Well, good afternoon. Welcome you all to session 1051 Is this bud for you the science of medical cannabis? I'm David Goralek the chair and also I'll be presenting from the University of Maryland in Baltimore The two other speakers to my left. Dr. Kevin Hill From Beth Israel Deaconess Medical Center and Harvard Medical School and to his left Dr. Smita Das from Stanford University and Lyra Health I May briefly go over the agenda after my brief introduction Review the history current legal status and give you some idea of the epidemiology of medical cannabis in the u.s Then dr. Hill will speak on the qualifying conditions for medical cannabis which vary by state because it's a state regulated issue not federal and discuss the scientific evidence Versus the current state laws Then dr. Das will review the practical clinical pharmacology of medical cannabis Issues like what doses strains ruse administration drug interactions We're not saying you should or shouldn't Recommend medical cannabis, but if you or your patients are discussing it, here's what you should know If you're deciding whether to go ahead and that will include a few hypothetical case scenarios which Based on past years, we won't have time to discuss during her presentation, but we'll Discuss them during the question-and-answer session And then finally I'll wrap up with a brief overview some of the highlights not a comprehensive review of the public health consequences of legalizing medical cannabis in the u.s. Both the harms and the potential benefits and then we'll have the question and answer oh And of course we all have disclosures to make I Get speaking fees from hospitals and organizations for talking about cannabis in general and medical cannabis in particular I get royalties from Walters Kluwer for writing the cannabis articles for up-to-date and That's a meaningful COI because I get paid by the click. So if you click on the cannabis articles, I have a cent or something I Also get a fixed honor area from Springer nature and Colorado State University Pueblo for serving as editor-in-chief of the Journal of Cannabis Research dr. Hill also gets paid for speaking at hospitals and organizations for presentations on medical cannabis He gets consulting fees from the National Football League and has written at least two books on the subject of cannabis for which he gives royalties from Hazleton press and also Walters Kluwer and Dr. Das has equity stake in is employed by lira health, which I believe you actually co-founded Let's see Okay, so let's briefly review the history current legal status and Epidemiology of medical cannabis. So here's a very compressed to circle outline of cannabis use And we have archaeological and some written evidence going back almost 5,000 years for its medical use in China and in South Asia And continuing up through the Mediterranean region Greece and Rome But medical cannabis really came to Western by which I mean European North American attention In part through the work of a British Army survey Surgeon, dr. William O'Shaughnessy who served in India and saw a medical cannabis use by the indigenous population, so he brought it to To Britain and then it spread throughout Europe it was used in the United States. It was actually in the pharmacopeia And you know widely prescribed for a variety of ailments obviously in those days with little or no explicit supporting evidence and then for what I'll briefly call sociopolitical reasons it was made illegal Indirectly at first in 1937 by putting a very high tax on prescribing or selling it And so it became impractical for physicians to prescribe it or pharmacists to dispense it and then explicitly in 1970 with the Controlled Substances Act, so That law actually set up a scientific committee For a review process to decide what schedule the various psychoactive substances that were of general concern at the time Should go in. Cannabis was an exception it went through that review process and the committee actually, I don't actually remember what lower schedule they Recommended but the President at the time decided that it would go in schedule one So that was done by administrative order And so there it remains to this day Well a lot of order, but I'll get back to what that means in a moment, but first let's go ahead to the epidemiology so It still remains in schedule one effectively illegal, but the u.s.. Being a federal system I see it, but Anyway what this slide shows is that since 1990? Since 1996 when I think California actually was the first state to legalize medical cannabis 41 states and territories there we go I Should use this and not the computer. Sorry about that my technical error So currently 37 states the District of Columbia in three Territories Guam u.s.. Virgin Islands and Puerto Rico Have legalized medical cannabis actually This spring several other state legislatures are considering it so by now this slide might have to be updated No states legalized last year though So here's a map Of the situation as of February So in addition to the 37 states that have legalized medical cannabis We're not going to talk about this, but for completeness sake I'll mention that 21 States have legalized recreational so-called adult use Cannabis which means you don't need a doctor's recommendation. You don't have to go through any Pseudo-medical process to get it to buy it Cleaning my own state of Maryland which passed the law just a few months ago. It takes effect July 1st Now there's another 10 states That have what's called CBD oriented, and that's largely because of the interest in Cannabidiol as a treatment for childhood seizures which dr. Hill will talk more about later So 10 states do allow CBD sales, but not High THC you know the type that you'd buy if you wanted to get high So If you take those into account they're really only three states, Idaho, Wyoming and Nebraska that have no type of medical cannabis program This map is incorrect, South Carolina is in orange, but actually does have a CBD low THC program So getting back to the legal status as I mentioned The cannabis plant and all cannabinoids that are in it or made from it are illegal to possess sell or dispense as schedule one of the CSA and There is legal definitions. That means there's no currently accepted medical use in treatment in the United States There's lack of accepted safety for use under medical supervision and a high potential for abuse So what I stress is these are legal determinations and legal statements It doesn't necessarily mean that the current scientific and medical evidence Supports those statements as you'll hear shortly Synthetic cannabinoids what used to be called spice or k2 on the street Again, we don't have time to discuss them are also in schedule one illegal to possess or sell But since 2018 with the farm act has been an interesting loophole. So If you go back to the history slide There's been a long history of the fibers from the cannabis plant usually called hemp having industrial uses ropes sails For ships often made from cannabis fibers or hemp also the seeds a very nutritious high in oils and protein Used in many countries for animal feed and so on So in the 2018 from law hemp defined as a cannabis plant With less than 0.3 percent of THC content is legal. It's not under the jurisdiction of the Drug Enforcement Administration It's not considered a scheduled Compound and that's why you see legal can have a dial being sold in theory It's derived from a hemp plant not a cannabis plant. So it's perfectly legal The current uncertainty of the law is what about other cannabinoids That come from hemp like Delta 8 Delta 10, which you may have heard about again. You don't have time to discuss that today And that's a gray area the DEA goes back to the original definition that I mentioned anything coming from the cannabis plant is illegal But some attorneys differ So we have the curious situation that can have a dial if it comes from hemp is legal in the u.s But any other source is illegal Now In practice though the US federal government does not prosecute a state authorized state legal medical cannabis program As long as it meets certain administrative Requirements so that used to be an official Department of Justice policy that was actually revoked in 2018 But it's followed de facto you by the current Attorney General, but it's backed up only by statements before Congress not an official Memo, but there is a law So far included in every u.s. Appropriations bill. I don't know what will happen this year there's other controversies about government appropriations bills, but That Congress puts in a rider that prohibits the Department of Justice for using any funds to prosecute State authorized legal cannabis industry. So either users growers producers and so on Also, you're protected under a circuit court decision of 20 years ago free speech grounds For discussing or recommending or certifying medical cannabis with your patients So you don't have to worry about prosecution for that That was a concern at the time because we all depend on the federal government the DEA to get our DEA licenses So we prescribe scheduled compounds wouldn't want to lose that Now again another kind of interesting quirk is we actually have three cannabis compounds that are legal went through the standard FDA review and approval process So we have synthetic THC As long as it's synthetic doesn't come from the plant. It's legal It's called or dabbing all generic name and they have two companies that make marinol and syndromes that's under schedule three then we have a synthetic THC analog nabalone schedule two and Can have a dial extracted from the plant. So it's actually not synthetic brand name at PD Alex, that's Actually no longer scheduled at all and Approved for treating a certain attractable childhood seizure disorders now not in this country But Canada and several countries in Europe we have a plant extracted combination of THC and CBD called in the big civil Which is approved in other