We will not have formal closing remarks at today's end, but at the end of today's paper sessions, we will include some reminders for you. Our daily housekeeping information about recording availability, CME credit, and slide availability can be found in the virtual conference lobby in the conference information section, items two and three. I wanna remind you all that we are having a meeting next year, December 4th through 12th, 2022 in Naples, live, with some hybrid components. Our first event of the day is our third symposium, Cannabis and Cannabinoids, From Science to Practice to Policy, an International Perspective. This symposium picks up on many of the threads from yesterday's presentations and will surely inspire further lively discussion. Please be sure to use the Q&A box to submit questions to the presenters throughout the prerecorded presentation, and presenters will answer as many as they can during the live Q&A session moderated by Dr. Severino. It's now my pleasure to introduce the symposium chairperson, Dr. Gregory Bunt. Gregory Bunt, MD, graduated from NYU School of Medicine and completed his residency in psychiatry at the Albert Einstein College of Medicine. He's an assistant clinical professor of psychiatry at NYU School of Medicine. He's a fellow of both the American and International Societies of Addiction Medicine. Dr. Bunt is the past president of the New York Society of Addiction Medicine and the past president of the International Society of Addiction Medicine. He's authored over 20 publications and speaks nationally and internationally about addiction medicine and addiction psychiatry. We will now see the prerecorded component of the symposium, which will last an hour and 18 minutes, followed by some polls, and then our live Q&A. Okay, I'm Dr. Gregory Bunt. I'm the past president of the International Society of Addiction Medicine and the New York Society of Addiction Medicine. And it is really a privilege and honor to be a part of this very important symposium on cannabinoids and an international perspective on cannabinoids. I do want to thank the AAP president, Kevin Severino, for being part of this important panel. And I also want to thank our speakers, Bernard LaFolle and Jana Kosin, for their expertise in this very important subject. And this is a joint ISAM-AAAP symposium, which is very interesting, an opportunity for AAAP and ISAM to join in addressing important issues of the day. And so all AAAP members are actually ISAM affiliate members, if you don't know already, and should be privileged to be part of that partnership. So I'm going to start today with cannabinoids, what addiction psychiatrists and physicians need to know. My disclosures, I'm the PI of the NIDA ISAM conference grant, and very unfortunately, I have nothing else to disclose. I want to go over the objectives of the symposium today that participants will learn about the distinction between THC, CBD or cannabidiol, and the other cannabinoids and cannabis, which are often co-mingled too frequently. And that's a problem. And also the participants here will learn about viewpoints of their ISAM colleagues and ASAM colleagues, and with survey data from ISAM conferences and ASAM conferences. And also now we're going to have a survey of our AAAP members, which should be informative and illuminating with respect to this controversial area, very controversial and important area of cannabinoids, addictions, psychiatry and medicine. And it is my belief, and I've spoken about this at ASAM meetings and ISAM meetings. It's my belief that addiction physicians, particularly addiction psychiatrists and addiction medicine physicians, should be at the forefront of public education and policy making. And so that is something to bear in mind and that they should be informed of the fundamentals of cannabis and cannabinoids, because it's such an important and controversial area in our society. We have some survey questions about THC, its effect on individuals with chronic mental illness and predisposition to addictions, and cannabidiol, whether you would consider prescribing it off-label or recommending the hemp oil with cannabidiol, and whether AAAP should work on developing some kind of policy position on the subject. But those survey questions will be forthcoming. This is hemp, which is related to cannabis, but it has low THC and fair amount of CBD in many strains. This on the left is hemp, low THC with CBD, and on the right is the cannabis, the purple flowering plant that has a fair amount of the THC, very often high concentrations of THC that are then further refined and available and marketed with the commercial marketing and promotion and sale of marijuana or cannabis products. What I'm going to be going over today primarily is the importance of distinguishing THC from cannabidiol, CBD, and the other cannabinoids. Now, the other cannabinoids, there's certainly not enough science to be making any recommendations or having any conclusions about any therapeutic effects or adverse effects. But with cannabidiol, that has some promising therapeutic effects, and I'm going to go over that. And THC, while it does have some therapeutic effects, clearly it has adverse effects, which all addiction psychiatrists and physicians should be aware of. This is cannabidiol, and most interesting of the cannabinoids under research at this point in time. Nora Volkow, the head of NIDA, has testified to Congress, testified to Congress, that cannabidiol has potential medical benefits. There are barriers to research that she talked about to Congress, and she also said that in preclinical studies, in some clinical studies, the potential for specific conditions of cannabidiol for treating neurological disorders, pain, inflammation, anxiety, and other neuropsychiatric disorders may be significant. And so we need to further our research of cannabidiol in relation to understanding the science of the cannabinoids. She also, however, published, Nora Volkow published, on the potential adverse effects of marijuana use, and she's opposed to the legalization of the commercial sale and promotion of marijuana, and is very concerned about the effects of THC, particularly the high-potency THC, on young adults and adolescents. And so that addiction psychiatrists should be mindful of. Marijuana use among teens, young adults, and adolescents has jumped tenfold since the legalization at the statewide level. A publication in the American Journal of Public Health in 2019 is a reference. And then the World Health Organization report found that youth use has been in an upward trajectory since 2015, when the legalization of the use was really at its height. And then that the ongoing policy debate and its coverage in the media appear to have impacted risk perceptions of harm caused by cannabis use, especially among young people. And that's a real problem that we need to be aware of and address in clinical practice and in advocacy and in interaction with policymakers related to public policy. Now, cannabidiol is available widely over the internet, in pharmacies now, in dispensaries, and even as a medication, FDA-approved medication. But in relation to cannabidiol, the clinical considerations for recommending or prescribing clinical cannabidiol are the source, the THC content, and the efficacy and safety related to varying dosing schedules and various doses that range the spectrum. And we're going to be going over some of the basics of the dosing of cannabidiol. The hemp industry is in a battle with the DEA. The DEA still classifies CBD as, I believe, a Schedule 5 controlled substance, although there's no evidence that it has any abuse potential. Can you get a high from CBD or hemp oil? No, there's no evidence at all that you can get any intoxication from cannabidiol. Now, one of the problems with some of the CBD products is that they're overpromoted with exaggerated medical claims or they're promoted in forms that are not healthful. So, pre-filled disposable vaporizers, a lot of our colleagues are opposed to. Cannabidiol comes in an oil that can be taken orally and absorbed, why they need to have it in vaporizers, which then can be used for mixing other substances, particularly among adolescents and young adults. And adulterated with other substances is a real concern. Dr. Oz, I believe, is one who had spoken about this. I respect Dr. Oz, a good integrative physician, but I would be concerned about the vaporizers for hemp oil. There are many celebrities that promote CBD. There are several that have a line. This is Steve Harvey. Another is Jeanine Pirro's conservative commentator promoting the CBD line and claiming that it has helped them and had a therapeutic effect in doses that generally range from 10 milligrams to 50 milligrams a day. And we'll be talking about the doses. And then in the area of integrative medicine and functional medicine, which is now mainstream and a lot of well-known organizations, Harvard and many other organizations and universities throughout the nation have integrative medicine as part of their curriculum. And in many professional forums, they have integrative medicine conferences where CBD products are widely discussed. There's attention to them in symposium and booths, commercial booths for promoting the sale of cannabidiol. And this is Kevin Hill, who is a very well-respected and leader in AAAP of cannabis and cannabinoids in addiction psychiatry. And he is the author of the marijuana publication that I think is the most important fundamental. I recommend this to colleagues and patients. Gives you a very, very well-rounded description of the potential therapeutics of the cannabinoids and the potential adverse effects. He was going to be a speaker at the Integrative Healthcare Symposium, which I attend every year in September. Unfortunately, it was postponed until February of 2022, but I look forward to seeing him. And so there are very well-known leaders in our field who talk about the potential therapeutic effects in integrative medicine of cannabidiol. But you have to be concerned about the forms of cannabidiol. There's the pharmaceutical grade. The cannabis dispensaries, you really have to know what is being accessible to the individual. And we're going to talk more about that over the counter on the internet. With hemp oil, you can have CBD that's less than 10 milligrams a day, which is negligible, or 25 to 50 milligrams, which may or may not be therapeutic. And that is a question that we have to answer, hopefully, with some science. And then the THC content. Now, some of the products have no THC content, and you can verify that. Others have less than 0.3. That's considered the cutoff for negligible THC. Others have more than that 0.3%, which is not negligible. And then others even have more than 3% if you get them in the dispensaries. That clearly is a THC level that can cause intoxication and the toxic effects of THC. There are many cannabis-related medications. THC is one, Marinol. I prescribed it for nausea-related cancer