content products, primarily for the treatment of intractable childhood seizures, similar to the cannabidiol product that's FDA approved. That leaves us with only three states, Idaho, Nebraska, and Kansas, with no form of legal medical cannabis program. I should point out that Virginia legislature recently approved recreational cannabis in February, so we'll soon have an additional state in that category. So overall, about two-thirds of the US population lives in a state with legalized medical cannabis, and about one-third live in a state with legalized recreational cannabis. And we have no exact figures on the number of medical cannabis patients, because most states don't keep comprehensive patient registries for obvious legal and privacy reasons. But here's an estimate generated as of May 2018 by a private group, Procon. They estimated 2.1 million patients taking medical cannabis, primarily in Western states, New England, and the Northeast. And there's also been a dramatic increase in the number of medical cannabis patients registered in states that keep a registry. In 2009, about 72,000 such patients from three states, and by 2017, that had increased to almost 900,000 in 17 states. Now let's turn to the public health implications of legalizing medical cannabis. In the brief time I have, I'll try to provide a framework for evaluating the existing evidence and then briefly review potential public health benefits and harms. One has to be very cautious in interpreting the evidence for medical cannabis effects, because most of the studies are epidemiologic at the population level. And therefore, they're evaluating associations, which do not prove causality. An association could be due to an antecedent factor that's common to both the independent variable, in this case, a change in the law, and the outcome variable. For example, it might be that low perceived risk of cannabis use in the population promotes both changes to the cannabis-related laws and increased cannabis use. So there's an observed association, but not a direct cause and effect. To try to tease this out, the most rigorous statistical design we have is comparing difference in differences. This compares the differences before and after passage of the law in states that did versus states that did not legalize medical cannabis. So you're comparing across states, which somewhat controls for national secular trends, that is changes in characteristics in the general population. But there are also limitations in public studies in terms of the variables that are studied. For example, the classification of the status of the state medical cannabis program. Is the program actually operational? Is it actually providing cannabis to patients? Passage of a law doesn't necessarily mean the program is functional. For example, in my own state of Maryland, the law passed in 2015, but the first cannabis dispensary didn't open and dispense cannabis until two years later, December 2017. The strictness of the program may also influence the effects. Does it allow growing your own cannabis, or must you purchase it at a licensed dispensary? Does it require a recommendation from a physician with a bona fide physician patient relationship that is physicians who perform the typical medical evaluation history, physical examination, and so on? Or is it a five minute cash only appointment in a so-called medical cannabis mill? These maps illustrate the difference between a statewide legalization and whether a county actually has a functioning medical cannabis dispensary. Even in 2015, you see the states in light blue had many counties that did not have a functioning medical cannabis dispensary as indicated in the dark blue. Here's another example. It's a study on the association of medical cannabis legalization and per capita treatment admissions for substance use disorders. So the left graph shows the association with the change in the law at time zero. What you see is over time, there's a trend towards a decrease in treatment admissions. It doesn't quite reach statistical significance, even at year five after the change in the law. In the right panel, you see the association with the presence in the counties of an actual active dispensary. Here you see that by three to five years after the change in the law, there is a statistically significant decrease in treatment admissions. Clearly, the variable one measures makes a difference in the outcome you observe. Many of the studies rely on patient self-report as whether a person changed their medication use in response to using medical cannabis. But is this self-report always valid? So a small study from New Mexico recently found that more than a third of patients in a medical cannabis program who claim that such treatment allowed them to stop using prescription opioids were actually still obtaining opioid prescriptions as evidenced by checking their prescription drug monitoring program records. So with those cautions, now let's turn to potential public health benefits. A major focus of attention has been addressing the current opioid crisis. Might cannabis use substitute for opioid use? So there are several types of evidence, including decreased opioid analgesic prescribing, decreased opioid analgesic misuse, such as decreased treatment admissions, and decreased opioid-related mortality associated with opioid use. And decreased opioid-related mortality associated with increased number of county dispensaries. So this latter study is more like the last one I showed you. It's not statewide epidemiology. It's looking specifically at counties with open active dispensaries. And this did find a significant decrease in opioid-related mortality. The beta coefficient is minus 0.15. That can be interpreted as saying that for every additional open county dispensary, there's a 15% decrease in opioid-related mortality. However, I'm not aware of any evidence that medical cannabis has any benefit as a treatment for opioid use disorder per se. This slide shows a meta-analysis of seven recently published studies on the association between legalized medical cannabis and various measures of opioid abuse. And you see here a mixed findings. Five of the studies did show a significant benefit, two did not. But the overall meta-analysis does show a significant beneficial effect size of 0.59. So in clinical terms, that's moderately significant. Here's an example of one specific study on opioid prescribing for Medicaid enrollees. And again, you don't see overall major effects. So the passage of the medical cannabis law had a barely significant effect in decreasing overall opioid prescribing. But looking specifically at the schedule two more potent opioids, like oxycodone, hydrocodone, there's no significant effect. While there is a significant effect on the less potent schedule three, less potent schedule three to five opioids. And there are studies that show evidence of no benefit at all on the opioid crisis. So Shover and colleagues recently tried to replicate earlier published studies on the association between medical cannabis legalization and opioid overdose deaths. So they looked at the period 1999 to 2010 and did find the apparent benefit, a 22% decrease in overdose deaths that previous studies had found. But when they use the same techniques, just expanded the timeframe to 2017, the apparent benefit now became an apparent harm, a 23% increase in the opioid overdose deaths. Now, the authors don't really think that the effects of medical cannabis suddenly changed around 2010. What they say is that this change in outcome reflects the caution needed in interpreting these kinds of epidemiologic population level associational analysis. But there is one recent study that