countries for muscle spasticity and pain from multiple sclerosis So Unfortunately, this is a somewhat complicated area to discuss as you'll hear from the other speakers because there's no uniformly recognized definition of medical cannabis the cannabis plant itself contains hundreds of Probably active compounds many of them not even studied Scientifically besides the cannabinoids we have the terpenes which contribute to the scent and flavor of cannabis Plant products and flavonoids which are found in all over the plant kingdom Now also the different cannabinoids the ones we've studied extensively have different effects. So it's Delta 9 THC that causes the subjective effects euphoria sedation anxiety and odyssea that most recreational uses at least one can have a dial while psychoactive is not euphorgenic so you can't get high from it and Recent studies have shown it doesn't impact driving ability. For example the way THC does But it is anxiolytic analgesic and anticonvulsant And an issue again, we probably won't have time to discuss but it's been raised in the field does cannabidiol somehow Ameliorate some of the subjective effects of THC So, you know mellow out THC that's why they believe it on the street But the scientific evidence from controlled studies is actually kind of mixed there Certainly many studies that show it does not Okay, finally the epidemiology so we don't have precise figures because Of course, it's illegal federally and in some states and people have concern about being in a registry It certainly can still affect your employability and eligibility for certain government benefits, but 27 states do keep registries and Those states have 3 million registered patients But it varies widely and I don't know the reason for this is anybody here from, Oklahoma I'd be interested in hearing in the question period So almost 10% of the population of Oklahoma is registered as a medical cannabis On the other hand and I'm sure many more actually use but don't want to get registered Whereas only 0.4 percent of North Dakota is Regardless that's more than a fourfold increase When somebody counted up the registries in 2016 and that was of course with only 20 states But using other guesstimates the marijuana policy project there are five and a half million Registered patients as of two years ago in all at that time 36 states where it was legal Again, nine point three percent of Oklahoma, but overall about over two percent of the population of those states So it's not a trivial issue And just to briefly As an introduction to dr. Hill's talk by far the major reason people say they're registered to use medical cannabis Is either cancer or pain and by cancer we mean the symptoms like pain nausea and vomiting that it's not disease modifying At least not in people And it followed by epilepsy and multiple sclerosis It's also not a distinct population so several surveys estimate about 40% of medical cannabis users also use cannabis for non-medical or what I'll call recreational purposes and Conversely about 40% of recreational users say that they do also use it sometimes for medicinal person purposes again mainly for pain insomnia and anxiety And as a practical matter in states that have both the medical cannabis users tend to gravitate to the recreational dispensaries for Seemingly obvious reasons you don't need a physician referral saved on costs and you have a broader selection of products So there's been some concern in the public health terms that legalizing recreational cannabis will actually Be detrimental to the medical cannabis users and you see that Recreational When recreational use is Is legal the medical cannabis registration is not increasing as it is in other states And this is an example so the Red Lions, Oklahoma and for some reason you can see the great boost in medical cannabis registration whereas other states On the left panel, which are the recreational states all states have had very stable medical cannabis registration So Let me stop there. This is my talk at the end and I'll turn it over to dr. Hill to talk about the evidence And I mentioned we'll save all questions for the end Okay, dr. Hill So just want to thank everybody for coming I know there are a lot of choices that you can make today There are a lot of sessions going on that seem pretty interesting There's one about fanaticism and the Joker going on right now that you've chosen this over So and if you feel like you want to take off for that one because you didn't know about it That's okay, too. But I also wanted to thank David for organizing smita for joining us My contact information is there feel free to think of me as a resource moving forward if you have cannabis questions we've got 20 minutes or so to cover really the issues related to therapeutic use of cannabis and then specifically is there evidence for Cannabis and cannabinoids for psychiatric conditions, then we're gonna throw in a little bonus Talk about CBD. So David mentioned my disclosures a couple of books on Cannabis and I'm the co-chair of the NFL pain management committee So I think when when you talk about cannabis to me, I think that you can have legitimate debates about whether or not Certain policies make sense, right? So decriminalization legalization of recreational use of cannabis medical cannabis So, you know, how are those things going to be implemented? I think is the real issue But you know, so why you can have good debates about whether or not they make sense I think what is not really a debate is that in the United States in particular the implementation has been poor and I think you know, it's been around for a long time, right? So California had medical cannabis in 1996 and I think one of the issues has been Really there haven't been a lot of edits made to the policies that have been implemented I know that some states are interested in this I just had a meeting on Friday with some folks from Massachusetts to try to Strengthen the policies that we have but I think to me there is a real difference here between ideas and implementation on these policies But what we're going to talk about really is where is the evidence for therapeutic use of cannabis and then specifically as psychiatrists thinking about? Your patients asking you should I be using cannabis and a lot of times they're already using Cannabis CBD other cannabinoids to treat psychiatric conditions. So where is the evidence trying to arm you with? some evidence for those conversations as David mentioned I think it's important to start with what is available and a lot of times When you think about using cannabinoids therapeutically there are options to go through the FDA approved route Right, so I have a in my division We have a cannabis clinic and so in one hour might treat 20 year old person using cannabis multiple times a day Meeting criteria for a cannabis use disorder and the next hour. I might sit down with somebody who is in their 60s They've got chronic low back pain. They've tried multiple medications and injections and they're wondering about cannabinoids and in that case You don't have to jump towards Writing certifications for medical cannabis. There are options And so again, you should know that dronabinol you've probably heard of nabalone is a cb1 agonist Maybe you're less familiar with and they're FDA approved for two one of two things nausea and vomiting associated with cancer chemotherapy and an appetite stimulation certain wasting conditions like HIV and then as David mentioned also Epidiolex is FDA approved since 2018 for three seizure disorders And so, you know one point that I like to make when you think about that Recent approval relatively recent approval is that you can do this in a rigorous way it has been done So one of the things that comes up when people and again, there's so many Zealots on both sides of this debate a lot of times when people are looking to use medical cannabis for a given medical condition They will say well there isn't you know, they haven't done the research yet, but I still want to go ahead and do it Well, you can do that research and when you talk about the barriers to the research and this comes up a lot I do think as David alluded to the scheduling matters It is a barrier, but I don't think it's the biggest barrier to me I think the biggest barrier is the amount of funding that goes towards it and the stakeholders So the states that you live in that I live in are making a lot of money in Taxes and that money by and large is not going back into the research and there are you should also Recognize that there is a distinction made somebody can offer and have a research program, but it's sort of their In-figure only right? It's just there because they want to say they're not really putting a lot of effort towards it So I think that's been you know a large Problem here in addition the people that are making money selling these products. They're not really interested That's something that I've seen in my work with the NFL. A lot of people wanted to partner with the NFL in selling CBD products, for example. We talked to hundreds of groups, but when you talk to them about do they want to do rigorous science to find out does CBD work for a given medical condition, then a lot of those folks really aren't interested at that point. This is a paper we published last year in Psychiatric Clinics of North America, and I'll be referring to it a little bit. And really what we're trying to do, David and Malik Burnett and I, we're trying to look at whether or not the medical cannabis laws in the United States are becoming more tightly tied into the science. Has there been progress in that way? And David mentioned this too. I think that we have to understand wherever you are on this issue, you should recognize that the train's left the station. This is where things are going. People want this. So I think it's important to think about from a clinical perspective and a policy perspective, how can you give people what they want while mitigating risk, right? Certainly there are clinical discussions that need to take place. Is this the best treatment for a given medical condition? But when it comes to policy, you have to recognize this is where it's going. So a lot of times a sensible conversation about cannabis or cannabinoids might increase the likelihood that someone's gonna accept an evidence-based treatment that is not one of those things. So that's something that I often encourage. And so what we saw in the study that in the states that have medical cannabis policies, there are a lot of the same conditions, right? 