chemotherapy. We know the dosing, the adverse effect, the warning signs, and so forth. It's a controlled medication, as I think many of us think it should remain because of the abuse potential. Then there's Sativex, which is a combination of 50-50 THC and CBD, not yet available, but could be if we advocated for that in the United States. And then there's the Epidiolex, which is the pure cannabidiol used for certain seizure disorders, pure cannabidiol, pharmaceutical grade. In these dispensaries, again, you have to be careful. There have been cases where people have purchased what they thought was pure cannabidiol, and it had THC in it. There's one truck driver who was suing a cannabis dispensary because he got in a serious motor vehicle accident. The level of THC in the product that he thought was pure CBD was significant, so you have to be cautious about dispensaries. However, there are a lot of products on the Internet. They range in doses from negligible to all the way up to 50 milligrams per capsule, which is, I believe, I'm not seeing any more than the 50 milligrams available on the Internet. Fifty milligrams a day, many people tout that as being therapeutic for insomnia, for stress, for pain, and we don't know the science to that, but that's what's available. Again, you have to be aware of any THC involved in these, but you can check with the lab. Now, there are some products that tout 750 milligrams of the hemp oil, and some consumers think that they're getting 750 milligrams of CBD. That's not the case, and you have to really look at the amount of CBD, which can be negligible in some of these very expensive products that are available on the Internet. There are various warning signs and issues about CBD, including transparency, the extraction, and lab testing methods. Some of the companies will give you verified lab reports, and you can also send them to, and I have done this, send them to labs to get it tested for the THC, or you can take their urine and verify that they're not getting any THC. They do have a non-psychoactive stamp with approval on some of the products, which you can research and determine whether that's satisfactory, and there are some products that claim that they are THC-free, completely zero. I actually had obtained this product, tested it, and it was completely free of THC. I sent it over to a lab, and it was free of THC. Some athletes are touting CBD for athletic performance, particularly for the treatment of pain and inflammation related to injury, sports injuries, but also for insomnia and even inflammation in general, and some well-known, famous athletes have claimed that it really helps them, CBD, and in the forms that are available over the Internet, up to, as I said, 50 milligrams per day. This got kicked over to the World Anti-Doping Agency because some of the athletes were using it, and the question is, was it going to be prohibited or permitted? Extensive research was done by the World Anti-Doping Agency, and they determined that, based on everything, CBD is not prohibited. It's permitted, so any athlete in athletic competitions, including the Olympics, can use CBD that's not prohibited. THC is prohibited, and with THC, that's a different story. Now, the World Health Organization then evaluated it, the same World Health Organization that determined that the legalization of marijuana has led to an increased use and warned about the potential dangers of influencing young adults to use marijuana. They determined that CBD is not addictive or toxic, and they also determined that there are no known public-health-related problems associated with the use of pure CBD. World Health Organization. This is Carrie Richardson, an Olympics, national sprinter who won some of the sprinting, I think, of 200 and 100, 200, 400-meter competitions, and she was a candidate for a gold medal in the Olympics, Tokyo Olympics in 2021, and she was disqualified because of THC in her urine, and the World Anti-Doping Agency prohibits THC. Now, the World Anti-Doping Agency has raised the level from 50 to, I believe, it's 150 now nanograms per milliliter of THC, so you can have some THC, but it can't surpass this cutoff of now the increased level of 150. This is very controversial. Carrie Richardson very humbly apologized for it. She said her mother had died very recently, and she used some THC, and unfortunately, even though she won a competition, she was disqualified from the Olympics. Very controversial about whether she should have given another opportunity with urine that was free of THC to sprint again and enter the competition. That controversy is the ilk that many addiction physicians discuss. However, I hope that she will be eligible for the 2024 Olympics and maybe get a gold medal, and that would be a very nice ending to that story. So, the problem with some of this cannabidiol products, however, is, as I said, the over promotion, the exaggerated medical claims, it treats everything from anxiety to depression and post-traumatic stress disorder to blood sugar to cancer and so forth. And the FDA has actually gone after and sued some of these companies with these overreaching claims about the therapeutic effects of cannabidiol. So, that's something addiction physicians and psychiatrists should be mindful of and warn people about. The FDA also issued these warnings about potential harm of CBD. They talked about liver injury or hepatotoxicity. However, hepatotoxicity is generally associated with the high doses that are recommended or prescribed for these seizure disorders, 1,000 milligrams or more, and I'll be going over that. The vape oil, as I said, a real concern, particularly for adolescents and young adults who might be using it and then getting THC in it, which is a real problem among adolescents and young adults nationwide, and adult threats, including fentanyl. This is the package insert for Epidiolex, pure pharmaceutical-grade CBD, and the recommended dose for prescribing is 20 milligrams per kilogram a day. That's 1,400 milligrams a day for a 150-pound individual. So, it's considerably high, and that can lead to liver toxicity and other adverse effects listed here. But this is the transaminase elevations. As you can see, at 10 milligrams per kilogram, it's 8%. At 20 milligrams per kilogram, over 1,000 milligrams a day, it's 16%. Physicians need to know this when recommending cannabidiol. This is the very well-known cannabidiol study for opiate withdrawal by Yasmin Hurd at Mount Sinai. She published it in the American Journal of Psychiatry in 2019, and she found that cannabidiol reduced the Q-induced cravings and anxiety in opiate withdrawal of heroin addicts who got 800 milligrams a day, 800 milligrams orally a day, for two weeks. That led to no adverse effects and the therapeutic effects, and she distinguished between CBD and THC, and she said that the CBD at 800 milligrams for two weeks for opiate withdrawal resulted in significantly reduced cravings and anxiety compared to placebo. This was picked up by some renowned addiction psychiatrists. Mark Gold is one. He received a AAAP award a few years ago. He's a very well-respected colleague, a good colleague. I know him well, and he was very interested, as I am and many of our colleagues, can CBD help in the treatment of opiate withdrawal. This is something that we would want to know, and the question is, now, why hasn't more research been encouraged and funded to determine whether CBT can help with opiate withdrawal? In that regard, I think perhaps AAAP and ASAM could advocate for NIDA to issue an RFA, a request for applications for more research, because if, indeed, cannabidiol can help with opiate withdrawal, I and many of my colleagues want to be able to prescribe it, want it covered by insurance. If, on the other hand, corroborative studies don't validate that it's effective for opiate withdrawal, we should know that, too, so more research should be done, but the seminal study by Yasmin Hurd that was published in 2019 should be validated, or at least repeat studies should be done, and I believe we should advocate for that among AAAP and ASAM and NISAM. Now, the precautions about commingling the exciting research about cannabidiol with cannabis and THC is a concern. I spoke to Ed Saltsis, who was a co-investigator with Yasmin Hurd on the study, and he said, yes, this is a real concern that people now take this data and then use it to promote the commercial sale of cannabis with THC. The American Medical Association came out against the legalization of the commercial sale and promotion of cannabis. American Psychiatric Association said there is currently no scientific evidence to support the use of cannabis now with THC as effective treatment for any psychiatric illness, and the ASAM, American Society of Addiction Medicine, came out with a strong recommendation that cannabis should not be encouraged, cannabis use, for the treatment of opiate use disorder. In fact, it can probably do more harm than good, and so this is a consideration for addiction psychiatrists and for the leadership in AAAP. Internationally, you have the Australian and New Zealand College of Anesthesiologists on the Faculty of Pain Medicine and the International Association for the Study of Pain, both advising that cannabis and cannabinoid products should not be recommended now, particularly because of the concern about THC and the sedative effects and interaction with other medications and neuropsychiatric effects. So that's the conclusion of the International Association for the Study of Pain. I now turn to some of the International Society of Addiction Medicine survey data that I promised, and in the interest of time, I'm going to go through these very quickly, this data. And the first question out of the 2015 participants were generally physicians, international addiction physicians, numbers between 80 and 85 who responded, and they were asked a set of questions about the models that were either good or harmful to society. And we're going to be talking, we have a speaker who's going to be talking about the Holland model, we're going to be talking about the Colorado model, and is the unrestricted legalization of recreational marijuana, the Colorado model, harmful to society? How about the Holland model, which is a restricted legalization of the Holland model? In 2015, in California, they didn't legalize recreational marijuana, but medical marijuana was unrestricted. Is that a good policy? And in New York, medical marijuana, they were proposing a restricted legalization of medical marijuana. The respondents indicate that the Colorado model overwhelmingly over two-thirds felt that they felt it was harmful to society. The Holland model, over 50%, the majority felt that this was a good public policy. The California model, over 50% felt it was not a good public policy. But the New York model, restricted legalization medical model, they felt it was kind of a spectrum across the board, evenly distributed. Do you think that marijuana is harmful to