Okay. Good afternoon, everyone. I'm ready to start the webinar. My name is Joao De Aquino. I'm an Assistant Professor of Psychiatry at the Yale School of Medicine. I will serve as a moderator for today's APA Emerging Topics webinar on Medical Cannabis for Psychiatric Indications, What Physicians Need to Know. Thank you for joining us today to learn about the latest advances on this exciting topic. I'd like to introduce our speaker, Dr. Ranjith Radhakrishnan, who is an Assistant Professor of Psychiatry at the Yale School of Medicine. And before we dive into our topic, there are a few housekeeping items I wanted to cover. The first is Continued Education Credit. In support of improving patient care, the APA is jointly accredited by the ACCME, A-C-P-E-A-N-C-C. The APA designates this live webinar for a maximum of one and a half EMA PRA Category 1 credits. Physicians should only claim the credit commensurate with the extent of their participation in this activity. Captioning for today's presentation is available. Click Show Captions at the bottom of your screen to enable. Click the arrow and select View or Transcript to open captions in a side window. Please feel free to submit your questions through the presentation by typing them into the question area down in the lower portion of your control panel. We will be reserving 10 to 15 minutes at the end of the presentation for Q&A. I'd like to hand it off to our speaker. Thank you. Great. Thank you, Dr. DiAquino. And thank you all for joining in. This is a very current, exciting topic. And that's something that's relevant to, you know, the care of our patients and our practice. And again, by introduction, I'm Rajiv Radhakrishnan. I'm an assistant professor at Yale. And I work, most of my research is on looking at the effects of cannabinoids. And so I don't have any relevant financial conflicts of interest. I do have some NIH funding in terms of grants. There's one study that looks at the effects of cannabidiol and microbial activation. And Jazz Pharmaceuticals is providing us the cannabidiol for that. There's some funding from the Yale Center for Clinical Investigations. But the views expressed are my own, and they're not of that of my employer or funding agency. So in terms of an overview of the presentation today, I'm going to talk about the medical cannabis landscape in the U.S. We'll talk about cannabis and the brain endocannabinoid system. We'll talk about medical cannabis and CBD for psychiatric indications in terms of what the current level of the evidence is, the risks versus the benefits, and then some conclusions and takeaways. So the landscape of medical cannabis in the U.S., you know, this has been vastly changing. So this is a slide that shows the landscape probably in 2020, when there were about 29 states that had a medical cannabis program, and there were nine that had, you know, recreational cannabis program, or which allowed for recreational cannabis use. And these are highlighted in, like, the light green and the dark green of the slide. Now, things have changed since then, and this is the slide from 2023, as of November, 2023. As you can see, there seems to be like a green wave. Most states have adopted some form of a medical cannabis program. Now, there've been different categories of this. There've been programs where, which allow for both adult recreational use and medical use. There are programs which have just adult use, but no regulated medical program. There are what are called comprehensive medical cannabis programs, and these are the vast majority where people are allowed to use medical cannabis, use the entire plant, the flower. Some states allow them to grow their own medical cannabis as well. And there are also states, which in light green, which are those which have programs tailored towards use of high CBD and low THC programs. As you can see, there are just about, so 38 states plus, you know, District of Columbia have legalized medical cannabis in some form. There are nine states that allow the low THC, high CBD products for medical reasons. And there are three states in which all forms of medical cannabis are illegal. It's Idaho, Kansas, and Nebraska. Nebraska incidentally has a trial program that's not open to the public. So the other piece that came to the floor with COVID was that, you know, a lot of people were using medical cannabis. It was also considered to be an essential business. You know, when there was a period when all non-essential businesses had to shut down, the vast majority of medical cannabis, you know, stores or programs were open. Now, the other change that we see is the way people use cannabis. Traditionally people have used the flower or the bud and the black resin, which was called, which is typically called hashish. But then things have changed now. Now there are, you know, concentrated forms of cannabis, which are called dabs. There are people who