42 conditions overall, but there's probably a core group of 10 to 20 conditions. A lot of those conditions have zero evidence. So again, another take-home point here is that there is some evidence for therapy use of cannabis and cannabinoids, but it isn't nearly as much as some people would like to project. So the number of qualifying conditions per jurisdiction was five to 29 or so. And so we're gonna refer back to that. But I also wanna mention that when it comes to the best evidence outside of the FDA indications, to me, I think the best are really in three areas. When I say best evidence, I'm not saying that this is rock solid evidence, but I'm saying it's enough such that if I have a patient come to me with one of these conditions, and hopefully they're not coming to me for spasticity related to MS, I'd like to have them see a neurologist, but if they were coming to me for one of these conditions, I think it's worth having that conversation. There's enough. There are positive RCTs for chronic pain, neuropathic pain, and spasticity such that I think you can engage in a legitimate conversation with them about whether or not these treatments make sense. And a lot of times for me, it might be a third line treatment, maybe, in certain circumstances. And so this was another paper we published at the tail end of 2021, where we looked at the topic we're gonna focus on today. So for psychiatric conditions, where is the evidence? Because again, like I said, so many people believe that cannabis or cannabinoids may be helpful for a host of psychiatric conditions. So let's just take a look at the evidence briefly. So for anxiety, one of the main reasons a lot of people say they use cannabis, there's limited evidence of efficacy. So 31 studies, 17 RCTs, it's a nice meta-analysis by Black et al in 2019 that looked at this. So there is some evidence for certain anxiety disorders, and there's also a theoretical basis for some others. We'll talk about PTSD in a second. But as is often the pattern here, there really aren't specific rigorous studies done looking at medical cannabis for anxiety disorders. So then the question becomes, how much evidence should you have before you use a given treatment, right? And so I think that's one thing that you see with cannabinoids. A lot of patients are willing to go ahead and do that without much evidence. And I think that has led to a lot of the products that we see that are available, right? You know, in other talks, I will talk about sort of this cannabinoid playbook that I refer to, where people can come up with a new cannabinoid, and if they're really good at marketing it, they're gonna have a lot of success selling it. And then the question is, how much staying power does that cannabinoid have? I think a lot of people misuse the cannabinoids. The doses aren't correct. We're gonna talk about CBD in a couple of minutes. And I don't think that they're gonna continue to buy those products unless they really believe in the placebo effect. But you can get a lot of sales if you are smart about how you do this. If you have, whether it's CBG now, or your THCA, right? I get emails every day about these things. So people do a good job of marketing, and that becomes a problem for psychiatrists, right? Because your patients are using these products. For post-traumatic stress disorder, again, very common that many groups, including veterans, talk about using cannabis for PTSD. The evidence, there's not a lot of evidence. The evidence that is there, we grade it as a moderate level of evidence. 13 studies, two RCTs. The most famous RCT, the one that you should know about, is the JETLI study. So that was Nabolone, which I think also raises the question, if you have a positive Nabolone study, what does that mean? Are you gonna extrapolate that to whole plant cannabis? Right, I think that you have to be careful about that, certainly, but patients are often willing to do that. I should also mention that beyond the RCTs, there are some nicely done studies that are negative. Right, so Marcel von Miller's group did this crossover trial, where they had folks using whole plant cannabis. That was negative. And then the nice Sam Wilkinson observational study, looking at over 2,000 veterans. So that study showed that cannabis use was associated with worse outcomes. So again, association study, certainly we're gonna preface it that way, but it's a nicely done study, large sample size. So overall, I think, in the interest of time, I think if you're thinking about cannabinoids for PTSD, Meg Haney and Eden Evans published a nice paper that you could look at, which kind of says that if you're gonna pick a cannabinoid with the most promise for PTSD, it probably is cannabidiol. But the evidence is not great. And so, I think this is an example where people are hoping, a lot of people are suffering out there, they're hoping for effective treatments, and veterans in particular are latching on to cannabis. And I think that the pro-cannabis groups and also people who sell these products are kind of cheering them on in that way when they're talking about the ability to use cannabis for PTSD, when really the evidence is weak. Depression, I mean, it's kind of a non-starter, right? In fact, when you grade the evidence, there's limited evidence of harm, in fact. None of these studies looked at primary depression. None showed benefit. So that should be an easy conversation to have. It is rare that patients will say that cannabinoids help their mood, but we just want you to know what the evidence says. Terms of cannabis use disorder, no medical cannabis trials. All the FDA-approved cannabinoids have been studied in well-designed trials. So the Dronabinol study, Dr. Levin in the audience, as a matter of fact, so that study showed better treatment retention, less withdrawal than placebo. So reason to be hopeful about the concept of cannabinoids as treatments for cannabis use disorder. Of course, there are no FDA-approved treatments for CUD at this point. And then the Tom Freeman, their group from the UK looked at CBD. And note, as sort of foreshadowing for our CBD slides, 400, 800 milligrams safe and more efficacious than placebo. So that's sort of setting the stage for the idea of dose. Everything related to cannabinoids is the dose is important. As I like to say, the dose really matters when it comes to adverse effects, when it comes to therapeutic use. So clearly, even with CBD, that's important. For OUD, I think there's an extra layer of danger here. It's so important to talk about the idea of how cannabinoids could fit in, possibly as a treatment for OUD, which is a life-threatening condition. We have 2,000 deaths every year in Massachusetts related to opioids. So Yasmin Hurd at Mount Sinai has done great work. Human lab studies, again, 400, 800 milligrams of CBD. Reduction in craving and withdrawal symptoms for OUD really hasn't been studied in RCTs yet. I know some groups are doing that. But to me, I think you really have to think about what that role will look like if there is more data here. And it would be as an adjunct treatment to the medications for OUD that we have. Three FDA-approved medicines that are really excellent medications that we can't seem to get people to take. And so what happens in these states that have medical cannabis is, and it happens in Massachusetts, I know, still happening. We have docs, often cannabis clinicians, who will certify folks to use cannabis for OUD as a monotherapy. And so if you do that, I think the level of risk is astronomical. So you're really taking a chance there. And it just seems, I would say, foolish almost, right? This is a life-threatening condition. So to think that you're gonna use a cannabinoid instead of buprenorphine, methadone, or naltrexone, it doesn't make a lot of sense to me, but it still is happening every day. So let's shift gears. So CBD, it's everywhere. I snapped this photo. David has us meet and go over the presentation. So we met yesterday. Everything has to, you know, it's a fine-tuned program that we're trying to deliver here. Let's not say where. We don't want to promote it. So this is right across the street here. As you can see, CBD is everywhere, right? It's in your drink for 25 milligrams. And so, you know, one of the stories that I like to tell, so I have two daughters and my wife, and so I have an endless parade of packages that shows up in my house every day, usually not for me. But one day, you know, I don't know what got into me. I decided to slice one open to take a look, and there was a CBD inside. I said, well, what is this? And my wife said, well, you know, somebody in my networking group said this was great for, I can't remember what it was. And I said, well, you know, you know this is what I do, right? So I don't think that she continued to use it, but that's really what happens, right? People are intrigued about it. I mean, you can get it in your flavored water now, but I will tell you, and I think that's one of the things that we want to talk about here, is that 25 milligrams in your black cherry sparkling water, probably homeopathic, probably not gonna do anything. So that has pros and cons there, right? I think, to me, I think that if you're hoping for something, you're not getting it, you're not gonna continue to go back. But we should point out that CBD is not harmless, and that's really what we want to talk