adolescents, or those with chronic mental illness, or those predisposed to addictions? And in this set of questions, the international respondents felt that it was harmful to adolescents, overwhelming majority, harmful to those with chronic mental illness, and harmful to those with predisposition to addictions. However, harmful for opiate addicts in recovery, interestingly, this was more of an even distribution, with the majority either not sure or believing that it is not harmful for opiate addicts in recovery. I'm not sure why that is so, but that is the data. Interesting, from an international perspective. This is data from an ASAMP meeting. Again, respondents now between 85 and 90, and this was a question about prescribing cannabidiol off-label, cannabidiol, pharmaceutical grade, for the treatment of pain, insomnia, traumatic stress, or opiate addiction. And what you see is, for the treatment of pain, the majority actually are not sure or agree that they would consider prescribing cannabidiol off-label for treating pain. More of a cross-section with insomnia and traumatic stress, but they were in disagreement that it should be, they would consider prescribing it for the treatment of opiate addiction. The majority was strongly disagreeing with that. This also is the same set of questions for recommending hemp oil with cannabidiol, but no THC for the treatment of pain, insomnia, stress, or opiate addiction. And here you see that the great majority are either not sure or agree that they would consider recommending cannabidiol and hemp oil with no THC for the treatment of pain. More of a cross-section with insomnia and stress. And if you notice in the lower right-hand corner, would you consider recommending it for treating opiate addiction? The majority disagree, clearly, and probably because they don't want to mislead patients with opiate dependence in trying something that has no scientific evidence that it would treat that disorder. In summary, and this is my conclusion, I think that addiction psychiatrists are central and should be to public education and public perception and should be also central figures in the development of public policies related to cannabinoids and cannabis, a very critically important issue nationally and internationally. We have to know more about the science of the efficacy and safety of various doses of cannabinoid product, particularly CBD and the THC content, of course. And I think that the viewpoints of our ISAM colleagues and our ASAM colleagues, and now with the survey, our AAAP colleagues will be very instructive and illuminating about how we perceive these very controversial but very important, critically important issues in addiction psychiatry and medicine. And again, I want to thank Kevin Severino, the organizers of the conference of the American Academy of Addiction Psychiatry for putting together this very important symposium, collaborating with the international group ISAM and AAAP. I want to thank our speakers for their expertise, and it was an honor and privilege to be presenting this today. And I look forward to a very informative and interesting, interactive discussion with questions and answers. Thank you. So, hello. I'm Dr. Bernard Le Fall. I am a clinician scientist at the Center for Addiction and Mental Health in Toronto, and I'm also a professor at the University of Toronto. I would like to thank the organizer for the opportunity to be here today with you. And today I will talk about cannabinoid drugs for mental health treatment. I'd like first to start with some disclosure. So, I have received grant support from various industry partners, and the industry partner that is relevant to this presentation is Canopy, which is a licensed producer that sells cannabis in Canada and in other countries. And also, I received in the past supply from JW Pharma and Aurora, and I have been part of an advisory board meeting with Endivure. So, the presentation objective will be to provide an overview of the potential of the endocannabinoid system to modulate brain function, provide an overview of the clinical trial conducted in various mental health disorders with a focus on addiction, anxiety, post-traumatic stress disorder, and psychosis. And finally, to describe the potential of endocannabinoid modulator as new agent for therapeutics. So, cannabinoid receptor, you have two types of cannabinoid receptors that have been identified. The cannabinoid CB1 receptor is expressed at very high level in the brain and in multiple brain area that control very important function, such as learning, memory, and others. You have also the CB2 receptors that have been primarily found in the immune system and have been also recently identified in the brain, but the role in the brain is still relatively unclear at the present, and CB2 have very low expression level in the brain. So, there have been in the past drugs that have been developed by pharmaceutical company to target this CB1 receptor. And I would like here to remind you about a compound called Rimonaban. This was a compound developed by Sanofi Laboratory and it was developed as a CB1 antagonist and also an inverse antagonist. So, mostly this drug was able to be effective to produce weight loss in obesity and also improve metabolic risk factor. So, you can see this drug was tested in multiple clinical trials published in very good journals, such as the New England Journal of Medicine, Lancet, JAMA. And this is one of the results of those clinical trials that you can see on the left here, the impact of Rimonaban administered at two dose, 5 milligram or 20 milligram in those clinical trial and was able to produce significant weight loss over time. And you can see in the right the change of level of HDL cholesterol and here you have a reduction of the cholesterol level over time or so with Rimonaban. So, this compound was then put on the market and primarily in Europe, was never used in North America. Rimonaban has also been at the time been tested as a drug for smoking cessation. There have been a series of clinical trials conducted at the time that was called the TRATUS program. Over 7,000 patients were enrolled worldwide and mostly using the similar type of dosage regimen as what was used previously in the obesity trials. So, this slide was presented by Dr. Siri Prini at SRNT in 2006. And you can see here the result of the smoking cessation trials. The results are expressed here as odds ratio compared to placebos. So, typically, if you have an odds ratio of two, that means you will double the success rate of abstinence compared to placebo. And you can see here overall Rimonaban was effective as a smoking cessation agent, but with a pool odds ratio of around 1.6, which was a moderate effect. Typically, the drug we use like bupropion or nicotine replacement therapy have an odds ratio of two and varinicline an odds ratio of three. So, it was likely a little less effective than the currently used medication. Rimonaban was also tested for schizophrenia and schizoaffective disorder. So, this is a trial performed by Meltzer and colleagues. Results were published in American Journal of Psychiatry in 2004. And you can see here on the left, the result obtained in the placebo group and on the right is a group proceeding Rimonaban. And mostly the result for schizophrenia were obtained here with various clinical scales, but there was no significant impact of Rimonaban on any of those scales. So, Rimonaban was not an effective drug to treat psychosis. So, but what has been learned over time with this clinical trial is that Rimonaban also had some significant side effects. And this is here a meta-analysis performed on the psychiatric side effects of Rimonaban in the obesity trial. It was published in Lancet in 2007. And mostly here the findings indicate augmentation of the odds ratio for occurrence of depression and also anxiety symptoms during those trials. And those trials also in some patients that was reported suicidal ideation and also some suicide attempts. So, those psychiatric side effects led to the removal of Rimonaban from the market. And at the time, mostly all companies that were working on developing drugs for the cannabinoid system stopped their program of development because it was seen as not a valuable drug target. So are there any other ways to modulate the endocannabinoid systems that could still maybe retain some of the therapeutic efficacy? So there are now renewed interest on this area and I will mostly provide an overview of various clinical trials. So one of the drug targets that we hear a lot these days is cannabidiol. So it's a drug with complex pharmacology. It has been approved for several forms of epilepsy. So cannabidiol is also compounds that affect cannabinoid receptor. You have also different cannabinoid agonies that are available. So THC is the active ingredient in cannabis producing the addictive component of cannabis and the intoxicating effect. But you have also on the market in some countries derivatives that are available like nabiximol which is dairy from the plant and it's a combination of THC, CBD. You have nabilone which is a synthetic oral THC analog and ronabinol also that have been available for some time. And you have currently novel drugs into development. Those are the fatty acid amide hydrolase inhibitor and various CB1 drugs. So let's start with cannabidiol. So cannabidiol have been approved for treatment resistant epilepsy. It's available in the US approved by FDA but it has a complex pharmacology. You can see here various target are listed like and notably you see in blue some agonist effect or antagonist effect and there's agonist negative allosteric modulation. And clearly it appears that cannabidiol is blocking CB1 and CB2 function. So cannabidiol has been tested now in various clinical trials. So on the left here, you have some findings by Morgan et al. It's a trial performed in the UK in smokers but it was a very short duration of cannabidiol exposure in this trial. And what's reported here is that cannabidiol was effective to decrease the number of cigarette smoked during the trial duration. Freeman et al in the middle here have reported on a clinical trial of CBD for cannabis use disorder treatment and they reported improvement of cannabis use over time, notably reduction of urine positive for cannabinoid metabolite and an increase of day abstinence during the trial. And on the right, Erd et al in 2013 reported that placebo, CBD was superior to placebo in reducing heroin use craving in patients with opioid dependence. So you have also some negative findings that have been reported. Here you see on the left, a clinical trial performed in Montreal testing CBD versus placebo for cocaine use disorder treatment. And you can see clearly here that CBD had no impact on relapse to cocaine or on cocaine use assessed by positive urine drug screen. There have been also a series of preclinical and some clinical studies suggesting the potential of CBD to affect alcohol drinking, but