looked at individual substance users followed within subjects, in this case, 213 adults studied for 13,271 days with daily self-report of their substance use and pain. So in this study, they found that on days these individuals use cannabis, opioid use was actually more likely adjusted odds ratio of 1.86. And how much pain they were experiencing that day had no influence on this association. So this study looking at actual individuals did not find any evidence for cannabis substitution for opioid use. If anything, cannabis use was associated with increased opioid use. So overall, I would argue that the level of evidence is quite mixed as to whether medical cannabis is going to be a success in addressing our opioid crisis. Now, let's look at other potential public health benefits. There are two studies that found an association with decreased psychoactive medication prescribing. And some studies have claimed decreased alcohol use, especially in adolescents, but other studies do not find this. So I think the jury is still out. Here's an example of association of state medical cannabis laws with medication prescribing for Medicare Part D enrollees. So this is a very large nationwide sample. And it found significant decreases in prescribing of medications for specific indications in states that legalized medical cannabis. The most dramatic effect was for pain, where you see what is a magnitude decrease in prescribing of analgesics. There are also significant decreases for sleep disorders, seizures, psychosis, nausea, depression, anxiety. Now, some of these make pharmacological sense. As I mentioned earlier, jonabinol, synthetic THC, is already FDA approved to treat nausea and vomiting. But it's not clear why medical cannabis would decrease prescribing for depression and anxiety, given there's an association between at least recreational cannabis use and anxiety and depression. There is no association found with glaucoma and spasticity. Again, this is a little surprising because, as I mentioned earlier, nabixamols, a combination of THC and CBD, is approved by national regulatory authorities in other countries for the treatment of spasticity. Now let's turn to the potential for public health harms. The one of major concern is increased cannabis use or increased cannabis use disorders. And here, several epidemiologic studies do find an association with increased use, but by adults, not so much by adolescents. And the increase in cannabis use disorders may depend on how strict the state's medical cannabis regulations are. In other words, does it require a bona fide doctor-patient relationship? Does it restrict the recommendations to certain specific indications with a specialist doing the recommendations? Two other harms where there is some modest evidence are increased cannabis-associated motor vehicle accidents and increased unintended cannabis overdose. And I'll also address the potential concern that's been raised about increased crime around cannabis dispensaries. This, of course, is an issue that's long been raised around liquor stores and methanol maintenance clinics. So in terms of increased unintended overdoses, here's data from calls to Colorado poison control centers regarding cannabis intoxication between 2004 and 2014. And as you can see, around the time that Colorado legalized medical cannabis, there's a significant increase in such calls. This is mainly for children and mainly with oral cannabis or so-called edibles. And in fact, this trend has led to stricter regulations on packaging and labeling of cannabis products. Now, in terms of violent crime around medical cannabis dispensaries, here's data from a study in California, which used county-level data on whether they were operating cannabis dispensaries. And as you can see, over the four years after the law went into effect, there's no evidence of increased violent crime around operating medical cannabis dispensaries. If anything, there's a trend towards decreased crime, although it does not quite reach statistical significance. You see a similar pattern for non-violent crime and drug-related crimes. So no evidence to date that there's increased crime associated with operating medical cannabis dispensaries. So in conclusion, there's no high-quality evidence of causation between medical cannabis legalization and any public health outcomes, because most studies are epidemiologic. They study associations, so can't prove causation. And many studies have restricted timeframes and restricted populations. So we saw earlier in terms of opioid-related deaths that just expanding the timeframe to include more years flipped the observed association from a benefit to a harm. The observed association from a benefit to a harm. We really need our interventional studies that might prove causation. We do have evidence for some potential benefits, such as reduced prescribing of some medications. This might be evidence of cannabis substitution for other medications. And we have some evidence for potential harm, particularly increased unintended acute intoxication, especially in children and especially associated with oral forms of cannabis. And we have increased cannabis-associated motor vehicle accidents. So overall, I think we still have to be very cautious in approaching both the public health benefits and harms associated with medical cannabis legalization. Let me stop here. I thank you for your attention, and I will turn it over to Dr. Hill. Thanks, David. So I have about 25 minutes or so to cover the indications for medical cannabis, and we'll talk about the juxtaposition between where the scientific evidence is currently and where the state laws are. And as David mentioned, we have 36 states plus D.C. that have medical cannabis laws. We've got 15 states plus D.C. that have legalized the recreational use of cannabis. On this slide, you see my contact information below, my email address, social media. Disclosures were mentioned before. A couple of books that you can check out, one in 2015 on marijuana and then a 2020 book on medical cannabis, much of the topic that we're going to cover today in my allotted time. So what we're going to cover, really, three things. Number one, talk about the current laws. We'll describe what states have done in outlining their laws governing medical cannabis. We're going to talk about the state of the evidence, really the most important piece. Where is the evidence right now for the therapeutic use of cannabis for various medical and psychiatric conditions? And we will also take a detour into the world of cannabidiol or CBD, something that's been very hot recently. So we'll talk about the evidence for therapeutic use of CBD, but we'll also talk about the risks. And so at this point, we've got about this much interest in CBD, and we have about this much evidence. And so it's very precarious, the position we're in, and in the sense that people are talking about using it for myriad medical conditions. And while the evidence is limited, there is a growing body that describes, body of evidence that describes the risks. And so we'll cover that as well. Just a quick word about what I do, my background. So I'm a clinician, first and foremost. I direct the Division of Addiction Psychiatry at Beth Israel. I have a private practice in which I work with special populations, including pilots, athletes, and some other groups. I've done small clinical trials, looking at all three FDA approved cannabinoids that David mentioned earlier and that we'll touch on briefly during my talk. And then the last bullet is really what we're doing today, trying to bridge the gap between what the science says and what public perception is, really in all aspects of substance use