about in the next few slides. So only one formulation is FDA approved. So 98 plus percent of the CBD that your patients are using is not that. And I've never been able to get that product approved off label, not once. And if you have, kudos to you. So what is happening then, while it's a very promising compound with most of the evidence being preclinical, again, you're kind of opening up to this great question about how much evidence should you have for a given treatment in order to use it widely? So it is promising, certainly, and it earned that FDA indication for Dravet's syndrome, Lennox-Gastaut, and seizures associated with tuberous sclerosis, but people are using it far beyond that. Then you get into issues of purity and potency. So that's been shown over and over and over again, mostly by Marcel von Miller's group. So he was a co-author on the Spindle paper. He came out in 2017 showing that only 30% of commercially available CBD products was accurately labeled. The Poclis paper, I think, is kind of a cool wrinkle because it shows that other stuff is often in these preparations, including THC and dextromethorphan in that study. And then just a couple of weeks ago, from Cambridge Hospital in Boston, was a paper that came out, I think, in JAMA Network Open, looking at melatonin and CBD. And again, so with those products, you know, again, you don't know what you're getting. So I wanna be clear. I think there are some products that probably are well-manufactured and are probably good products, but you're taking a chance when you're buying things online or at these stores, clearly, or across the way when you're having lunch. So what are the problems associated with CBD? So, and that's actually, I'll direct you back to the 2021 AJP paper that we published. I think a couple of the cool things that I like to talk about when I have more time on CBD, we have a couple of really nice figures in that paper looking at the multitude of receptors that CBD interacts with and the doses that you need in order to interact with those receptors. So that's important. And we also have some figures that show receptors and how CBD interacts with receptors in a variety of different ways. So the dose is very important here. And then if you are using CBD in the hundreds of milligrams, which I think you need to be in order to have it as a off-label treatment for anxiety or whatever we're talking about, liver toxicity. So the Watkins paper looked at a couple of the Epidiolex studies, and in one of the small studies, I think five out of 16 participants had LFTs greatly elevated. So if you are using CBD in the hundreds of milligrams, you gotta check LFTs. And you gotta run, as we'll see in a second, you have to look for drug-drug interactions. The second bullet here, I think, is one of the scary concepts here. When people are thinking about using CBD instead of evidence-based treatments, I always tell the same story. I had somebody come in my office and say, hey, doc, I heard about you, and I wanna use natural treatment to treat my depression. And I said, it's rare, but it does happen. And this person had multiple medication trials and ECT. And I said, oh, we don't wanna go there, right? We don't wanna think about CBD as a monotherapy for depression for someone who has treatment refractory depression. So there's, again, with cannabis, there's so much misinformation out there, and patients who are hurting, they want help, and so they're looking for it in a variety of different ways. So I think it's great to be able to have those conversations, and hopefully steer people towards treatment that is evidence-based. Finally, I wanna mention that if you are coaching somebody or helping them use CBD to treat, let's say, anxiety or any condition, it's very expensive, right? So you're buying it online. What I will do is say, look, we're gonna need to be at least 200 milligrams or so. Think about the formulation you prefer, and then sort of think about how much it's gonna cost. And so it's very rare that people will use it in an ongoing way because it is, it's prohibitively expensive. And then finally, drug-drug interactions. This was a paper we published over two years ago now, time flying, but the idea that potentially powerful medication, so it has drug-drug interactions. So although it's really not, we're not using the FDA-approved product, we need to recognize the drug-drug interactions, and we need to encourage patients to tell their other treaters that they're using CBD so we can make sure that we don't have any of these problems. And as you can imagine, with an anti-epileptic medication, you're gonna have interactions with other medications that could be used for seizures too, and other things too, including morphine, warfarin, and things of that sort. So overall, to me, I think we're in this precarious position where policy is way out in front of the science, right? The paper that we had last year in psychiatric clinics, we're not, the gap's not narrowing either, right? I think that's one of the frustrating pieces here is that when we're treating a patient and we try a treatment and we wanna evaluate whether or not it's working, we're gonna make a change, right? If it's not working, we're gonna make a change, and we really haven't done that with medical cannabis policies, unfortunately. A lot of these policies are the same as before, they're not really that novel. So there is some evidence, use far outpaces the evidence, and we need more evidence there, and then it becomes a question of who should pay for it. And just wanna briefly thank my team for freeing me up to come do a talk like this. Thanks. Thank you. Thank you, Dr. Hill. Let me just add, you alluded to it, but actually, one of the conditions the DEA made for FDA approval of Epidiolex, that is, natural plantarib cannabidiol, is it cannot be prescribed off-label. Generally, once the FDA approves a medication for an indication, we as physicians can prescribe it for anything else, maybe with more malpractice risk, but you actually cannot. The pharmacist will not dispense it unless you can show your pediatric urologist or equivalent specialist treating someone with these disorders. So they closed that loophole before you could take advantage of it. All right, our next speaker, Dr. Das, will give you some information, should you, despite what Dr. Hill said, want to take the plunge and discuss medical cannabis with your, yeah. You want to discuss it with your patients, she'll give you some of the practical tips. All right. Well, I want to first thank, and it's hard to follow, Dr. Gorlick and Dr. Hill for their excellent presentations and for inviting me to stand in today. I am standing in for Dr. Robin Williams, who wasn't able to make it to the conference today, and so I appreciate much of his content is in here. Here's my standard disclosure, but I think it's also important for me to add one more disclosure. I am chair of the Council on Addiction Psychiatry at the APA. The things that I'm saying today don't necessarily represent that council, but it's interesting that I led authorship of the APA position statement, APA position statement in opposition to cannabis as medicine, and here I am at the Science of Medical Cannabis session. So that's where I'm coming from, I just wanted to say that, because as Dr. Gorlick just said, if your patients are still wanting to use cannabis or CBD, it's useful to know about the pharmacology. So first we're going to start with composition, strains, and potency. Much of this has already been discussed, but I'll review it one more time here. So cannabis is very complex. It's made from, it's composed of over 500 compounds. We went over some of them, THC, CBD, with THC, delta-9-THC being the primary psychoactive compound, and then CBD gaining in popularity, as Dr. Hill mentioned. Variability in form, potency, onset, and dosing is very difficult to comment on, although I will try my best to comment on how to think about dosing. It's useful, I think, to know that for the purpose of research, 5 milligrams has been recommended by NIH at this point. CBD and hemp, this was discussed by Dr. Hill just now, may have antipsychotic, anti-THC, anti-seizure effects, and it's largely unregulated. So THC content must not exceed more than 0.3% for something to be considered hemp, but at the same time, there is a lot of mislabeling, and the composition of these products is variable. And they are rather costly if our patients are going for kind of what should be more pure forms. It's also hard to think about dosing. He flashed the sign of the can that had 25 mg, but we'll talk a little bit more about the dosing that might have effects when it comes to CBD. Most people report using it for pain, anxiety, and depression in surveys. So for our patients who are coming to us and reporting that they use medical cannabis, what is a standard dose? There is state-to-state variability. So Washington and Colorado have set the dose at 10 milligrams, and Oregon chose to set it at 5 milligrams. And that's also useful to mention, as was already discussed, that CBD studies have used doses of 4 to 800 milligrams. So that is very different from the 25 milligrams in a soda can. So when you're talking to your patients about using cannabis for indications that are popular, and here's a great resource I appreciate from the National Academies of Science Medicine is they have the health effects of cannabis and cannabinoids, which was a good summary several years ago, or a few years ago rather, of cannabis and cannabinoids. If your patient's coming in for one of these popular and most common indications, ask, did they start at a low dose? And especially in older folks and older patients want to know, or if they're cannabis-naive, did they start at a lower dose? And did they titrate upward? So just like we would do with any medication, we want to try to have folks, people on the effective, least high, and most effective dose. So optimize that point there. We don't