use vape pens. There's a whole range of edible cannabis products that are out there in the market. There's a concentrated form of cannabis called shatter and it's called so because it does, it is very crystalline and shatters, but also is very potent and has high THC concentrations. And there are also products for your pets, if you may so please. The change has also been in terms of how people use cannabis. So there are joints, there are blunts, there are spliffs. Now people have, you know, there are bowls or pipes and people have also evolved techniques like the volcanoes where all they inhale is just the smoke and none of the actual plant. There are vape pens, there's Juul. And one of the techniques that is fairly common among youngsters and teenagers, it's what's called hot boxing or where people roll up the windows of a car, one person smokes and everybody gets high. So the change has not just been in the legal status, but also in the ways people use cannabis nowadays. So a little bit about understanding, you know, cannabis in the endocannabinoid system. So when you talk about cannabis, we refer to the whole plant, but what people typically smoke is the white inflorescence of the, you know, the female unpollinated flowers. And those are the places where those stalked trichomes, which have high concentrations of THC, which is the active ingredient in cannabis. Now there are more than 70 different plant-derived cannabinoids, which are called, what are called phytocannabinoids. The main ones that we know of are delta-9-THC, which is thought to be the main psychoactive compound in cannabis. And the other is cannabidiol. Now cannabidiol and THC have very similar structures. The only difference is the hydroxyl group is different, but otherwise they seem very similar. Now cannabis contains a lot more ingredients than just the phytocannabinoids. There are more than 430 ingredients altogether. There are some cannabinoids, which are called minor cannabinoids. There are terpenoids, and these are compounds that give it the characteristic skunk-like smell. There are compounds like flavonoids, like cannaflavin and quercetin, which at least in vitro in animal studies have been shown to have some anti-inflammatory properties. So the other, the key point here is that the other constituents of cannabis also seem to have some molecular targets, like myrcene is, you know, has effects on the GABA-A receptor. There are compounds which change GABA-A levels. Linolol has effects on NMDA receptors and start to in some ways prevent conditioned place preference in opioid models in mice. There are, you know, limonene is thought to have some anti-anxiety effects by working on both GABA levels, glutamate, and the adenosine A2 receptor. Beta-caryophyllin has effects on CB2 receptors, and some of these terpenoids also, at least in animal models, are thought to have some analgesic effects. So how do these cannabinoids act in the brain? And so the two main receptors that they act on are the CB1 receptor and the CB2 receptor. The CB1 receptor is the main receptor in the brain. CB2 is primarily on inflammatory cells, and this also includes the microglia, which is a form of inflammatory cell, which is in the brain. But cannabinoids also act on other channels, like the TRIPV1, which is the, you know, the receptor on which capsaicin acts, and also on GPR55, which is thought to be the mechanism by which cannabidiol or epidiolex has its anti-seizure properties. So the CB1 receptor is very well, you know, studied in both rats and in humans, and this slide just demonstrates the distribution of the CB1 receptor. The more bright it is, is the more high density of these receptors. So you can see that they're primarily cerebellum, hippocampus, substantia nigra, globus pallidus, the caudate, and the putamen. So regions that are primarily involved in memory, motivation, coordination. So these are regions that are rich in CB1 receptors. And it's not very different in humans as well. So this is a study looking at the CB1 receptor in humans. And the distribution, as you can see, is pretty much similar, primarily in the caudate, putamen, cortical regions, also the hippocampus as well. The regions involved in motivation, memory. So the big question was, why does the human brain have cannabinoid receptors? Like for a compound that's in plants, for a long time, the joke was that, well, God put it there so we can all smoke cannabis. But then that didn't really pan out to be true. There are certain compounds that are produced within the body, which are called endocannabinoids, which also bind to these receptors. The two main ones are anandamide and 2-AG or 2-arachidonylglycerol. Anandamide is derived from the Sanskrit word anant, which means bliss. And it is a molecule that is responsible for the runner's high. So when people feel good after running, it's primarily because of these endocannabinoids or