disorders. But I think that when you talk about cannabis, there's no greater divide because it's so popular. And there's so many people that have political and financial skin in the game. And those folks are people who often will distort the evidence because they're trying to get people to vote one way or another. And as David mentioned earlier, more than half the country essentially has some form of cannabis laws in place. And so they've already voted on these issues or they're currently voting on these issues. And we get emails, the three of us, probably every day from people who were in states recently, Minnesota, West Virginia, et cetera, who are going through the same type of thing. And we'll talk about how we'd like to see some of those laws perhaps change, thinking about where the science is. But unfortunately what you see when people are making these kinds of laws, again, people who have financial skin in the game try to distort evidence and get people to vote one way or another. And when the laws get passed, oftentimes they really aren't considering the evidence in the way that they should. A lot of times people are pressed for time and they are duplicating some of the mistakes that have been made and we'll touch on that. So when we talk about the debate, when we talk about really the three levels of cannabis laws, decriminalization, medical cannabis, legalized recreational cannabis use, you can have spirited debates and you can make good arguments on either side really for any one of those three things, particularly legalization. And David talked about some of those studies and how they may help and hurt certain areas. But I think what you can't argue is the fact that in the United States, the implementation of these laws has been sorely lacking. And that's unfortunate. I believe that we should be trailblazers when it comes to how to implement laws that give people what they want while mitigating risks. And unfortunately we really haven't done that for the most part. Think about legalization of recreational cannabis. One can make the argument while their policies are imperfect, Canada has probably done a better job than we have at this stage. And so I think we could do better. We still can. With states, as we mentioned before, still considering these types of policies, there's an opportunity for the laws to be better than they have been. And that really focuses on looking at where the evidence is, looking at previous laws and where they've come up short and how they can do them better. So let's talk about where the science is. Where is this, the scientific evidence for therapeutic use of cannabis? I've written some things on this. I think places where you could start, I mean, the books that we mentioned at the top, the 2020 Walters Kluwer book, there are some really nice freely available PDFs from the World Health Organization in 2018, the expert committee on drug dependence reviewed both therapeutic use of cannabis and cannabidiol. So that's a great place to start. These are a couple of papers, one that was in JAMA in 2019. Dr. Williams and I have written a fair amount on this. This was a paper on the bottom of this slide that came out in the Annals of Internal Medicine, which covers in a very superficial way, a lot of the important topics that people wanna know about, risks and benefits, how to treat cannabis use disorder, which isn't the topic for today. But there are plenty of places that you can start if you wanna become more educated. And I think you should really. This is not going away. If you've tried to avoid learning about cannabis to this point, there isn't much use in that. Your patients are probably asking you about it on a daily basis. David mentioned this earlier. We have three FDA approved cannabinoids now, Dranabolone and then CBD. It's worth pointing out that when we think about the cannabis plant, we've got hundreds of chemicals in the cannabis plant. We have over 140 cannabinoids. Those are chemicals specific to the cannabis plant. And so that helps you begin to think about why patients may see some benefit or perceive possible benefit when thinking about whole plant cannabis. If you have 140 cannabinoids in the cannabis plant versus any one of the three that are available to prescribers, you can begin to wonder, might a combination of cannabinoids outperform any one of the three that we've got? Cannabidiol, we're gonna spend more time talking about that later, but when you see the proposed mechanism, a negative L steric modulator, I think you begin to think about the many gray areas with CBD. There are many possible mechanism of action for CBD. Like I said, it sort of indirectly affects CB1, CB2 receptors. It's an agonist at 5-HT1A. It's an agonist at TRPV1. It's an antagonist at GPR55. So it's a very complex chemical. And I think that's another take-home message when thinking about cannabinoids, people try to simplify the topic. And of course we try to do that in a limited 75 minute allotment that we have, but it's a very complex topic overall. And that's why whenever people are thinking about using cannabinoids for medical purposes, no matter what cannabinoid they're interested in or a combination of cannabinoids, it should be done under the physician's supervision. I think that's something that's often lost. And we'll talk about that with CBD in a minute. So again, CBD is FDA approved for three seizure disorder conditions that we'll talk about in a second. When we think about the laws in the states that have medical cannabis laws, we're talking about particular medical conditions oftentimes in those states. So in my state, the Commonwealth of Massachusetts, we have eight debilitating conditions that include many of the conditions you see in the first bullet there. And these are serious medical conditions. And so I think that people vote for medical cannabis because they don't want to keep a medication out of the hands of a terminally ill cancer patient, for example. But you really should be thinking about what is the level of evidence for cannabis for each of these medical conditions. And so what you see in states that have these laws is that they have stipulated conditions, oftentimes where there is little or no evidence to support the use of cannabis or any cannabinoid to treat these conditions. I think that is an issue, unfortunately. And beyond that, and again, Massachusetts is an example, you don't have to have one of the eight debilitating conditions. In many of the states that have medical cannabis laws, there's a loophole. And so it says in the Massachusetts regulations that as a physician, I can certify my patient to use cannabis for any condition that I think it will be helpful for. I just have to state that when I'm writing that certification. And again, it's not a prescription, can't prescribe a schedule one substance, as David mentioned earlier, federally illegal, but you can write a certification to sort of endorse the use of cannabis for that patient. But that's a real problem that you'll see. So there is evidence, and we're gonna talk about it in just a second, for the therapeutic use of cannabinoids, including cannabis, but we have all these extra conditions in the states. When you look at these states, there's a core group of approximately 22 or so conditions that are consistently cited in the regs. But overall, there's over 50 conditions. So again, when you think about evidence for this many conditions, but we've got this many conditions and some of them repeatedly are stipulated and there really is no evidence. Glaucoma is an example. Conceptually, using cannabis can decrease interocular pressure, but, and there probably aren't any ophthalmologists that are gonna tune into this