want to put our patients on too high of a dose of any medication. We want to try to have that optimal place. It's also important as your patients are coming in using medical cannabis for those indications to think of relative contraindications. So a few of them are listed here and I think that I'll just highlight the last two, working in a job requiring drug testing, that is very relevant, and also in pregnant and breastfeeding. I'm going to go over this case briefly. We won't discuss it because we want to make sure that we get to questions. But it's a good case to kind of have some questions in your mind. So a 32-year-old single employed male has been coming to a mental health clinic for the past few months for treatment of dysthymia, is on a citalopram 20 mg with some benefit. Recently bothered by anxiety and insomnia more and requests a prescription, a prescription for medical marijuana after hearing that a friend said it worked better and faster than antidepressant or anxiolytic meds. The state in which the practice is located in is approved for medical marijuana program a few years ago but the staff psychiatrist is not sure if anxiety is an indication for enrollment and is worried about medical legal liability. Psychiatrist explains these concerns to the patient, Mr. Jones, but he gets frustrated and says, fine. Then I'll just go to Colorado and buy some without your help. Some things to consider as you're thinking about that case is can physicians prescribe cannabis products? How is this patient going to be taking them? What is the potency, purity? Is it efficacious? This person came in for anxiety. If they were coming in for depression, would that be efficacious? Side effects and mental health risks and finally our roles in caring for our patients. We're now going to move on to the modalities of use, pharmacokinetics and interactions. So traditionally cannabis is consumed by smoking, kind of the term that we would use for a rolled up bunch of cannabis would be a joint, is quick onset of action within one minute and a typically shorter duration of action. This is compared to some of the other modalities which we'll talk about in a second here. There are many new methods and a lot of these methods are to try to get an intended different effect. So for example, vaping cannabis products can, depending on how that's constructed and how the vape liquid is put together, can be a very effective way of absorbing cannabis. Oral products, also known as edibles, they have slow onset to action, understandably, and at the same time their duration can be much longer in terms of effects. And so this is where clinically it's useful to talk about that with patients because if they use the edible and then it doesn't give them an effect and they use more of an edible and use more, use more, then at some point they've had much more than was recommended in the edible packaging, for example. And then of course it's important to talk about these high potency cannabis products. For example, the hash oil concentrates, wax or butter, and how some would say that these are less considered cannabis or marijuana products and these are THC concentrates instead in many cases. It used to be that top grade cannabis used to be 20% delta-9-THC and these days some of these products can exceed 80%. So they're much more potent. It's a different, it's not the cannabis of the 60s that used to exist. There are other ways of using them and some of them, for example, sublingual is a sublingual formulation, but that's not approved here in the U.S. These are the routes of administration and as I mentioned, smoked takes effect much more quickly in the graph on the side and then oral or edibles takes a longer time to onset, but a longer duration. So let's get back to dosing and strains. So a typical joint size in the U.S. is about two-thirds grams and the potency is about 8% THC. Again, that's a lower potency than many of the new products. And so that would get about 5.28 milligrams yield. If there's higher THC, then we can get to about 10 milligrams. A high or euphoria can be experienced from two to three milligrams. And then vaping versus smoked, there's a 90-10 rule and 90% of THC is absorbed with vaping and 10% absorbed with smoking. So as I mentioned, depending on how the device and the oil is put together, then there can be much more of an effect of absorption from vaping. Drug-drug interactions, this was discussed by Dr. Hill. I think it's important when, again, when our patients are coming to us and they're interested in these products or they're using them to think about potential drug-drug interactions. We're psychiatrists and so I'll focus in on the psychotropic agents here. So THC is a 2C9 inhibitor. So that can affect things like fluoxetine and a 1A2 inducer. Examples here are caffeine, which I think is very relevant, but also others like duloxetine. The clinical significance of these interactions has not been established, but it is still something useful to discuss with our patients and to be aware of, especially as we're often prescribing many of these medications. Side effects, there are physical health impacts that can occur as a result of using cannabis. And I think the one that's always popular and asked about is cannabinoid hyperemesis syndrome. But there's also other effects. For example, in an older patient that I might see, it might be useful to talk about orthostatic hypotension when they are interested in these products. I think the lungs, my research originally was in tobacco use disorder. And so I do a lot of talking about tobacco. And folks will always ask me, what about the lungs when it comes to cannabis? And so while cannabis, each individual item for item, cannabis is more harmful than a cigarette, somebody isn't going to go through 20 joints in it, hopefully not going through 20 joints in a day. And so that's where smoking actually does affect, probably does affect the lungs much more often. There's a lot of co-use, so it's really hard in the studies to discern what is related to cannabis and smoked cannabis versus what is related to cigarettes. I already mentioned the NASEM resource, and it summarizes well things like cannabis use disorder as well as mental health effects of cannabis. And let's see here. We will go to our last case, which is Mrs. Jones. She's a 77-year-old married retired woman with generalized anxiety disorder. She's been successfully treated with duloxetine 60 milligrams. She also has hypertension, she's taking propranolol, hydrochlorothiazide, and a recent hip replacement. So she's taking the psychotropic, might have been in the list earlier, as well as propranolol and hydrochlorothiazide. And she may be somebody we don't want to have fall. She struggles with twice weekly physical therapy and is becoming increasingly anxious. And so she's looking for some relief. Her neighbor told her about medical cannabis dispensary that has products her friend used to get through a recent surgery and asks if you can tell her what to use because she doesn't know if it will be safe. So things that we may consider. We might think about the route of administration in terms of how potent it is as well as for somebody that's her age. Drug-drug interactions because we know she's on other medications, side effects, and mental health risks. We know that she might be a fall risk. And then our roles in advising patients about third-party products. So to conclude my section, cannabis is complex. THC and CBD are the main, Delta 9 THC and CBD are the main of main interest pharmacologically. Dosing, while I went over some numbers that are common, there is a state-to-state variability in what's considered a dose compared to what's considered a dose in research compared to what's actually available in products. Routes of administration are changing. This talk is different than a talk that would have been given on the same topic 10 years ago. And there's drug-drug interactions. And finally, there are side effects that exist and it's important to consider, especially nuanced patient populations. I'll hand it back to Dr. Gorlick now. Thank you, Dr. Das. I know we have a lot of material to cover very briefly. So we'll try to, and even with the Q&A time, I'm sure we won't have enough time to answer all the questions. Plus, this is being live streamed and I also already have two dozen questions from the audience you can see. Although we're not going to take their questions. We'll mix them with yours at the end. But my point is, I forgot to mention this, we have our email addresses on the opening slides and it's in your handout that you got. Feel free to contact any one of us after the meeting. We'll be happy to answer follow-up questions. We'll provide you with more material. So up to now, you've been hearing a focus on the individual patient that sits in your office. I want to turn briefly to the broader public health or population level, which hopefully, but as Dr. Hill said, not always, or not often enough in my opinion, should inform legislative and regulatory policy. So I'm going to try to briefly cover three areas. First, give you a framework for evaluating the epidemiological evidence because every new study that comes out generates accompanying press releases and media excitement and claims that often are not supported by the actual evidence being published. I'll send this to the screen for you. Oh, I'm sorry. Oh, it's no problem. You can keep talking. Then I'll cover... I'll have to go again. Excuse me. No, well, it went back to the beginning. Most of my talks are on the same slide set. There we go. Secondly, then I'll try to cover what's known, and I'll say right off the bat, very little with high quality evidence, both the potential public health benefits and the potential public health harms. And again, as I think Dr. Hill alluded to, for some reason, most of the media and the industry emphasize the potential benefits, not the possible harms. So here's why I think we should be cautious