anandamide. There are two others like oleamide, which is thought to be important in sleep, and virodamide, which has effects the opposite of anandamide. So there are some characteristics of these endocannabinoids, which is very unique compared to the other neurotransmitters that we know. So the first thing that stands out is that it's a lipid neurotransmitter. Most others are remains, but this is a lipid neurotransmitter. It's derived from the cell membrane, so it's not stored in vesicles. It's synthesized on demand. There's a phenomenon of retrograde neurotransmission that I'll come to. There are some unique properties, at least in animal models. One is biphasic effects. So while lower doses may have a certain kind of, like, maybe anxiolytic effect, higher doses can also be anxiogenic. There's a concept of entourage effects, which I thought that the other cannabinoids and the terpenoids may act to amplify the effects of the cannabinoids. Again, this is seen in animal models, but has not really been demonstrated convincingly in humans as yet. Another property is that of functional redundancy. So 2-AG and anandamide in some ways compensate for deficits in either of those. Just to give you a sense of how the endocannabinoid system operates, this slide is a schematic of what you may see at a synapse. So you have a presynaptic neuron, the one in pink. You have the postsynaptic terminal in blue. When there's an action potential that reaches the presynaptic terminal, there's a release of a neurotransmitter, in this case glutamate. And if you can follow along from the numbers 1, 2, 3, 4, so glutamate binds to the MgluR1 or 5 receptors in the postsynaptic membrane or the AMPA receptors. Now this triggers the synthesis of anandamide and 2-AG from the lipid membrane. Anandamide and 2-AG, since they're lipids, they can cross the synaptic cleft, and that's the retrograde signaling. It goes all the way back and binds to the CD1 receptor on the presynaptic terminal. And this then acts as a break and can reduce the release of neurotransmitter. The interesting thing is that the CD1 receptors are present on both glutamatergic and GABAergic neurons. So you can see how the endocannabinoid system can then work as a break. If there's too much of glutamate, it can break that. If there's too much of GABA, it can break that as well. So it's not surprising that the endocannabinoid system plays a critical role in homeostatic mechanisms and maintaining this balance between excitation and inhibition. It starts to be relevant for circadian rhythm, sleep, appetite. The endocannabinoids play a critical role in neurodevelopment in terms of embryogenesis, the development of the brain, neuronal migration, modulation of stress. And like we said, CB2 receptors are present on immune cells or microglia, and so there's a role of inflammation as well. So the phenomenon of pruning that occurs in adolescence is thought to be driven by microglia. So this is the process by which the brain is fine-tuned during adolescence. And so some of the synapses that are not being used as much are pruned away, and the microglia are thought to play an important role in that process. So the pharmacology of phytocannabinoids is fairly complex. We know that delta-9 THC or tetrahydrocannabinol is a partial agonist of the CB1 and the CB2 receptors. Cannabidiol, the mechanism is not very clear. There's some studies that show that it can act as a negative allosteric modulator on the CB1 receptor, which means that in the presence of THC, it can reduce the effects of THC on CB1 receptor. There's some evidence to suggest that it may work as a fine inhibitor, so it may change endocannabinoid levels. They may bind to the serotonin 1A receptor, which may be responsible for some of its anti-anxiety effects, or the TRPV1 or the receptor on which capsaicin acts for some of the pain effects of cannabidiol. Interestingly, it's also an important inhibitor of 2D6 and 3A4. These are the cytochrome P450 system enzymes, and this is relevant to most antidepressants, antipsychotics that we use. The cannabidiol can modulate or change the serum levels of those drugs. There may be entourage effects of terpenoids. Again, this is seen in animal models, not been well demonstrated in humans as yet. So the takeaway is that phytocannabinoids are not the same as endocannabinoids. So people make the case that, well, you know, it's a natural compound. We have endocannabinoids in our system. With smoking cannabis or using cannabis is very different than the endocannabinoid system, and the reasons are because the effects are non-physiological. So like endocannabinoids are released on demand, phytocannabinoids are not on demand. It's whenever a person uses it. The phytocannabinoids are not degraded readily. Their affinity for the CB1 receptor is tenfold more than that of anandamide or 2AT, which results in this prolonged action. And another piece