on-demand product, but no ophthalmologist is gonna recommend that somebody use cannabis to treat glaucoma. And yet state after state after state uses this as an example of a condition for which cannabis can be used. And it's just so unfortunate that continues to happen. David mentioned earlier opioid use disorder, no RCTs to support the use of cannabis as a treatment for OUD. And that's even more egregious because as we know, we know we're three addiction psychiatrists presenting today, those patients die. Patients who have OUD can die any day from an opioid overdose or other medical complications from their use. And so if you're going to choose to use cannabis or CBD to treat OUD, I think as a monotherapy in particular, I mean, that's quite a mistake, especially given the fact that the medicines that we have for OUD, the three FDA approved medicines that we have, buprenorphine, methadone and naltrexone are very effective. So you begin to appreciate how important these laws are and really why we need to improve. We can't keep making the same mistakes that we've made over and over again. And then the final bullet here, as we talked about whether or not there's evidence to support the use of cannabis for these conditions, most people don't have any of these conditions when they get a medical card. So there are very, very flawed. And that's what I meant when I said, there's a difference between an idea wanting to have people have access to cannabis where appropriate versus implementation where it's just a free for all. And as David also alluded to a lot of the ways in which these certifications are procured are highly problematic. You're not getting them from a doctor that knows you oftentimes. But where's the evidence? So talking about the levels of evidence, at the first point I wanna make, there are over 50 clinical trials of cannabinoids, including cannabis for a host of medical conditions. So you can look at it either way. That is a fair number of trials. However, again, when you think about the sheer interest and when you think about as on the previous slide, over 50 medical conditions, again, the level of evidence, the number of RCTs do not match the interest unfortunately. And there are many reasons for that. There should be research being done at a greater rate in a greater scale than currently is the case. And that's because a lot of people who are profiting from sale of cannabinoids, and that means states, that means many companies, they're not contributing to the science in any way. Because why would they if they're doing well selling it and profiting from taxes or selling a product? And so we're really not advancing the science in the way that we should. But where is the best evidence? And so according to me, paper I wrote in 2015 in JAMA, I said at the time, the best evidence outside of the FDA approved conditions that David mentioned, I mentioned a second ago are for chronic pain, neuropathic pain, and then spasticity associated with multiple sclerosis. And when I say best evidence, I'm saying that there are multiple positive RCTs. Could there be better evidence? Absolutely. But as somebody who treats these patients, I mean, I treat these patients every day. Not only, I mean, I treat patients who have cannabis use disorder as well, but in the next hour, I may have a 60 year old patient who has chronic back pain, and they've tried multiple medications and multiple injections, and they've been sent to me. And depending on the clinical circumstances, I may do this. And I think that having multiple positive RCTs allows that conversation to take place. There is some level of evidence. So I'm talking about more than half a dozen RCTs in each of these cases. And again, the sheer volume of evidence could be better. The quality absolutely could as well. Duration of studies could be better. Sample sizes could be better. I think we need to agree upon uniform outcome measures for these studies, but these are things that I and others are currently working on with various groups. So there's much room for improvement here, but there is some evidence. And don't just take my word for it. So in 2017, January, 2017, so also another thing to think about when we look at the evidence, my paper 2015, this report from NASM in 2017, they're starting to become dated. So now we're four years out from the NASM report. Are we gonna continue to advance the science? Are we gonna continue to report on it? So an excellent, lengthy report came out from NASM in 2017. What did they say? I quote, conclusive or substantial evidence that cannabis or cannabinoids are effective for chronic pain in adults, chemotherapy-induced nausea and vomiting. That's the FDA approval. And then patient reported MS spasticity symptoms. So echoing some of what I had written previously, also the whiting meta-analysis, a great paper, also in JAMA, she said moderate quality for chronic pain and spasticity. And so there's some disagreement, but I think the important takeaway here, not only as a clinician who may treat these conditions, but if you're somebody who may not, and you're just thinking about this big picture, again, there is some evidence. It's not zero. I think it's easy for psychiatrists, it's easy for addiction psychiatrists to dismiss this entire concept and just say, well, we know that cannabis is addictive. We know cannabis can be a problem for so many people. We're just not gonna entertain the possibility that it may be used therapeutically, but you can't ignore that really. I think that the evidence is growing. It's not just NASM, right? American Academy of Neurology. Other groups are acknowledging this too. Also acknowledging the weakness in the evidence that is there, but there is some evidence. So we have to do better. We have to find out more. If we had better studies on pain, for example, I think we'd have a better sense of whether or not this could really help and how and what patient population might be best for. So moving to CBD, I think it's important to talk about CBD these days because again, the interest is incredible. It's a billion dollar industry, companies. I hear from companies every day, people who are selling CBD products and also from patients who are using it or thinking about using it. There's a lot we don't know. So as David mentioned, it is FDA approved, but only the one version that's put out by a pharmaceutical company. So 95% of what people are using is not FDA approved. And so that's a real problem. Like I said earlier, the mechanism is disputed. You can talk to experts who work in this every day and they disagree. And even the company that is selling it is very particular about how they want the mechanism described, but the train's left the station, people are using it. So as I mentioned, only Epidiolex is FDA approved. It's very, very promising. So we'll talk about where the evidence is in just a second, but also critical to note that the majority of the evidence, the majority of the promise is preclinical. So these are animal studies. These are human lab studies. And so when you think about using a medication on a large scale with thousands of patients, you want randomized controlled trials. And that's another trend that's taking place these days where people are trying to more or less use various strategies to come up with consensus opinions on really anecdotal evidence or non-RCT evidence. And that's a dangerous trend, really. We should be striving to get RCT evidence when we can, and we can here. There's no reason that we cannot. But Pisanti is a great, it's another, if you want to start somewhere really looking at the evidence, Pisanti paper in 2017. As I mentioned earlier, the lack of regulation of CBD is a major problem. So