in interpreting the evidence we have. So if you're doing a population-based study or an epidemiologic study, you're studying associations, not cause and effect, as we do with an interventional, like a randomized controlled trial that Dr. Hill mentioned. Associations never prove causality, although if done rigorously, which many are not, in my opinion, they can give you circumstantial evidence. So I'm hoping this is all review for concepts you learned in medical school, but sad to say, I mean, I'm at the University of Maryland, before that I was at UCLA, I'm not always sure of that. So I'll go through this briefly. So when you see a statistically significant association, you can't stop at that. You have to think of, could this association be due to an intervention, or could it be due to a cause? And I think that's a good question, because I think that's a good question, and I think could this association be due to an antecedent factor that's common to both the independent variable, in this context, cannabis use, and the outcome you're studying? So could the low perceived risk of cannabis use, for example, which is a psychological construct, could promote both changes to cannabis-related laws and increase cannabis use? So if you look at the association between changes in laws, legalization, for example, and increased cannabis use, you can't be sure that that association means the legal change caused the change in cannabis use. So the way epidemiologists try to address this, the most rigorous design, in my opinion, is what's called the difference-in-difference design. So you compare a set of states, so again, as the federalists would say, the federal system in the U.S. means the states can be laboratories for change. So you take states who have legalized medical cannabis and states which haven't, and you look at each, the two sets of states, and compare any changes from before versus after the passage of the law. So for the states that didn't change their law, you take the date that some nearby state changed the law. And that way you control for overall what are called secular national trends. Maybe something's been changing throughout the population, but it did change differently in states that legalized versus didn't. So then we have some practical problems in interpreting the published literature, even with that most elegant design, difference-in-differences. So what's the classification of the state medical cannabis program? So my own state, I mentioned, passed the law in 2015, and so many of the published studies will treat Maryland as, well, the legal status change in 2015, look at before versus after. But in fact, there were no working dispensaries until December 2017. So really, 2018 should be the first year where the legal change might have had some actual impact. And for some reason, authors continue to overlook that. Also, programs differ in their strictness, and that clearly affects, in the cases worth the study of the outcome. For example, some states let you grow your own cannabis. Actually, Maryland's new law, which takes effect in July, will allow you to grow a few plants of your own. But I suspect, like in other states, most people will still buy their cannabis from a licensed dispensary. Do you have a physician recommendation based on a bona fide physician-patient relationship, or do you have a cannabis mill? At one time, California, where I used to work, you just walk in, and for $200, no questions asked, you'd get your regulation in five minutes. Don't have to take off your clothes. I don't need to check any other medical records. You'd get it. Maryland is different, I can tell you, but there's still a variation in how legitimate, how intensive the evaluation is. And as you heard from Dr. Das, there are serious contradications and side effects you should be discussing with your patients. Now I'm going to just highlight what I think is some of the most relevant data from these population level or associational studies. So one of the benefits, public health benefits, touted by proponents of both medical and recreational cannabis, actually both, is it will reduce harms from other substance abuse, as I'll go in a minute. This slide shows admissions for substance abuse disorders, but there's a lot of publicity about it reducing opioid use and hopefully opioid overdoses, which, as you heard from Dr. Hill, is certainly a big public health problem nowadays. And this slide in the left-hand panel shows an analysis looking at the date where the medical marijuana law was passed by the legislature. And you see, actually, the horizontal red line is before and after the law. There's no change. There's a slight decline, but the variability is so large, there's not a significant effect of the legal change, per se. But in the right-hand panel, they reanalyzed by when were there actively operating dispensaries, so people could actually get the medical cannabis. And there, you see the same decline in those two or three years after the change in the law, but the variability is less, and so there is a statistically significant decrease in hospital admissions for treatment for substance use disorders. Now, there's a whole other discussion we don't have time for. Just because it's statistically significant, is it clinically significant? Okay. Now another limitation of the existing literature, in my opinion, is many of it, almost all of it, depends on patients' self-report of what they used or what their condition was or even whether they were registered in states that don't have registries. But that's not always valid. So some investigators in New Mexico actually followed up on 64 chronic pain patients who were in medical cannabis programs and claimed it was a great drug. They were able to stop getting prescriptions for opioid analgesics. Well, that's exactly what the promoters are saying. However, these investigators went to the state prescription drug monitoring program and found that more than two-thirds of these people actually were still getting opioid prescriptions. Now, you could argue they were getting the prescriptions but not using them, but I consider that unlikely. As I mentioned, a lot of publicity about addressing the opioid crisis by legalizing medical cannabis and using it for opioid use disorder. Well, you've already heard at the individual patient level, RCTs, there is no good evidence, as Dr. Hill said, that cannabis is a treatment for OUD. If you look at the epidemiologic level, some studies do show decreased opioid analgesic prescribing for various populations where you have medical record access, so Medicare Part D or Medicaid enrollees, or decreased misuse based on looking at treatment admissions or decreased opioid related overdose mortality associated with functioning county dispensaries. So these may be indirect effects given that there's no patient level data for treatment for opioid use disorder. I'm going to skip some of this because when you dive a little more deeply, there's some interesting anomalies. So Keith Humphrey's group, actually, it's down the road at Stanford, looked at one of these difference in difference population level analyses, and if you look at the period 1999 to 2010, you see a 21% decrease in opioid overdose deaths associated with having a functioning medical cannabis program in that state. Well, that looks impressive. Even a 21% decrease would save a lot of lives. But a few years later, when they reanalyzed the data, sending out to 2017, so you added seven years, now medical cannabis availability was associated with a 23% increase in opioid overdose deaths. So did medical cannabis suddenly become dangerous? No. Their conclusion, which I personally agree with, is both analyses are artifacts of using population level data. So to me, that's a very interesting paper. And again, if you look more closely, Garfinkel et al. looked at patient level data, but using what was called ecological momentary assessment. So the participants carried around smartphones, and they responded many times a day. These were adults with chronic pain, and they were asked to daily report their substance use and their level of pain. So it turned out that they were more likely to use opioids for their pain on days they also used cannabis than the other way around. So it suggests the opioid use did not substitute, I mean, cannabis use did not reduce their need for using opioids. It was not a substitute. And this association was not influenced by how much pain they had. So it happened whether they had little pain or they had severe pain. So another touted benefit is decreased prescribing of psychoactive medications in general. Again, this is large samples based on medical records, in this case Medicaid enrollees. And what you see on this slide is most of the indications that were studied, prescriptions decreased when there was medical cannabis available. Some of these, as Dr. Hill pointed out, have excellent evidence for efficacy, such as pain and nausea and seizures, but spasticity, which is actually a regulatory approved indication in Canada and Europe, that's the mixables, did not respond to cannabis in this case. So I think the evidence is weak, if not in the opposite direction. Now turning to potential public health harms, which again are usually not much talked about in the media, we as addiction psychiatrists have a big concern about increased cannabis use or increased prevalence of cannabis use disorder. And the evidence there is mixed. There's evidence that cannabis use is increasing in older adults and in some studies even in adolescents. But some of this lack of a clear effect may be due to the fact that cannabis use, even where it's illegal, is already so prevalent that it's hard to see a significant change with legalization of medical cannabis. And similarly with cannabis use disorder, mixed evidence, there is some evidence of increased cannabis use disorder with adults, although not increased hospitalization with a diagnosis of cannabis use