this has not yet been tested in a treatment trial in treatment secure patient. So cannabidiol has also been tried for schizophrenia treatment. And here you can see a study that compared cannabidiol to Amisulpride, which is a typical dopamine blocker. And this study reported some clinical improvement of psychosis symptom with cannabidiol, similarly to Amisulpride. In another study on the right by Meir et al, CBD group also reported a lower psychotic symptom suggesting some antipsychotic efficacy of CBD. But there have been also some negative study, for example, Boggs et al found no advantage of adding CBD in patient already on antipsychotics. So I would say this is very encouraging, but not yet fully demonstrated. CBD has also been proposed as a drug that could be used to treat anxiety. And the first study here shown on the left tried mostly as an effect of an acute CBD administration. And that was using a public speaking task that is able to induce significant anxiety on subject. And CBD was able to reduce anxiety level in this study. You have also another publication reporting that in adolescent with social anxiety disorder, CBD was able to reduce some anxiety symptoms. So those findings suggest that maybe CBD could be an effective drug to treat anxiety symptoms, but it has not yet been validated into large scale randomized clinical trials. So what about cannabinoid agonists? So I mentioned there are on the market various drugs that are cannabinoid agonists. And Nabilone and Ronabinol have been available for many years and primarily used for nausea management in the context of chemotherapy, for example. But you have also Nabixibol, which is a spray that contain THC and CBD that has been approved in various country, notably for management of spasticity associated with multiple sclerosis. So those cannabinoid agonists have been tested in some small scale study for their potential utility for mental health disorder treatment. And here on the left, you can see that Jaitley et al reported the utility of Nabilone to reduce nightmare or increase functioning in subjects that had PTSD. And this study was positive, reporting improvement of well-being, decrease of nightmare, but the sample size was very small with just 10 subjects and it was a crossover study design. You have also some other indications that THC or cannabinoid agonists may be beneficial. And here it's imaging study showing that THC administration reduce amygdala activation in adults with post-traumatic stress disorder. So mostly those type of findings suggest that cannabinoid agonists may be beneficial, but so far it has not been validated in large scale clinical trials. So the cannabinoid agonists could also be useful as a substitution therapy for cannabis use disorder treatment. So as you know, the typical management of drug addiction consists of administering an agonist. For example, nicotine replacement could be used in smoker or we use also methadone or suboxone in the subject that have developed opioid use disorder. So here there is this idea that maybe a combination of THC slash CBD could be used as a substitution therapy in subject with cannabis use disorder. So here we tested this idea first in a laboratory measure of cannabis withdrawal and we found that Sativex fixed dose, high dose was able to reduce symptom of cannabis withdrawal. But there have been also clinical trials conducted primarily in Australia, but also in Canada by your group, indicating that cannabisimol administered for multiple weeks in clinical trial versus placebo reduce cannabis use during those clinical trials. So those are relatively small scale clinical trial that seems to indicate positive effect, but this still needs to be replicated in larger trial for validation. So what type of other drugs could be used also to produce some impact on the cannabinoid transmission? So you have here a representation of a synapse and you can see on the post-synaptic side, that's where anandamide get synthesized and mostly anandamide is a retrograde signaling that's act as a break to prevent overexcitation of the post-synaptic neurons. And anandamide is enzyme that is involved in its degradation is called fat, so fatty acid amide hydrolase. And if you block this enzyme by an inhibitor, you will produce an elevation of anandamide level. So, and this is shown here on the right in some basic clinical model, you can see that compounds that block fatty acid amide hydrolase was able to elevate anandamide levels significantly, but not change the level of 2AG, which is another on the cannabinoids. And what was interesting in those initial paper was the discoveries that if you block the enzyme fatty acid amide hydrolase, you produce some antidepressant effect. And you can see here, one of those animal model, the ligand called ULB597, which is an inhibitor of FAR, was effective as was desipramine to produce some antidepressant effect. But also in the elevated plus maze, which test, which is a model of anxiety, you could see here that the compound ULB597 was able to produce anxiolytic effect, suggesting that blocking FAR could be both anxiolytic and antidepressant. So, but FAR blocker initially was developed as a way to modulate pain. So there is lots of interesting finding linking FAR to pain. And so the first trial that was conducted with FAR inhibitor was targeting pain. And here it was a trial targeting the pain associated with osteoarthritis of the knee. And in this trial, they did a comparison of the FAR blocker versus naproxen, which is a typical drug used to produce analgesia. And in this trial, mostly they found no effect at all of the FAR blocker on pain management, which led to early termination of the trial. But there have been more recent studies that came out. And here on the left, you can see Schmidt et al that reported some result from a novel FAR inhibitor tested in social anxiety. And mostly this score measuring anxiety level in the subject decreased in the trial, but there was improvement also in the placebo group. The difference between the two group was not significantly different. So there was maybe a slight better improvement in the group treated with the FAR inhibitor at end of trial, but it was not statistically significant. Another way that FAR blocker could be used in therapeutic is maybe to boost endocannabinoid transmission. And you can think that it would be a way also to reduce maybe cannabis withdrawal symptom because clearly one subject that used cannabis chronically stopped using cannabis. They may have a deficit in the transmission related to the cannabinoid system. So there have been this idea that maybe FAR inhibitor could be helpful as treatment for cannabis use disorder treatment. And indeed, Deepak D'Souza has run a clinical trial and found some beneficial effect of FAR inhibition in subject with cannabis use disorder. And this is currently being replicated in a larger multicenter trial. So another interest that I mentioned earlier of potential use of cannabinoid agonist is to modulate possibly post-traumatic stress disorder. So there have been not yet a direct study testing an inhibitor of fatty acid amide hydrolase for PTSD treatment, but there have been an experiment, translational medicine experiment conducted and with RC volunteer. And in those recent results, they report clearly that the FAR inhibition produced an elevation of anandamide in this volunteer, but also they found that FAR inhibition potentiated recall of fear extension memory and also attenuated autonomic stress reactivity. So those findings suggest that possibly you could reduce the impact of stress in humans by administration of a blocker. So this supports this idea of maybe testing FAR inhibitor for PTSD treatment. So in conclusion, in terms of the substance use disorder, what we can say for sure at this point is that cannabinoid CB1 antagonist such as rimonaban were drugs that were effective to block cannabis effect and also effective for smoking cessation. And also I mentioned put in the market at the time for obesity treatment, but the use of this class of ligand has been limited by psychiatric adverse effects. So it has been, rimonaban has been removed from the market. More recently, it seems that cannabidiol, which is also derivative from cannabis plants that seems to block CB1 and CB2 receptor seems to be possibly useful for treating substance use disorder treatment. We notably encouraging data in a clinical trial for cannabis use disorder treatment and some very early findings that support maybe utility for smoking, opioid or alcohol addiction, but this has not been validated in clinical trial yet. And at this point, it seems it's not useful for cocaine use disorder treatment. And there is a great excitement about maybe using CB1 antagonist with things like nabiximol or phainhibitor as a substitution therapy for cannabis use disorder treatment, but this is still experimental. So in terms of post-traumatic stress disorder, so there is some pilot studies supporting the potential use of cannabinoid antagonist, but it should be noted that it's small-scale trial and this needs to be replicated with larger sample size. And there is a human translational study supporting the use of phainhibitor to modulate fear processes, anxiety in human subjects. In terms of psychosis, the drug rimonaban was not effective as an antipsychotic, but there have been recently emerging data supporting the use of cannabidiol as a potential antipsychotic drug. And this is very interesting because the current antipsychotic drugs such as the D2 blocker have lots of side effects and possibly this new class of drug may have less side effects. In terms of social anxiety disorder treatment, we know from lots of preclinical studies that direct CB1 receptor activation has the phasic effect of anxiety. Often stimulation of CB1 is anxiolytic at low dose, but when you push the dose, you produce some anxiogenic effects, which is a little bit complex. And phainhibition has not been producing convincing effect in the large-scale trial that was conducted, despite some strong preclinical evidence supporting phainhibitor as anxiolytics. But it seems that cannabidiol could have some anxiolytic properties in humans, but here again, limited data collected so far, and we need also long-term randomized clinical trial to validate. So mostly the main message I wanted to give you is that cannabinoid drugs are available have some real potential for mental health treatment, but this will really need to be validated in clinical trials before being useful in therapeutics. So I would like to acknowledge over the years the participation of multiple member of my labs, and I would like to thank you for your attention. Hi, everyone. My name is Janne Kozijn, and in this talk, I will tell you more about cannabis use, science practice, and policy from the perspective of the Netherlands. But first, I have no conflicts of interest to declare and I would like to thank my collaborators, but also NIDA, ERC and NWO for supporting