it's not regulated, often mislabeled. So Marcel von Miller, who's a great researcher in this area published a paper in JAMA letter in 2017. And what he showed was that only 30% of commercially available CBD products are accurately labeled, only 30%. So you're either getting more CBD than you bargained for, or oftentimes little CBD or no CBD frequently. The Pocklist paper added a nice twist to it because they showed that not only can you get various ranges of CBD in these products, but you can also get other substances, including THC. So that's another major issue here. People who use, I mentioned earlier, I work with a lot of athletes and we've had many, many athletes, and this has been going on for years, unfortunately, where they're using CBD products and they're having positive urine drug screens. So that can happen. You have to trust the product that you're getting. And that gets to a lot of the regulation that the FDA provides. And so the FDA often malign, but they do, I think, a pretty good job of trying to protect patients. And so when you don't have that, and this is treated as a supplement, you've got a lot of issues here. And I think that's really the take-home point with CBD, a lot of promise, but you gotta be careful about it. And again, if you're going to do this, you gotta encourage your patients to use this under the guidance of physicians like you. So FDA approved for three epilepsy conditions, Dravet's syndrome, Lennox-Gastaut, and tuberous sclerosis. And that's based upon strong RCT. So when we look at how these things should be done, CBD is actually a great example, how you can do it. You can get indications from the FDA for specific conditions. And so the trials that were done for these conditions are outstanding, published in The Lancet, New England Journal of Medicine. So the best journal, so they, it takes time, but they had very rigorous trials. And so they got the FDA indication as they should. In addition to that, when we talk about other clinical conditions for which CBD could be considered, I think anxiety is one of them. So treatment refractory anxiety based upon a couple of studies. So again, not a huge amount of evidence, but if your patient has worked their way through behavioral interventions and medications, and you are gonna talk about the risk benefits, thinking about the possible side effects for CBD, I think treatment refractory anxiety is a place that you could consider CBD for. So Masataka in 2019 published a small paper on social anxiety disorder. Bergamashi in 2011, an older paper, they did a simulated public speaking exercise. So I think there is some evidence there for CBD. Schizophrenia as well. So when you think about the, you know, THC causing psychosis for some people, and then CBD functioning as a buffer of sorts with an antipsychotic characteristic. So it makes sense that there have been some studies. So as a monotherapy, Lewicki in 2012 published a paper that said that CBD can mitigate some symptoms of psychosis. A McGuire paper in American Journal of Psychiatry in 2018 showed CBD effective as an adjunct medicine for schizophrenia, but importantly, not all papers are positive. So Boggs in 2018, and I think it was pharmacology, it was a negative study. So as an adjunct to antipsychotic, CBD did not improve outcomes on the PANS, I believe it was. So it depends really if the patient has tried multiple medications here and you're struggling, maybe it's something to consider adding. If you think about that patient and potential side effect profile. Yasmin Hurd at Mount Sinai has always done very creative work. And so she's had really, she has multiple trials ongoing, but also published, I believe it was in American Journal of Psychiatry 2019, that CBD reduced opioid related anxiety and Q reactivity. So some promise there for CBD as a medication for substance use disorders, including OUD. But let's talk about the myths. There are many. And so people really don't talk about the potential problems of CBD. So I think it's great that we have an opportunity to do that in a couple of minutes. And so no evidence for using CBD for insomnia or THC. In fact, people often talk about using THC and CBD for this purpose. And so THC, in fact, like alcohol has been shown to decrease time in REM sleep. CBD, if you talk to experts, Ethan Russo, for example, they believe that, or he believes that the effects, the sleep promoting effects of CBD more have to do with what the compound is dissolved in, other chemo bars involved there. So really no evidence yet. And maybe at some point we'll see evidence, but we don't yet. The route of administration is important. So many people are buying topical CBD creams. They're not absorbed into the bloodstream. So they are perhaps effective local anesthetics like commercially available products that you can buy. And if that's what you're expecting, then great. But what I find is that I have patients who don't have a lot of disposable income and they have very high hopes for these products. And they go into dispensaries and other places. They spend a lot of money for really small tubs of this stuff. And there just isn't that level of evidence there. So you can go to the store and buy capsaicin products and probably just as good. And if topical CBD is better, then let's do the studies and show me that. So that hasn't been shown. Companies are making outrageous claims all the time. You know, CBD can protect you from getting chronic traumatic encephalopathy and things like that. And so, you know, there are preclinical studies that are promising, like I mentioned, but you cannot make these claims. And a lot of companies have been taken to task for that, but it's hard to sort of take it back once you promote it. And that's happened in many other areas too. So there are outrageous claims being made all the time about it. People sometimes believe when they talk about positive urine drug screens that CBD can convert to THC, that cannot happen. So if you have a positive drug screen for THC, you may have a CBD product that contains THC, or you may, a lot of people are using actually cannabis with, you might have a higher percentage than normal of CBD, but it has a lot of THC in it. So if you do have a positive THC urine drug screen, then you use THC, you didn't use a pure CBD product. So that does not happen. Other problems, so liver toxicity, I think an important paper people are not talking about came out in 2020 Watkins and clinical pharmacology and therapeutics. So in one of the open label trials of CBD, there were 16 patients, five of the 16 patients who used CBD in therapeutic amounts. So that's just another kind of segue I wanna talk about in just a second, if I can remember, but they used considerable amounts of CBD as you need to. And they did it over a period of two to four weeks again, which you also need to, to get therapeutic benefits. And they had ALT levels that were five times the normal limit. So just something to keep in mind that if people are going to use CBD, we use other medications that can affect the liver, but there are ways to mitigate the risk. Checking baseline LFTs, checking LFTs moving forward, but nobody's talking about it. So we have this paper, I mean, this is documented risk and nobody talks about it. So again, just kind of to finish that thought, if you are gonna use CBD, a lot of times people are buying products where they're using five milligrams, 10 milligrams, it's probably not gonna be a therapeutic dose. When we look at the trials that we've talked about for various conditions, including the seizure disorders, we're gonna be in the hundreds of milligrams. So that's something that people don't realize that it's something that needs to