disorder. And it may vary with the strictness of the medical cannabis regulations in that particular state. So here's an example, I believe from Massachusetts, I think your colleagues did this study, showing they took two groups that had applied for a medical cannabis card in Massachusetts. And some individuals got the card right away and could start accessing medical cannabis. And the other group had a, I think it was a 12 week or three month delay in getting it. So they started out, presumably comparable in their desire to use medical cannabis and their need for medical cannabis and so on. And it turned out that the group with the 12 week delay had a significant, I mean the group that had the immediate access over 12 weeks had a significantly increased risk of developing cannabis use disorder. So they presumably convinced the physician there was a legitimate read for a recommendation. They got it under state regulation and yet they still were at increased risk for developing cannabis use disorder. So I think that should give us all pause when you weigh the risks and benefits of recommending medical cannabis. And lastly, another big concern, not just in the US but in other countries like Australia, the risk of cannabis associated motor vehicle accidents. So this has been observed in, well, let me start by saying there's no doubt that it's not good to drive on the influence of cannabis. I mean, that's been shown in laboratory studies. It showed in driving simulator studies and shown in on-road observations. What we're talking about here is does that risk increase when you legalize medical cannabis? And that's certainly the case in some cases that have legalized it like Colorado, although it's not clear that this is definitely due to the change in the laws. What is clear is you have an increase in unintended cannabis overdoses, especially among children who have access to oral cannabis of the edibles. And Colorado and other states, and it's already gonna be in the law in my state of Maryland when it starts July 1st, is you have to have childproof packaging and take other public health steps to reduce access of minors to cannabis. And another issue that in the addiction psychiatry field, this comes up, of course, around methadone clinics is the NIMBY issue. Do I want a medical cannabis dispensary in my neighborhood because there'll be increased crime? And people have started to look at that using geographic studies. You can plot crime. You can geocode the location of the clinic and look at the crime data. Many police departments now will give you the precise location of the crime. And it turns out there's not strong evidence that crime is increased. Here's a study from California looking at violent crime. And again, the curve dips after legalization, even after the first year, but large variability, so it's not clinically significant. So to close, so we have time for questions. I don't think there's high-quality evidence of causation associating medical cannabis legalization with some of these harms or benefits, for that matter, usually because we don't have enough evidence to infer causation. We really need the population level, I mean, the patient-based interventional studies to prove causation, as Dr. Hill alluded to. But the touted potential benefits are reduced prescribing of some medications, perhaps opioids, due to cannabis substitution, definitely evidence for harms, increased acute intoxication, particularly in children, increased cannabis use and use disorder, at least in some populations, and that maybe could be mitigated by stricter medical cannabis regulation in that state, and increased motor vehicle accidents. So let me stop there, and we'll take questions. So we are live-streaming this, and the live-stream audience has already asked several dozen questions, so to be fair, I've been asked to alternate. And then we'll direct the questions to the panel. So I'll start with the audience, and you already know the drill. Line up at the microphones, state your name and the question. Sure, I'm Dr. Renee Bayer, and I'm the medical director for an inpatient mental health unit. One of the struggles that I have had is evaluating comparable doses, what people are using, and it is a changing game. So when I'm evaluating a patient who's coming into our unit, I'm trying to figure out how much are they using. And just when I think I've got a handle on it, the price is all dropped. I'm trying to translate from wax to, like many of you probably, to flour or edibles. My specific question for you is, is there a tool out there somewhere that says one joint is equivalent to, you're a half a gram is about equivalent to X amount of vape equivalent to, or is that really, are they that different of products? Like am I trying to compare cocaine to crystal meth for the difference in product? So actually I'm gonna have to be kind of the tough guy here because that's actually a recreational cannabis use question. I mean, one of the tattered advantages of legalization for medical cannabis, all the states I know of, certainly Maryland, by law you must list the content of the top six cannabinoids in the product. So you have the patient bring it in, it'll tell you how much THC, how much CBD, and so on. So I'm trying to help the patient who I know is gonna be withdrawing. They may be telling me that they smoke eight grams a day, and I know what to do with that, or what they're probably gonna need while they're withdrawing. So I'm really asking this from a, like helping a patient withdraw. So you mean they're using unregulated cannabis, not medical cannabis? Yeah, yeah. So if the panelists can give a very brief answer, because like I said, we have questions here and we have lots of questions in the audience, and this is a problem I've had at other venues, try to keep it limited to medical cannabis. We could do a whole day's symposium on recreational cannabis, but. Yeah, so I think number one, you're ahead of the game by trying to figure out how much they're using right away, because so much of it is sort of a black box, people aren't sure. So the more specific you can get, like you're doing, what are you using, how often are you using it? If you can, have a label, that's helpful. But I think Smita had a slide, you know, again, the route of administration is gonna make a big difference, like you said. Vaping, more bioavailability certainly. So I think that you want to specifically look at, like you're doing, how much are they using of what product, and then kind of make a, I mean, you are guessing. There isn't, the short answer to your question is there isn't such a tool, but I think you can make an educated guess based upon the kind of detective work that you are doing. Yeah, let me just add from a research point of view, this is the reason why, unlike the literature on cigarette smoking or alcohol intake and health hazards, the literature on cannabis never or rarely uses as an independent variable quantity or amount of THC. We focus on frequency, because there's no way to know, because people are, even if you ask the individual, they don't know what they're using, unless you buy it from a, in the US, a regulated dispensary, which by most, I think every state law, they must put on the label what the content is of the major cannabinoids. So I'm gonna have to cut off to this question there, because we have our first question from the live view audience. If there are more than 100 different active compounds in the cannabis plant, how do you know what to study, or how do you know if the study is valid? Dr. Hill, you wanna take that? Well, the study's looking at a particular cannabinoid, usually. So I think that, it's a great point, right? One of the things that I always like to say is there are over 140 cannabinoids, and we only talk about two of them, mostly. But beyond those two, CBD and THC, there is a growing body of evidence for other cannabinoids, and I think you get back to the question that I asked earlier, how much evidence do you need before you start using something therapeutically? And so most of the studies for the other cannabinoids are preclinical studies, and I would think about what we're trying to treat. Are there treatments for those conditions that have better evidence? There usually are, at this point. Now, a question from the live audience. Who is next? I wasn't keeping track. My name's Dr. Bokta, and I practice in the East Bay here in California. So my question is, since the legalization of marijuana, I've found an increase in physicians coming in using it, and they're saying they're using it for medical reasons, but the reality is, as I start talking to them more, they're using it recreationally. And so I wanted to know if there's any guidelines in terms of if I'm supposed to report especially if they're surgeons, let's say. But then again, it's not fair if they're, I mean, but I think I should have the same standard if they're, let's say, an internal medicine doctor, and then they're smoking, and then I hear they're going and treating patients or doing their online emails at midnight. So I'm very concerned about that. That's a policy issue that applies across the board. I mean, should employers drug test for cannabis when it's legal to use? So I think most of the state laws don't allow employers to keep doing that, but I'll let Dr. Das answer the specific question about physicians. I'll just, and being from California, too, and knowing what the medical board has written. So it says they don't have a policy regarding a physician's use of cannabis for medicinal and or recreational purposes, but views the use of cannabis like it does the use of other controlled substances and alcohol. So if a physician is impaired, the board can take disciplinary action. There's some more information about reporting and complaints, but it does vary state to state. And so, yeah, the California board, luckily, has a clear page on guidance for that. Okay, now, from our remote audience, for THUs for anxiety, does