my research. The learning objectives for this talk are to familiarize you with the Dutch cannabis policy, the impact it has on individual health and research, but I will also discuss some of the general issues surrounding cannabis science and how to move forward. What you see here is where I used to work in Amsterdam. And what makes this place special is not only its location in the city center, but also the cannabis outlet that you will find just in front of the main entrance. And from an international perspective, this is crazy, being able to buy and smoke cannabis right at the doorstep of an educational institution. So this shop and its regular customers is actually where my scientific interest into the mechanism's underlying trajectories of use towards dependence started. How come some users develop addiction while others do not, even after prolonged heavy drug use? At the University of Amsterdam, I founded the Neuroscience of Addiction Lab, which is currently in transition to the Erasmus University Rotterdam. And I'm intrigued by this fine line between addiction risk and resilience. And together with my team, I study how the brain and the interaction with its environment shape individual trajectories across the lifespan. If we really want to understand the underlying mechanisms, an interdisciplinary focus is crucial. As such, we study hardcore neurobiology in mice and men, but also the role of social dynamics and culture. Just to give you some examples, we currently compare cannabis addicts from Texas and Amsterdam to explore the potential role of cannabis culture in shaping addiction. And we are comparing the effects of cannabis intoxication on liking and wanting of softer and harder drugs between Americans and a Dutch sample. As you probably all know, today's world is experiencing shifts toward lenient cannabis policies and similar shifts in public opinion. These parallel global increases in treatment demands for cannabis dependence. And cannabis has been decriminalized in Netherlands for more than 45 years. But like you can see in this figure, treatment demands have also risen here the past two decades. It currently is the most prevalent addiction among young adults requesting treatment in the Netherlands, but also in many other countries. Only an estimated 17% of users believe they can get addicted. And while cannabis is less addictive than some other substances, the negative impact is comparable to other addictions, with only one in five achieving remission after treatment. To create optimal policy that minimizes individual and societal harm, we need knowledge about both harms, but also potential benefits, and about the impact of certain policy measures. So the burden of proof really falls on scientific research. Cannabis was officially decriminalized in 1976, classifying it as a Schedule II drug. Cannabis is still illegal, however, but use and possession were allowed under certain circumstances. So the goal of this policy was to separate the cannabis market from other hard drug markets, the idea being that it would prevent cannabis users to come into contact with hard drugs. Since then, users were no longer classified as criminals, but use was more and more seen as recreational behavior, and in some cases as a symptom of some underlying psychopathology. So currently, you are not prosecuted if you possess less than five grams, less than five plants, and use in the privacy of your own house. Cannabis products were initially sold by house dealers, but since the 80s, most of the cannabis market surrounds the so-called Dutch cannabis coffee shop. And the coffee shop was actually never the intention of the government, but as long as they kept to strict rules, the owners weren't prosecuted. In a coffee shop, you can safely buy and use cannabis, but it's forbidden to drink alcohol and smoke cigarettes. In the picture you see here, you see an example of a menu card of one of the coffee shops in Amsterdam. Everything that happens at the front door of the shop is tolerated, but everything at the back door is still illegal. So production, transport, and stocking of supplies is prohibited and actively prosecuted. This paradox, and it's really a tangle of rules, is a major issue. There is a large criminal scene involved, and coffee shop owners have to operate in the dark. Also, there are currently no legal ways to really check product quality. As such, there's a strong need to establish a closed circuit from cannabis cultivation to selling to customers. And the government recently started an experiment in some cities with legal supply, but things are moving really slowly, which results to be expected in 2025. Medical cannabis use has also been legal since the year 2000. So GPs can prescribe on a patient-by-patient basis, so there are no specific rules regarding the kind of symptoms cannabis can be prescribed for. Medical cannabis can only be produced by one company, Bedrocan, and they offer five different strains of herbal cannabis with varying levels of low to high THC and CBD. This is actually also the only cannabis we can use in research. We are not allowed to get it from the shops. So what is the typical Dutch cannabis user? An estimated 87% prefer smoking cannabis joints with tobacco, so aka spliffs. For comparison, this is 4% in the US, 11% in Canada, and 37% in Australia. The average THC levels has been stably fluctuating somewhere between 15 and 17%, and the CBD concentration is generally low. A minority of the medical cannabis users actually gets their cannabis from the GP. They complain about the low quality of the cannabis produced by Bedrocan, and the patient group that does get it via the GP are mostly MS patients and cancer patients. So compared to other countries, cannabis potency, so an average of 16% THC, is relatively high in the Netherlands. So what can we conclude? Dutch users show a homogenous method and product of use, so smoking strong herbal cannabis with tobacco, with low CBD, and of course this also impacts the health effects of cannabis. So the Dutch cannabis policy aims to protect health and control nuisance and crime. The policy has been an example for many countries because it allows us to kind of foresee the potential long-term effects of a regulated recreational cannabis market. But does it really work? So far we know that policies unrelated to use rates, so Dutch use rates are stable and comparable to other European countries, but still a concern, especially among youth. There is less stigma, there is a safe place to use and buy cannabis, and the separation of markets seem to have decreased the correlation between cannabis use, cocaine use, and amphetamine use. However, if we really want to protect health, reliable product information is important, and this is currently missing and totally unregulated. So coffee shop owners don't have any means to test the quality of their products in a legal way. So what about the impact on science? So this is mostly from my own personal experience as a Dutch cannabis scientist. I believe the coffee shops offer us a great opportunity to conduct research in naturalistic settings. So the picture here, the supermarket, is one of the coffee shops that we regularly test cannabis users in. However, we're only allowed to use medical graded cannabis, and this is by no means comparable to the actual cannabis that is used by cannabis users. Also, it's quite difficult to obtain a permit to work with medical cannabis use. It took me two years and a lot of money. So in a way, this situation is kind of comparable to the US situation. Also, there is low national priority to invest in cannabis research relative to alcohol and tobacco. So there are almost no funding opportunities, and in my personal experience, I haven't been able to get funding for cannabis research in the Netherlands. Everything comes from either the US or from the European Union, and this isn't the case for alcohol and tobacco, and this is an opinion echoed by many of my colleagues. So where do we go from here? Especially given the worldwide policy changes, there is an urgent need to improve cannabis science. And why am I saying this? For a lot of health outcomes, effects are mixed and understudied. Most studies focus on the negative effects in ever-to-regular users, but it is really hard to integrate evidence in which the regional differences in cannabis use culture also play a big role. Regarding positive effects, there is mostly anecdotal evidence, and users report large effects on many different outcomes, but the scientific evidence is largely missing, especially for the effectiveness in treatment of treating mental health problems, which is one of the major reasons for which medical users use cannabis. So randomized control trials are missing. So my lab focuses on the effects of long-term cannabis use on the brain, and just to give you a brief update on the evidence out there. So there is sufficient evidence for impairments in learning, memory, attentional control, and increased risk for developing anxiety, depression, and psychosis. There is consistent but very limited evidence for impairments in emotion processing, particularly for negative emotions. There is inconsistent evidence for impairments in working memory, and insufficient evidence for impairments in decision-making and inhibition. So there are some suggestions about potential important moderators that need to be investigated, including of course dose, onset age, addiction severity, use severity, the ratio between THC and CBD, and method of use. There are initial indications that all these compromised functions recover after abstinence, but large-scale longitudinal studies are missing. And I think to me one of the biggest issues actually that studies in diagnosed groups, so groups diagnosed with a cannabis dependence, are missing. So most studies investigate ever users versus never users, or sporadic users, or chronic users, there are a lot of terms around, but not in this diagnosed group, which is of course very relevant if we want to know more about the impact of cannabis. So the cannabis research field is really young compared to, for example, alcohol, tobacco, and cocaine research. This is important to realize when you evaluate scientific evidence yourself. For example, Q-induced activity in reward-related brain areas is considered an important biomarker of addiction, but it was only eight years ago when we for the first time showed that this was actually also true for cannabis addiction. And interestingly, as can be seen in the figure here, activity was higher in individuals that showed higher levels of craving and cannabis use-related problems. We subsequently scanned our participants again three years later and found that craving and Q-reactivity industriates and predict use and problems three years later. It's kind of a no-brainer if we look at the general addiction evidence base, but I thought it's relevant to share that craving actually is a very consistent predictor of trajectories of use in