be titrated. You need to be on an extent, high dose for an extended period of time, usually. Other problems, people, the second bullet here, using CBD instead of evidence-based treatments. I've had this happen before where a patient comes in, patient who's had, a United patient who had ECT before and said, hey doc, you know, I heard about you. I know you're, you know, you're right about this stuff. I want to use an all natural product to treat my depression. I want to use CBD. I'm done with all this stuff, the medications and ECT, et cetera. That is not a good idea. So these are sometimes magical thoughts that people have about what these products can do. And it's just scary, really. But that's what's happening. And you may have seen it in your practice, but this is what's really going on. And then finally, even if you're going to do this, let's say you're going to do this for treatment refractory anxiety, and you're doing it under the guidance of a physician, it's going to be expensive. These are products that are not covered by insurance. You cannot get the FDA approved product approved for off-label use. You just cannot. I mean, I've tried many times in very serious medical conditions, people with serious medical conditions have not been able to get it approved. So if you're going to use CBD that you buy elsewhere, it's going to be expensive if you're going to use appropriate doses. So people need to know that. Drug-drug interaction. So this was a paper that came out last month, I guess, or maybe two months ago now, collaborated with the folks down in Mississippi who grow the marijuana, but their drug-drug interaction. So as we mentioned, CBD is FDA approved to treat seizure disorder. So it might stand to reason that it has drug-drug interactions with other medications, including benzodiazepines that you would use to treat seizures. And then other medications as well. The point is it has to be treated. If you're going to think about this as a medication like FDA approved medicines, then you also have to think about what are the other medicines my patient's taking? Our patients are often taking multiple medications and so for many reasons, it might not be a good choice. And so you have to consider these things. We just want people to be educated. And so if they decide to do this, they're doing it in a way that they're educated about it. That's really where physicians come in. I mentioned this earlier too. This is another paper that came out in the last couple of months, also in Annell's case study grand rounds paper, where again, we do review the evidence. This was a patient who had neuropathic pain, talking about pros and cons, about using cannabinoids of all sorts in this patient. And I think, again, we cover a lot of the important issues here that you have to really thoroughly think about the situation, what has been tried, what are the risks for this particular patient, comorbidities, other medications they take. And so there are times when I think you can do this, but it's not for everybody. So check that out. So overall, as we wind up, the policy is ahead of the science, and it pains me to say that. I've been saying it for years, unfortunately, that we really have not caught up to it. There's been an incredible amount of interest in the United States, and I can understand it beyond people who are trying to profit, but in terms of patients, they have medical conditions, they hear about promising medications and compounds, and they want to find something that's gonna give them relief. But we have to do a better job of helping them by advancing the science, educating people about the science, and hopefully incorporating that science into laws when thinking about what conditions should be stipulated for medical cannabis. So overall critical period, there is some evidence, it is not zero, but the use far outpaces the evidence. I think we're grateful that you tuned in today. You can do a great service just by knowing about cannabinoids and knowing about CBD. You can help a lot of people, you can help your patients, you can help your colleagues who may not be as informed. And then finally, we need research on this. We can do better. There's no reason that we should be having this kind of talk every year and saying that, yeah, we still don't know, still don't have great RCTs for cannabinoids, for chronic pain, for example, or neuropathic pain. I hope it changes. I'm collaborating with folks to try to change that. And I know there are other people doing that too, but it takes time to do that. So it would be great if there were more resources put toward that to try to advance that. That's all I have. I like to thank, this is my team here at the BI. This is my group. It's a lean group that treats a lot of patients with SUDs. So I'd just like to thank you. And I'd also like to thank David and Robin for inviting me. Thanks. Hello, everyone. Thanks again for joining us for this session. My name is Arthur Robin Williams. I'm an addiction psychiatrist on faculty and the Division on Substance Use Disorders at Columbia. For my section of the presentation, I'll be focusing on the clinical pharmacology of medical cannabis. This is an overview of considerations around dosing and strains of cannabinoid products, routes of administration, related pharmacokinetics, and possible drug-drug interactions, side effects. And if there's time, a brief case scenario at the end. So one important thing to be aware of is that even though there have been studies for quite some time at this point on the use of whole plant cannabis, and in particular of FDA approved cannabinoid products such as dronabinol and nabalone, there still is a really a lack in the literature of guidance on optimal dosing, especially for specific conditions for specific patients. Part of that is because if you were to think about whole plant cannabis, so these days with all of the products that are available, this is something that's more in the distance. In some states, patients still do receive whole plant cannabis from dispensaries, but in plenty of other states, they're not allowed to. But if you think about the cannabis plant itself, there are certainly well over 120 cannabinoids at this point, although most of the attention goes to THC, and in recent years, to CBD. As Dr. Grellick and Dr. Hill emphasized, we're trying to update the presentation to have more content around CBD, given the great volume of patient interest and use of various CBD products. In addition to THC and CBD, which are known as cannabinoids, there are many other potentially physiologically active substances in the plant, which is why some researchers or companies refer to the entourage effect, meaning that it's not just THC potentially that holds promise for some patients or some conditions. In addition to THC, CBD has received a lot of attention. As Dr. Hill pointed out, it may have the antipsychotic, anti-THC, anti-seizure properties. Clearly, it now has a strong evidence base for anti-seizure properties, but the evidence is a bit more mixed on many of the conditions or symptoms that it's promoted for use in particular, whether it's psychosis, as you just mentioned, anxiety, sleep, there's not a strong evidence base. One thing to know in terms of CBD and THC is that they share a common precursor in the plant. And so in general, as THC strength is bred to be higher, not always, but in general, it means that the CBD strength will begin to be depleted in the plant. Just some examples of ratios of wild-type cannabis plant. So what is a standard dose? Initially, when Washington and Colorado legalized adult recreational use of cannabis, they set a so-called dose of THC as 10 milligrams. Meanwhile, initially, Oregon