the patient experience more severe symptoms when the effects of the THC wear off? In other words, is there a rebound effect? Thank you. Yes, there is. Okay. So. You've answered the question. Yeah, okay, we'll move on. We'll move on. I like this. I have to be a moderator. Yeah, ask us. All right. Hi, I'm Laura Safar. I'm a neuropsychiatrist treating patients with multiple sclerosis and psychiatric problems for the last 15 years. And there is a lot to unpack about the efficacy of cannabis for hepaticity in MS. There are 12 to 15 randomized controlled trials. They have different proportions of THC and CBD, different doses. They are brief. The longest is six months. So it's very difficult to read. Clinically, it comes down to each patient and what happens to that patient and the cognitive side effects because you have the effects of MS and the effects of cannabis on cognition. So it's even the indication, right, where the most evidence is difficult. It's not as clear. And the same in terms of patients are complex, right? They have mood disorders, anxiety disorders, cognitive problems. So even when cannabis would be indicated, you always have to look at all these risks, right, for all these other comorbid conditions. Definitely, but I do want to add, I think it gets back to the fact that we have the capability of doing better science and we're not doing it. We're electing not to do it. So right, in this case, what you could do if you really wanted to find the answers to these questions, I mean, you could have a group of experts get together. What are the outcomes we're gonna study? I mean, we could standardize these studies in a way that we're not. And I think, I'll just make one quick plug. I think one of the good things that we've done with the work with the NFL is that we're actually funding a few studies looking at CBD and THC and combo products for pain. So it's so frustrating to be up here year after year saying, ah, you know, the evidence isn't good. And like you said, there are weaknesses in these studies. But when I look at those studies, you know, they're enough so that I think you can engage in a conversation with a patient. But there definitely should be better studies. Okay, we have an online question. If you're using CBD as a treatment, what low dose should you start with? How should you titrate upwards and what should your maximum dose be? Yeah, I just like to start with 25 twice a day and then gradually increase it with the understanding that if we're gonna be using, and it depends on what we're treating, but you're gonna at least be over 200, I would say. I think it's fair to say where you saw the studies, 400 to 800. But I like 25 twice a day, tolerate the medicine and then titrate. Okay, in-person question. Hi, my name is Steve Chan. I work at Stanford VA Palo Alto. We're hiring psychiatrists, by the way, for- No advertisements allowed, please. But the question I have is regarding apps. Our system has had apps for smoking cessation and CBT-I, but are there any web apps or websites or apps that talk about cannabis use disorder? Or for patients that we can- You mean as a treatment to use? As a treatment or some sort of informational resource. NIDA has an excellent page on cannabis use disorder, or not cannabis use disorder, sorry, cannabis in general. And obviously it's NIDA, so they're going to also address cannabis use disorder. Yes, you're right, the VA has some great apps about for many things. It would be wonderful if the VA had an app for that when it comes to cannabis. It's interesting though because they're a federal place and so they may be less fast to adopt that. But yeah, good question and hopefully something that can be available more for patients. From the APA, we have a cannabis toolkit that's available on the APA website and that has resources for psychiatrists, physicians in general, as well as families and patients. But specifically as a treatment application, several research groups, one I know of is in University of Washington, have developed smartphone-based apps, primarily targeted at adolescents and young adults to help them track their cannabis use, make them more aware that they may be having adverse effects and may qualify for cannabis use disorder and also quasi-CBT type interventions to help them deal with their craving or desire to use without actually using. Nothing FDA approved yet, but what they call technologically assisted treatment is a growing trend in psychiatry as in other areas of medicine. That basically to me means apps, smartphone-based or computer-based. So you look it up on the web, you may find some useful. Okay, time for a online question. All right, this is another dosing question. When considering a cannabinoid to treat chronic pain such as neuropathy, again, what's the usual range of effective doses? What dose would you start at? How would you titrate up? So I would try to use dronabinol and I'd start at 2.5 and go from there. I mean, you're probably talking about somebody that is more advanced in age and probably has multiple comorbidities and multiple medications. So I think 2.5 and see, usually you'll end up probably 10 to 15 maybe, but when you're in that range, you're probably gonna have some side effects, cloudiness, things of that sort. Oh, I should add here, I think it was mentioned by both of the speakers. In addition to age, cannabis experience is very important. That is, you do develop tolerance to cannabis effects, at least THC. And so I've seen an experienced user. So when we did research giving cannabis or THC to research participants when I was at NIDA for ethical and other reasons, we took only experienced users highly tolerant. So they could take 10 milligrams or maybe more and not be visibly affected. I mean, I might report self high, but their blood pressure, vital signs stay okay, they didn't feel drowsy and so on. As you heard Dr. Das say, for cannabis naive individuals, the NIH recommended dose is five milligrams. Now clinically or anecdotally, I've seen people put to sleep for eight hours by cannabis naive people with a dose of five milligrams. On the other hand, highly tolerant people could, as I mentioned, tolerate 10 milligrams. So a lot of factor, just like with any other medication, have to be taken into account. All right, live question. Hello, my question pertains to the level of consensus of experts in the psychiatric community on the evidence for efficacy of cannabis. And I want to reference a great Q&A with Deepak D'Souza at Yale in the Carlat report in the fall when he was asked about this. And he said, taking the very weak evidence for efficacy, citing a lot of the studies, Dr. Hill, that you cited, he said that in the robust knowledge of adverse effects at the present time, it's hard to justify recommending cannabis for any psychiatric disorder. And so I just wanted to ask about the level of consensus amongst the experts with that statement. I think that's a quick answer, Kevin. We agree. High level of consensus for psychiatric conditions. All right, so. A question on the evidence for the efficacy of CBD to treat psychosis. So there are three studies that I know of. I think two of them are negative, one of them is positive. Two of them are for CBD as an adjunct treatment to antipsychotics, and one is a monotherapy. Actually, it might be two positive and one negative. So mixed probably has some utility as an adjunct if you've explored a variety of other treatments. Okay, last question, please. Hi, yeah, I'm an addiction psychiatrist in New York, and I work at an outpatient substance abuse program with indigent and low-income patients. And a number of them have medical marijuana cards. And we check toxins weekly, and a lot of them, well, they have cannabis in their toxins. And when I check the PMP, they don't have prescriptions, they're not getting prescription marijuana. They're getting marijuana from wherever. So one of the things that I wonder about is that, well, first of all, a lot of them are mandated to treatment, so it's important for them to have negative toxicologies. And if they do have cannabis, it's important for them to have a card, because otherwise they can go to jail, they can lose their children, lose their jobs, all kinds of things. So they really need that card, but they don't have the PMP prescribed marijuana, so it's a problem. And then the other thing is that in New York, I'm pretty sure that the prescription marijuana is not covered by insurance, and it's expensive. So I was wondering about other states and how that works out, because I don't think they can really afford the prescription marijuana. Yeah, so insurance companies often don't cover things that even have evidence. So as you can imagine, without much evidence. And you said New York, you're saying it as though, are you from New York City or? New York City, yeah. Oh yeah, but you said like, there's more than just New York City, of course. Yeah, New York City. But yeah, no, no insurance companies cover. Yeah, my understanding is it's not so much that it's illegal, but it's not FDA approved. So even medications that have not controversial are not psychoactive. If they're not FDA approved, insurance won't cover it. So I'm not surprised they won't cover it. They can't afford to get the prescription marijuana, even if they wanted to. So it's like a catch-22 all around, you know? So I don't know if you have any comments on that from other states or in general. Yeah, I think that's true in every state in terms of the insurance issue. Yeah. All right, so we're officially ended. I have 5.15, but the panelists have agreed to stay another 15 minutes till 5.30 if there are other questions. Thanks for choosing us again. Yes, by the way, the program committee does pay attention to your comments. So.

medical cannabis

David Goralek

University of Maryland

historical landscape

legal landscape

qualifying conditions

scientific evidence

Kevin Hill

chronic pain

CBD

Smita Das

public health

opioid usage