multiple of our studies, from escalation to withdrawal severity to treatment outcome. So a general limitation of the cannabis research field is the difficulty to reliably assess cannabis use history because the product type, content, route of administration are highly variable between individuals and countries. The self-report measures vary from study to study and there's no standard unit like is the case for alcohol. Objective measures like hair analysis, blood and urine analysis are also suboptimal because they can capture combined acute and subacute effect of recent use and are very expensive. So there is an urgent call for standardized measures and terminology, and if you're interested in this topic, please read the papers by Lorenzetti and Freeman, collaborators, and the first paper on a standardized THC unit and the second one introducing the cannabis toolkit to assess cannabis use. So another thing I want to mention is that it's really important to embrace the mixed effects of cannabis on health. So we know there is evidence for positive effects, for negative effects, but the effects also greatly vary from person to person, so there are a lot of individual differences. And a nice study to demonstrate this was a recent study where we looked at the impact of the first COVID-19 lockdown in the Netherlands on cannabis use, and we found an increase in cannabis use, but not the severity of dependence. However, there were substantial individual differences. Some really benefited and others really showed a steep increase in their use and problems. And COVID-19 related worries, anxiety, motives for use, and family contact were all unique predictors for this changing use and such severity. The last thing I want to mention is actually like culture impacts cannabis products and the way users use cannabis, it may also impact cannabis dependence, so the disorder itself. For example, the tightness and looseness regarding cannabis of a specific community may impact the social problems a specific person has, and the pattern of symptoms may be moderated by cultural factors. Of course, it's extremely hard to pinpoint and operationalize these cultural factors, especially because policy, of course, also plays a major role. So it's really difficult to look at causal mechanisms, of course. However, in a collaborative study with Francesca Philby, located in Texas, we're currently investigating whether, well, our first goal is to identify neurocognitive mechanisms underlying cannabis dependence that replicates over space and over time. And our second goal is to explore the moderating role of cannabis culture. And taking a quick glance at the preliminary data, we already see that participants in the US perceived more positive and less negative effects positive and less negative effects of cannabis than participants in the Netherlands. This was actually against expectations because we know Texas is extremely strict regarding cannabis policies. So hopefully more interesting results in the future. And that brings us already to the end of this talk, and I would like to conclude with this take-home message. I think it's really important to realize that there is an urgent need to improve and expand our knowledge base, and a key focus should be on harmonization of methodology. So something we as a research community should collectively invest in, and also invest in studying the potential impact of cannabis culture, including policy, of course. So thank you. Well, thank you. My name is Kevin Severino. I'm going to act as moderator and presenting some of the questions that have been brought up in the Q&A, as well as some that I did. But I wanted the presenters today have all done a fantastic job, and I think this is really a great perspective because somebody like myself pretty much understands the cannabis environment from the United States, but the international perspective can be, I think, very informative. So let me start. I know that Dr. Bunt answered most of his questions within the Q&A, but many of the questions for Dr. Bunt actually involved the idea that people using CBD products ended up having a THC in their urine or wondering where they could get the most pure products. I know, Dr. Bunt, you had actually mentioned one product you yourself had had tested that was pure CBD and did not contain any THC. Any thoughts on where's the best source people can get their CBD products that don't contain any THC? Okay, a very good question, and I think it entails a little bit of research on the part of any physician who is encountering a patient who's using a CBD product. There are so many CBD products available, but there are some companies that actually can furnish a laboratory report that they say can be validated, they're open for audit, and so different companies have different standards. The dispensaries can vary very widely in reliability, so you have to be very cautious about dispensaries, but some of the companies will furnish these laboratory reports, and as I had mentioned, I actually sent a sample of a product that I obtained and had it verified that it had no THC. The cutoff, of course, is 0.3 for being negligible, and many products have less than that cutoff point of 0.3, and this, again, can be verified with a laboratory report that hopefully could be obtained from the company. Not all companies will do this, and so that's why each and every physician has to evaluate with the wide range of CBD products if they're concerned about having THC in that product to do their research and to evaluate that. Thank you, thank you. I jumped the gun a little, Dr. Bunt, where we were supposed to actually move to our polls first, so can you do that now? Yes, who's going to help us do the polling? Is it Kelly? I can help you with that, Dr. Bunt. I'll go ahead and start our first one. So, if everybody could answer the survey questions. First is, do you believe smoking or vaping THC is harmful to adolescents? Are you able to see, Sarah, how many have responded? Yes, give me just a second. When it seems to level off, let us know. Okay. So almost all, just like the ISAM and ASAM surveys, felt it was harmful. Okay, second question. Do you believe smoking or vaping THC is harmful to those with mental illness? We'll make sure I would say give it about 15 seconds to make sure we get enough respondents again, the vast majority over 90% agree or strongly agree that it's harmful with those with mental illness. The third question. Oops. Smoking or vaping THC. Is that harmful for individuals with a predisposition to addictions. And again, most, we've got 85% somewhat agree or strongly agree. The fourth question, now this one actually was a little different with ISAM. So do you believe smoking or vaping THC is harmful for opiate addicts, we should say those with opiate use disorder in recovery? this one was a little more strongly in favor of agreeing that it was harmful to those in recovery than the ISAM results. Is that right, Dr. Bunt? Yes, that's correct. That is indeed correct. Yes. Okay. Our fifth question. Would you consider prescribing CBD, cadaver dial, off-label for treating pain? So kind of the modal answer there is some would agree or not sure. And then more after that, disagree than agree. It's interesting, I'd like to know how many of our respondents treat pain. Okay, next question. Would you consider prescribing CBD off-label for treatment of opioid use disorder? And that's similar to the ISAM-ASAM data, which definitely skewed toward the idea many would not. We actually had 51% feeling somewhat disagree or disagree, and only 25% somewhat agree or strongly agree, which is interesting. Our next question. Would you consider recommending hemp oil with CBD, but no THC for treating pain? And I'm trying to remember, maybe you remember, Greg, how that relates to the CBD without the hemp oil in treating pain. Looks similar. Most somewhat agree and some are not sure. Yes, that's correct. Yes, so you get a kind of a cross-section leaning toward the gray. Next question. Would you consider hemp oil with cannabidiol but no THC for treating opiate use disorder? and definitely more on the disagree side for treating of opiate use disorder, which was also true for CBD alone in terms of treating pain versus opiate use disorder. And then I think we have one more survey question. I think nine is the last. Yes, it is. Do you think AAAP should develop a public policy statement or position on cannabis and cannabinoids? And I should mention, we do have a kind of a model curriculum which acts as our policy, but I guess the way I would think of it is, should we update that? And most strongly agree. I would agree. It's actually on my to-do list after this meeting to discuss with the Cannabis Special Interest Group all the feedback I've gotten during this meeting on that, given that we are, I think, behind the times. Another suggestion had been made in the Q and A's about whether AAAP should advocate for what separating out laws that deal with CBD versus THC-containing compounds, which I think is important because I agree with Dr. Bunt that there can be a lot of research on CBD, which in the United States is very limited by our inability to do that kind of research without following under a schedule in one problem. And Dr. Cousins also mentioned in the Netherlands, there's one source there, whereas what's in the street can be very different. Did you want to comment on the survey results, Dr. Bunt, before we went on to some questions? Well, I think it's very interesting and it leaves open the question of the future of this area, and in particular with addiction psychiatrists having a major role in advising patients and families and policymakers and in the development of public policy. But I think AAAP can have a very significant role in how this gets developed and unfolded. With CBD, of course, we still don't have, unfortunately, sufficient amount of research that would give confidence for many addiction physicians and psychiatrists to be able to prescribe it or advocate that it should be used or prescribed in clinical practice. But we do need more research. I think the very critical Yasmin Hurd study needs to be repeated. And if it shows that CBD is useful and therapeutic for treating opiate withdrawal, and maybe even on a longer term basis for treating opiate use disorder, then that would be very important for our field. And of course, the dosing also needs to be established. I mean, the 50 milligrams they can get over the internet, is that a sufficient dose? Or do you need the higher doses that are being used now for the treatment of seizure disorders? With the availability of Opidiolex, are you surprised that more research on CBD hasn't been done? I know we wouldn't do the dosing of 1,400 milligrams a day. It seems like such a ripe area to do research. And I'm just surprised we're not seeing more, especially in the realm of pain management. I've spoken to representatives from GW Pharmaceuticals, and they explain that it's very, very expensive to