chose five milligrams. So this is where, unlike alcohol, for instance, where there is an internationally recognized standard drink equivalent. With cannabis, we don't have that. With THC or CBD, we don't really have that. So some data points to consider, Marinol, which is dronabinol, synthetic THC, which is FDA approved for nausea, vomiting, AIDS-related wasting syndromes. That's produced in two and a half, five milligram and 10 milligram doses. Meanwhile, Nabilone, which is also a synthetic THC analog, which is more potent than dronabinol, is produced in one milligram doses. And this might be dose BID or TID, depending on the condition. Dr. Hill pointed out with CBD studies, that they're often using doses in the 400 to 800 milligram range. So it would really be a mistake to conflate THC dosing parameters with CBD dosing parameters. They're very different in terms of the doses required. Thinking about the use of whole plants, so back in the old times when people smoked joints or blunts or used bongs, so to speak, we're thinking about whole plant marijuana that's being consumed. And if you were to think about a typical joint that would have about 0.66 grams of plant material with potency of 8% THC, that would yield about five milligrams of THC. Of course, these days, most users are using THC that is at least 15 to 20% strength, and that would yield closer to 10 to 13 milligrams of THC. For reference, occasional users, so not naive users, but occasional users of marijuana or cannabis report feeling high from just exposure to two to three milligrams. So for THC, five or 10 milligrams certainly would be physiologically active, psychoactive. One important thing to be aware of is that vaping versus smoking cannabis yields very different levels of THC absorption. Vaping is a much more efficient way of consuming cannabis because it does not incinerate the plant material. It heats it to a level where the cannabinoids are released for inhalation. So dosing guidelines, as you can imagine, are to start low and go slow. And for adults, healthy adults, that would typically mean around five milligrams, perhaps 10 milligrams. But especially for older patients or cannabis naive patients, it's likely that you'd want to start with a much lower dose of cannabinoids. And you'd want to titrate towards the therapeutic effect while keeping an eye on adverse effects, side effects, mental health effects that I'll discuss in more detail later. One thing to be aware of is that the elderly and people who have not had prior cannabis experience may find it dysphoric, uncomfortable, disorienting, unpleasurable. So as with many intoxicants or classes of drugs with addictive liability, although there are a subset of people who find it addictive and run into trouble with controlling their use, there are also a subset of people, typically upwards of 30% or so, who don't enjoy it, who don't like it. This is true for alcohol, opioids, benzos. It's also true for cannabis. So even if we think of using cannabis for medical purposes, there are some people who may not be able to tolerate it in addition to those to go on to have side effects or mental health effects. That being said, the great majority, and this may be changing, especially in states with more medicalized programs, but historically, the great majority of patients who begin to use cannabis for medical purposes have histories, if not active histories, of recreational use. Why do people use medical cannabis? The great, great majority of people report using it for pain syndromes, whether it's a severe pain, injury-related pain, lower back pain, neuropathic pain. Another prominent reason is spasticity related to multiple sclerosis. And in more recent studies that have been more nuanced in terms of trying to assess daily users or near-daily users' use, there are also a lot of reports of using cannabis, whether the respondent deems it medical or recreational, but using cannabis for anxiolysis to help with sleep, to help with mood symptoms. This graph is from a study by our team at Columbia's Eva Cooper McHaney, looking at the synergistic effects of combining low-dose cannabinoids with low-dose opioids. And the point here is that subtherapeutic doses of either, when combined, actually have superior analgesia. So there's certainly an interaction in terms of pain relief between cannabinoids and opioids. This is part of what contributes to theories about cannabinoids, cannabis, possibly being opioid-sparing, whether this would allow people on higher-dose opioids to decrease their dose, or for patients on opioids who have refractory pain, if they were to introduce cannabinoids, that may prevent dose escalations of the opioids. Much more is needed to be studied here. Dr. Hill referenced a Yasmin Hurd study finding that there may be some benefits to patients with opioid use disorder in terms of withdrawal when exposed to cannabinoids. In our lab, we had looked at using Marinol for dronabinol for patients, for instance, with opioid use disorder, trying to induct successfully onto Vivitrol or looking at relapse. And we found that there was some symptom relief while using dronabinol. However, it didn't change self-administration of opioids. So there are some positive signals at the same time. Clearly, it's way premature in terms of thinking about opioid addiction for using cannabinoids as the primary treatment, although it may help with symptom relief for some individuals, depending on where they are in their treatment. I would say overall, there's a much greater appreciation in the scientific community and in the literature for interactions, strong interactions between the endocannabinoid and endogenous opioid systems. I think at this point, most people are familiar with these many different kinds of products. And that's part of why earlier in my section, I was emphasizing whole plant cannabis versus what's available on the market today, whether for medical use or recreational use. For those who aren't familiar, many dispensaries in the states that allow for both medical or adult recreational use, the dispensaries often have one door on one side for medical, one door on the other side for recreational. And the products are not necessarily any different. Some states require, have more restrictions on the medical products. But the point is that at this time, patients often have dozens, if not hundreds of products to choose from with different ratios of THC to CBD to many other cannabinoids that we would be less familiar with that certainly have been less studied, THC, ATHCB, and so on. So if you think about routes of administration, some of this is likely obvious, clearly oral ingestion of edibles, candies, drinks, anything that's orally ingested would have a slower onset, typically 0.5 to one hour. For others, it may be several hours. And it can last, the textbook may say four to 12 hours. For some individuals, it may be much longer. And for those who have worked in psych emergency rooms or other ED settings, you likely have seen people at this point who have ingested, whether for medical or recreational purposes, ingested edibles and remain psychotic for 24 hours, 36 hours. So for most people, it may be a span of four to 12 hours of activity, but there's certainly with higher exposure of oral ingestion, the possibility that this could last for a very long time. Vaporized or smoked, although in some states, New York, for instance, smoking of the products for medical use is not allowed, is going to have a much quicker onset of action. This is part of the justification for allowing vaporized use of products, especially for instance, for pain patients or people who have a difficulty tolerating oral ingestion that having