is that phytocannabinoids also cause a down regulation of CB1 receptors. So as you keep using more, chances are the effects of the drug are less with time. So one of the ways of being able to understand the effects of cannabinoids in humans is, you know, is by doing these laboratory studies with THC. And these can help us understand the effects of CB1 receptors and information processing and the risk of psychosis as well. So some of the advantages of this is that it's a standardized delivery. You know how much of THC somebody's getting compared to just when somebody's smoking cannabis. So there's a uniform dose. You can demonstrate a clear dose response. Subjects are selected very carefully just to make sure they're not at risk. And the analysis is within subject design, which adds to its strength. You can exclude the effects of other drugs, which is not typically possible when you do population studies. And you can look at the range of other outcomes as well. So this is one of the earlier studies that was done by Cyril D'Souza at Yale, looking at the effects of THC in healthy subjects. And this is one to demonstrate that THC can cause psychosis-like effects, even in healthy people in, you know, at least in a laboratory setting. So the figure, the blue is placebo, the green is 2.5 milligrams of THC, and the red is 5 milligrams of THC. On the y-axis is the PANS positive symptom score. And as the slide shows, both 2.5 and 5 milligrams of THC causes this increase in positive symptoms on the PANS. Now, the effects of THC in schizophrenia has also been well demonstrated in laboratory settings. So this is a study, again, where the y-axis is the change in the PANS scores. There were people, healthy controls, and people with schizophrenia who either got placebo, 2.5 milligrams of THC, or 5 milligrams of THC. And a greater than three point increase in the PANS was thought to be clinically significant. And as can be seen in this slide, people with schizophrenia were more vulnerable to have increased change in the PANS positive symptom scores, both with 2.5 milligrams and with 5 milligrams of THC. So the link between, you know, THC being psychotomimetic is well established both in population studies and in these laboratory studies. Again, there's also an opportunity to look at what does this do to just information processing in general. And this is an EEG analysis in the same study, which looked at a certain kind of waveform called the P3B. This is a measure of information processing. The blue is the placebo, the green is the THC condition. And compared to the placebo condition, even small doses like 0.015 milligrams per kilo and 0.03 milligrams per kilo causes a reduction in P3B. And this is something that's also seen in terms of deficits in schizophrenia where people have lower amplitudes of the P3B. Now, there is this link. So when we talk about the link between cannabis use and other disorders of why people may be using, you know, cannabis, like why does somebody with ADHD tend to smoke cannabis, there's some…we're beginning to understand there may be some genetic vulnerabilities that predispose to this. So this is a slide looking at different conditions from schizophrenia, major depression, bipolar, ADHD. And the last three are alcohol use disorder, nicotine use, and cannabis use disorder. Now, there is this strong genetic link between cannabis use disorder and ADHD, which is not surprising, at least clinically, we do see that a lot of people with ADHD tend to smoke cannabis as well. And the link between cannabis use disorder, so that probably is also something that is worth noting that when you have somebody with cannabis use disorder, it'd be helpful to also think about the possibility of ADHD in that individual. The link between cannabis use disorder and major depression is also in some ways mediated through ADHD. As you can see, other disorders as well have some genetic risk, but this seems to be standing out. So we've talked about people with schizophrenia being at increased risk. There's this link with ADHD. Now, one of the things in both schizophrenia and ADHD is this concept that neurobiologically, there may be a deficit in GABA in both these conditions. And so in healthy people, when we look at what does a GABA deficit do to the effects of THC, so we used a compound called iomazenil, which is an inverse agonist at the GABA-A receptor and can cause a GABA deficit. And when people received either THC alone, iomazenil alone, placebo, or the combination of THC and iomazenil, which is in blue, as the slide shows, the PANS total scores was higher with people who got the combination of THC and iomazenil. So in some ways, this kind of recapitulates the fact that in the presence of a GABA deficit, the psychosis-like effects of THC may be worse. And the same with the P3B as well. The blue is the placebo, iomazenil's in white, green is THC, and THC plus