do the clinical studies. However, I believe that NIDA could promote through an RFA. They could promote further research. I think we could advocate through AAAP and ASAM also, and ISAM, to have more funded research because the expense of these clinical studies is very significant and often prohibitive for a company, even like GW, that produces Opidiolex. We need to advocate for more funding in this critically important area because as we know, CBD may be therapeutic, but to use cannabis with THC, and that you get into a whole different area clinically and scientifically. Right, right. I wonder, a question for Dr. LaFolle. In Canada, are there as many restrictions on CBD research as you've probably heard about in the US? Yes, so thanks for the question. I think in Canada, it's a very unique situation because now we have lots of licensed producers that have been approved, and we have more than 100 at the current time. And if you think that those 100 licensed producers, they all sell a multitude of products, so we have indeed several hundreds of products that are available for any Canadians to purchase without any problem for recreational use. But for research, it is more complicated because if we want to study those products for, let's say, medical indication, then we have to provide the same type of requirement as if it was a drug under development. And so we need to get an investigational brochure. We need to get GMP product. We need to get a CT, a clinical trial submission to Health Canada. So mostly, the burden, the administrative burden to do those trial is very, very high, and we are in the situation where very few investigators have been able to study the medical indication of those products at the present time. Yeah, having worked with, in the same hospital as Cyril D'Souza in Connecticut, I've heard a lot about the challenges of doing cannabinoid research. And I think another complication in Canada, having trained in Quebec, is you always have to have two arms, a substance and a substance plus maple syrup to understand how it works for Canadians. A great question here. Given CB1 inverse agonist antagonists, I think they mean Ramanubandh, led to increased suicidal ideation. Are there any studies looking at full CB1 agonists in treating acute suicidality? So I guess THC would be a full agonist. I'm not sure. Yeah, so THC is a partial agonist to the CB1 and to the CB2, but it's not a bad idea at all. Like you could imagine that acute stimulation of CB1 could interfere with those type of processes. I don't think it has been tested yet. So it all also depend on the pattern of administration and how those drugs are administered. So that's why I found your questioning, your survey a little bit earlier, very interesting, but also it's very different. Let's say if you use a low dose of the CB1 agonist in a very stable manner, or if you smoke high concentration THC and you are addicted to it and you smoke it in a erratic manner. So I would say you can lead to potentially very different type of effects. So it's important to also consider like the dosage and the pattern of administration typically. Right, right. I am always struck when people discuss medical cannabis that in fact the control of the dosing and the administration once somebody gets home is so different than when we give a defined compound as a pill. And I've always kind of recoiled against the idea of calling it medical cannabis until we have a defined substance. I was wondering for Dr. Cousins or Cousine, I may be saying your name wrong, and Dr. LaFolle, your thoughts on the idea that with opioid use disorder, we have both antagonist treatment with naltrexone and we have agonist treatment with methadone and we have partial agonist treatment as well. So you've got effects of some possible effects of an antagonist on cocaine use, cannabis use disorder, but then you also have some promising data on agonists and treatment of cannabis use disorder. Any idea, did you cite, did either of you cite studies on antagonist effects on cannabis use disorder? Yeah, I can comment on that because I mentioned that in the conclusion of my presentation, but I didn't show the data. So those were mostly study testing, Rimon Avant on acute effect of cannabis and done by investigator at the National Institute of Drug Abuse and Traumatology Program. And they have shown that Rimon Avant could block some of the effect of cannabis, not completely, but partially. But typically like patient prefers the agonist therapy versus the antagonist therapy. It's typically their preference. So that's why maybe it's a good time now to continue to explore the agonist CB1 for substitution therapy, because anyways, CB1 antagonists are not anymore available in therapy. Thank you, thank you. Dr. Cusine, it was interesting to hear the experience with the Holland model. You had mentioned the idea that in one of the studies as during the COVID pandemic, cannabis use went up, but the severity of cannabis use disorder did not go up. By that, did you mean that those that had cannabis use disorder were not more severe or that the rate of cannabis use disorder didn't change? Yeah, I think there are just a lot of individual differences and the level of use does not necessarily translate to the level of the severity of the addiction. So you have some people that are daily users and function really well, and you have daily users that don't. And this may be an effect of basically the development of more symptoms lagging slightly behind. So it was only data from the early stages of the pandemic, the first lockdown. So it might be that the severity increased after a while, but I think most striking to me is that the effects are so different from individual to individual that you see people really benefiting from a lockdown and reporting less stress and less use and some people escalating. And to me, it appears that relative to other substances, cannabis has more, the effects of cannabis are more different from person to person than, for example, the effects of alcohol. And maybe this has to do with the balance of the endocannabinoid system and interacting with, because it's present basically everywhere. But is this something we should realize? And also these medical users reporting benefits and basically addicts reporting the same effects, but then as negative consequences are also really hard to integrate. So I have a feeling we find proof for everything, every claim out there, there's proof, but how are we really integrating everything into a solid knowledge base that could help patients, but also the recreational user to use it safely? I find that in the United States, state and federal, you know, Congress people and legislators have virtually no ability to integrate complex data. They either find something that supports their view or that's something that is against their, you know, or against the view and run with that, which makes it difficult to make informed public policy decisions. You had mentioned this idea that some of the criteria for a substance use disorder, and in this case, a cannabis use disorder are kind of socially defined. Yeah. And it was argued yesterday in one of our symposia that rates of cannabis use disorder, which common, you know, in the United States, it's felt somewhere between nine and 20% of those that smoke daily will develop use disorder. It was argued that that is a grossly inflated number because of society's view of cannabis. Yeah, there are multiple reasons there. Yeah, the inflation is definitely true, but it's also the way we measure it. The clinicians out there, psychiatrists know that if you perform a clinical interview with someone that comes to the clinic with a problem, that the DSM criteria are more reliable than if you have it as a screening interview by phone or an online questionnaire. So those rates are definitely inflated, but the cultural stuff, for example, if you live in an environment where people don't judge your cannabis use, even if you're a daily user, they don't see it as a problem, then some of the criteria are less likely, you're less likely to tick some of the boxes. But if you are an environment that is constantly telling you what you're doing is really wrong, then even a lower level of cannabis use could already lead to social problems and problems at work or problems with spouse and the family and friends. So these are really important factors to consider and maybe less so for the, of course, the withdrawal or that could be more the same in different countries, but the social problems, I think, differ a lot. And you could be a cannabis addict with totally different symptoms compared to another cannabis addict, but we still all call them cannabis addicts. It's the same, of course, true for alcohol use disorder and any other addiction, of course. Right, right. Okay, Koes, and I would like to ask you, are most physicians and medical providers satisfied with the Holland model as a system? Well, yeah. Cannabis regulation. I've been thinking about this question and to be honest, cannabis isn't really a thing in the Netherlands. So there aren't that many physicians really prescribing it, also because people, if they want to use it, they go to the coffee shop and just buy it. So it's kind of out of the system a little bit. And the most issues come from the psychiatric clinics where there's just a lot of comorbid use and for adolescents that if they are using cannabis a lot, then it's really difficult to treat anything. But for legalization, I think everyone is really at this point like, come on, either just fully legalize or stop because right now it's impossible to work around all the complexity of rules, as if we're kind of stuck and we can't move forward. One of the attendees asked, it sounds like there's some great data supporting CBD as having potential therapeutic value in the research of THA inhibitors. It might be a workaround for Schedule I issues. The question is, how can we support efforts to put research at the top priority for funding sources? I'd leave that open for all three of you. Well, again, I've had conversations with some of the representatives from GW Pharmaceuticals, and they say what's prohibited is the funding for these clinical studies in these other areas, but I think we need some strong advocacy to NIDA to fund these studies. Another, Dr. Pachano, indicated that there might be an issue for NIDA funding, or even pharma companies funding, research into cannabinoids, because it would compete with pharmacologic treatments already existing for opioid use disorder or mental illness. I don't know what people think about that, that the research community or the federal funding community is so invested in what's already on the market that we wouldn't try to compete with those drugs. I'm not sure I'd agree with that. Wow, it's hard. Do you really think that the effects of cannabidiol are really large? Do we really think, of course there are some studies out there showing really positive effects, but the effects