vaping as a route of administration can help them titrate their use. Whereas for instance, with oral, if the onset takes an hour or two, three, four hours, it can be much more difficult for people to have a sense of how much to use on a given day based on their symptoms or their condition. Dr. Hill was pointing out that transdermal has very little scientific data behind it. This is certainly true for CBD and for transmucosal or sublingual use, this has been approved. There's a strong evidence base for nabixamols, but all of these different routes are worth thinking about in a nuanced way when advising patients about what they're using. And if it's not clear, often dispensaries are suggesting that patients, if they have the money, purchase multiple kinds of products. So you might have a patient who's advised at a medical dispensary to use something sublingually TID, but then if they have breakthrough pain, that they might use a vape pen where they can have a cartridge in it. So remember that patients may be using different products with different routes of administration simultaneously. In terms of the PK here, this is a visual showing IV and smoked, very similar versus oral time of activity. And part of that is also to emphasize here, this may be difficult to see on the screen. So I added a green dot. This is showing the difference, and it's really a tremendous difference between ingestion of cannabinoids, in this case, THC at the top or CBD at the bottom, while in a fasting state versus a fed state. So remember that cannabinoids are highly lipophilic, and for people who are eating food, especially fatty foods, the C-max, T-max, and area under the curve are dramatically higher than for individuals who may consume edibles in a fasting state. And this is something people really don't talk about, clinicians aren't really aware of, and it's worth keeping in mind in terms of advising patients, especially elderly and firm cannabis naive patients in terms of how edible is the route of administration or oral ingestion may impact their exposure. I'm gonna move to drug-drug interactions. I know Dr. Hill at least referenced some of these, and it's not really clear how clinically meaningful some of these drug-drug interactions are. At the same time, especially in theory for some patients based on their genetics and their liver enzyme activity, this may rise to the level of clinical meaningfulness in terms of patients who may have, for instance, who are already on one or more psychiatric medications, that you may find their response either improves or worsens based on adding a cannabinoid, whether it's THC or CBD. For instance, both of them are metabolized through 3A4 and 2C9. 2C9 is an inhibitor of, whereas in CYP1A2, they're inducers. So if we think about how this could impact commonly used medications in psychiatry, I think a lot of the medications on this slide are familiar to everyone. So THC being a 2C9 inhibitor may impact the clearance of fluoxetine, fluvoxamine. THC is a 1A2 inducer, so that could affect caffeine, clozapine, duloxetine hormones. So the point here is not that it's, there isn't a strong evidence base in terms of how to change the dosing of these common psychiatric medications. I am emphasizing, though, just to be aware that especially this short list of medications could have drug-drug interactions when introducing cannabinoids into the regimen. In terms of contraindications, so it's true that cannabinoids, cannabis has a relatively safe profile, especially in terms of, clearly there's not overdose risk related to the singular use of cannabinoids. There often is not physiologic harm beyond upper respiratory infections, for instance. At the same time, it can have cardiac effects. So patients with cardiovascular disease who have had a history of heart attacks or at risk for heart attacks or arrhythmias, it is something to be cautious. Clearly there are hazard risks with intoxication or cognitive impairment. So thinking about anyone in a safety-sensitive job, implications for workforce, drug testing, and pregnancy and breastfeeding are contraindications. Clearly there are, and if anything, the literature has shown that in recent years we have many more individuals, women, who are using cannabinoids while becoming pregnant or breastfeeding. At the same time, the medical associations are consistent in advising against it. I'll speak more to that in a second. I touched on the physical side effects are mostly related to the upper respiratory system. There are also psychiatric effects. And while patients may say that they use cannabis or cannabinoid products to help with anxiety or insomnia, often over time, and this has been investigated from several different directions, patients who continue to use cannabis over time tend to have worsening of anxiety, worsening of depression and mood symptoms that may complicate PTSD symptoms and treatment. So there's certainly beyond paranoia and psychosis, other more subtle side effects or mental health effects that may accrue over time. There is a very real risk of cannabis use disorder or cannabis addiction. The textbook numbers are 9% for adults, 17% for those who begin regularly using as adolescents, but more recent national surveys have suggested that among daily users, it may be closer to 30% or more of individuals who meet criteria for cannabis use disorder. Pregnancy, as I mentioned, and breastfeeding, it's recommended not to use cannabinoids. This is a study that looked at outcomes among neonates and not a huge effect, but it's certainly suggestive that there may be more neonatal morbidity among neonates born to women who'd been using cannabinoids during pregnancy. This is mostly related to infection risks post-birth. So we have just a few minutes. So I'll touch briefly on this case. This is a sort of a generic or stereotypical young male who has anxiety, some initial insomnia, asking for medical marijuana. He heard from a friend it works better than the SSRI that he's on. And the clinician in this case is apprehensive about what it would mean to recommend it to this patient. So he says, fine, I'll just go to a state where I can buy it for recreational use. And this touches on a lot of the points that we've brought up over the course of the session, that one key thing to emphasize is that we don't yet have a psychiatric indication for cannabis use, certainly for whole plant cannabis use. The evidence isn't there yet, and there really is a need for much more research. There are lots of concerns here. Proceed cautiously. At the end, in terms of our roles for caring for patients, it may be that some of you already are or want to become authorizing clinicians, physicians for patients' use of medical cannabis. At the same time, you might not be comfortable with that, or it may be outside your area of expertise, but you would still want to be aware of what your patient is using as with any other prescribed medication. And you may also find it's very beneficial to be able to counsel your patients on these options, even if you're not the person who's authorizing the use of medical cannabis. So in conclusion, often we're talking about the horse already being out of the barn, this being the wild west. There really are many products and formulations across the country. There's a total patchwork of state laws that are constantly changing, if anything, changing very rapidly. And there's a lot more that hopefully will come to learn. References here. So thank you all for joining us for this session. We appreciate it. ♪♪

medical cannabis

legal status

public health consequences

medical indications

scientific evidence

state laws

clinical pharmacology

doses

cannabinoids

research

safety