are quite small. I'm just curious what you think. Do you think it is this major promise, or is it just, yeah? Well, that's a very good question, Dr. Koos. I think the Yasmin Hurd study does show a lot of promise. Now, the question is, can that be validated or not? If it is validated, then it's a very significant reduction in opiate withdrawal with 800, now that's at 800 milligrams a day for two weeks, which didn't lead to any adverse effects. I think that's really a springboard for more research to determine whether that is really significant as the publication indicated. Good points. I'd also point out that a treatment for opioid withdrawal is not necessarily an effective treatment for opioid use disorder. We feel that's the beginning step. We have drugs like suboxone or buprenorphine naloxone that pretty effectively treat opioid withdrawal, but then the longer-term lasting effects of the opioid use disorder have to be treated. Well, that is true, and certainly buprenorphine, we know it's a very effective maintenance treatment, but the issue is for some people, they would like to use perhaps a more natural product to hopefully wean off of buprenorphine. Now, that's a controversial area in itself, but if somebody wants to wean off of buprenorphine and wants to try cannabidiol, if there was some indication it could reduce withdrawal, then that would be significant and a significant area for us to research. Well, if you look out a year, those on buprenorphine, you've got less than 40% retention after one year. I mean, I'm a big proponent of using it, but it's not super effective in terms of long-term effects. For Dr. Cousins, I'm not sure that CBD will have high effect sizes, but in the chronic pain field, we're trying to latch onto anything to substitute, hopefully in combination with other agents, the strong belief that many people have in maintaining high-dose opioids. So, it's interesting to see how the endocannabinoid system interfaces with the opioid system. I had a question for, I think it's mainly Dr. LaFolle, but we'll see. There seems to be reasonable evidence that, you know, cannabis, smoked cannabis, is helpful for PTSD symptoms, but studies in the US VA have indicated it doesn't actually prove helpful in terms of overall function for somebody on PTSD. What's the sense of, do we know baseline levels of anandamides in those with and without PTSD? Because it may be that the effects in those that have low level of anandamides are very different than those that have high basal levels. Yeah. Unfortunately, in terms of the clinical trials, like it has not been really explored much, and I think it's too bad because there are some preliminary findings suggesting it could work. In terms of PTSD and endocannabinoid, there is a recent paper that came out from Toronto from Dr. Boileau using the PET probe curb. So, it's a PET imaging probe measuring the enzyme pha in the brain. And so, I think she just published a paper on pha binding and PTSD. And there may be also some endocannabinoid level in this paper, but it's not my work, so I'm not very familiar with the details. I think it's online now. Thank you. Greg A. Kamporak, a friend of mine, said, Kevin, I'd be careful about saying in pain we're looking for, quotes, anything to help us avoid opioids. What I meant was any approved medication treatment. But here's an interesting question. Given that alcohol hits cannabinoid receptors, I guess it hits everything, might THC, CBD, or other related compounds have a role in the treatment of alcohol use disorder? I'm actually not familiar with people looking at that. Yeah. There is lots of literature on this interaction of alcohol and cannabinoid system and typically if you stimulate the cannabinoid transmission, you increase the rate of alcohol drinking or motivation for alcohol. And the reverse, if you block the CB1 receptor, you decrease motivation for drinking. So, it's a mixed type of message from the literature. So, it could lead to a worsening maybe of the drinking. We don't know yet, but those clinical trials have not been done of trying CB1 agonist for alcohol treatment. Maybe it could work. We have similar type of effect where you give cannabinoid agonist and it's effective to offset opioid withdrawal, for example. So, it could maybe produce the same type of effect in people with alcohol use disorder. We just don't know. Here's an interesting comment that strikes near and dear to my heart because I've testified both federally and from the state of Connecticut when they went to legalize cannabis, recreational cannabis. The attendee says, this is an addiction psychiatry conference. The evidence that THC is neurotoxic destroys brain tissue that leads to psychosis and mania that can become permanent, impairs driving, leading to intoxicated homicide, is neurotoxic to the adolescent brain, causes cognitive impairment, increases depression, worsens anxiety, PTSD, et cetera. And it appears CBD without THC appears helpful in several areas. Why are we not actively speaking out about medical cannabis? I'll answer that first. I think that many of us are actively speaking out. I wouldn't be as strong as far as some of these effects as THC as the questioner is saying, but nonetheless, I believe there are significant harms. The frustrating thing to me is that very, I think, very respected scientists have testified in the United States and my guess is in your countries as well, but that voice tends to be drowned out by other interests. Any other thoughts on the political side of this? It's a hot mess and I think we should realize that each one of us has a bias in their opinion about cannabis, THC, CBD, and our opinion of course is shaped by our experience as a scientist or as a physician or as a psychiatrist and we have to watch out a little bit and take a step back and really look at the evidence, what's out there at the moment, and it's just, yeah, in my personal opinion, it's just a mess and it's too early to move into any direction and that would be my message, but in politics and especially of course in the US, there are very strong opinions advocating for both sides, even in science, so also if you read papers, know the cannabis scientist probably also is a little bit biased towards either believing in very strong harms or in benefits or in not having harms. Yeah, if I can comment also on this, like typically for drugs that we put on the market, we have a very good knowledge of the balance between the benefit and the risk and the challenge we have currently with the cannabis product, notably the one containing THC, is that most of the research has focused on the risk, but very little has been done to try to assess the benefits, so then we are in a situation where we don't know exactly what the benefit-risk ratio is and it's clear that there are risks with THC, risk of intoxication, some cognitive effects, some risk of addiction, whatever, but the benefit, it's much less clear, so the Academy of Science concluded that it seems there may be some benefit, but it's for most of the medical indications that people would use cannabis for medical purposes, we have no evidence at this point or very limited evidence, so it's more the anecdote, so it's clearly urgent to run those clinical trials so that we can determine the benefit-risk ratio and then if the benefit-risk ratio is worse than the existing medication, then the conclusion is clear, like we should start with existing medication for sure. I think that's very well put, that we need to to realize that there are, in cases where we're discussing legalization, if there is true benefit, we're depriving people of that and then in the United States, the criminalization of cannabis has had a harm that we also try to overcome, so there's that whole balance that the Holland model, I think, addresses a little of decriminalization versus legalization and then commercialization, which in the United States has very big companies behind it, very, there's a strong commercial interest for commercialization of cannabis, just like there was for tobacco. And I also think the politics are very complex, but that's why it's important for AAAP colleagues to know where our colleagues stand with that, and so some of these survey questions are important, but more importantly, I think the leadership, Dr. Severino, needs to be aware of how AAAP members feel about these very complicated political issues and determine then in either a position paper or some kind of publication or statement related to where we as addiction psychiatrists stand on the very critical issue of cannabis and cannabinoids. Right. From an international perspective, I feel in the United States, cannabis was long vilified because it was linked to other negative social connotations. In other parts of the world where it's more culturally sanctioned, what's the sense of whether the perceived harms are as great or is it felt basically not to be as harmful in countries where it's much more commonly used? Well, I think it really differs also on subcultures within countries, and yeah, so I don't think there's a single answer there, but my data at least shows that the US participants in our studies are way more positive and also believe that their environment is way more positive about cannabis use compared to the Netherlands, so that was what surprised me. I thought the Dutch people would be more positive. I wonder whether, because as you said, Texas law as far as regards cannabis use is fairly strict, whether in areas of the United States such as Oregon, where it's much more liberal, whether they would see the same, more positive view of cannabis compared, effects of cannabis compared to the Netherlands, or would it be more like the Netherlands? I think that it's generally more positive. There are some data out there and also less beliefs in harms, long-term harms. I would also say from an international perspective, it was Dr. Van der Brink who is very well known in Holland and internationally as an authority in this area. I've had discussions with him and he felt that what was happening in the United States is really an experiment because in other countries, while it might be tolerated, it's not legalized for commercial sale and promotion. The outcome of that will be unknown. He favored the Holland model, which is very regulated, but was concerned about how this would get played out with an unregulated, unrestricted commercial legalization of the commercial sale and promotion. Interesting. I'm afraid we may need to end this incredibly rich contribution to our two-day encounter with this very complex topic. Thank you to all the presenters, to Dr. Severino, moderated so elegantly. We're going to have to move on to our next activity. Thank you.

conference introduction

symposium introduction

recording availability

CME credit

slide availability

cannabinoids

addiction psychiatry

CBD

opiate withdrawal

THC

endocannabinoid system

clinical trials

mental health disorders

Dutch cannabis policy

individual health