iomazenil is in red. And as you can see, with the combination of THC and iomazenil, this P3B amplitude is a lot lower compared to just placebo, which again, in some ways, recapitulates what we see in disorders like schizophrenia as well. So we've talked about some of the neurobiology of the endocannabinoid system, cannabis, this relationship with possible psychotomimetic effects of delta-98C. But what's the evidence for medical cannabis and cannabidiol in psychiatric disorders? So this is a slightly dated slide. As you know, many of the states that have legal programs for medical cannabis have their own qualifying conditions. Many of them include things like amyotropic lateral sclerosis, cancer, glaucoma, HIV, AIDS, multiple sclerosis. The ones below are primarily those that we as psychiatrists may see, like TBI, post-traumatic stress disorder, anxiety or refractory generalized anxiety disorder, anorexia, agitation and Alzheimer's disease, Tourette's syndrome, autism. And there are some states in which any condition may be approved as per the physician or the medical board. This is a fairly dated slide. I think conditions have expanded beyond this. But the key message is that different states have different conditions where, you know, which qualify for medical cannabis. So the challenges that are faced by clinicians is that, you know, how does one decide, is there adequate evidence for an indication? And there's also this, the decision-making of weighing the risks versus the benefits. There are different types of products on the market. There are products called high THC, high CBD, the CBD oil. And there are these legal challenges that come because it's still a Schedule I substance or drug at the federal level. So the one characteristic about, you know, people who sometimes have experience with cannabis is that the concentration of THC has increased over time. So this is an analysis of cannabis products that were seized by the DEA. And you can see from 2009, where the concentration was about 9.75, to 2019, the concentration has increased to 13.88. So the concentration of THC that's available in cannabis nowadays is a lot higher than it used to be in the past. There are more than 2,500 different strains of medical cannabis. There are different names of these. There are some that are called cannabis or CBD strains like Charlotte's Web, which was popular because it helped a kid with epilepsy. There are high THC strains, those that contain greater than 20% THC. So the high CBD strains, any strain that contains more than 5% CBD is called a high CBD strain. The one caveat is that all CBD that's extracted from hemp contains some THC or THCA. And that may be something for us to pay attention to because as the laboratory studies suggest, even like 2.5 or five milligrams of THC can worsen psychosis in someone who's vulnerable. So what's important in most products have labels and what's important in looking at labels is the total THC content and to pay attention to if it is more than five milligrams. There is some products which will, you know, highlight THCA, which is a tetrahydrocannabinolic acid. And about 90% of tetrahydrocannabinolic acid can get converted to THC on combustion. So the total THC content needs to factor in both THC and THCA concentrations. The other concern is that there's a discrepancy between the labeling and the actual content of THC and CBD in products. There's a study that showed that there were only about 24% of products that were correctly labeled. So that is another challenge physicians or clinicians face. On the flip side, when there are compounds that act on the cannabinoid receptor, CB1 receptor that are already approved. So dronabinol is a compound that's also available on the VA formulary. There's a compound called nabalone, which is also approved for cachexia in cancer. There are nabiximol is a combination of THC and CBD in a one is to one ratio that's available in Canada. And epidiolex or cannabidiol has been approved for seizures in Dravet syndrome and Lennox-Gestalt syndrome in 2018, and also with seizures in tuberous sclerosis in 2020. So how does one decide about, what is the strength of the evidence? So most of the studies have looked at the grade score and the grade is a way of evaluating the evidence of a study. So studies may be randomized trials or observational studies like case reports or case series, open label studies, which are not double blind randomized trials. The key point to note is that a well done observational study with no serious flaws in quality and is fairly well done, is still considered to have a low grade in terms of its evidence. And the FDA standard for drugs to be approved is that you need at least two adequately powered randomized controlled trials. So there's a lot of emphasis on this concept of having a randomized controlled trial rather than an observational study to judge the strength of the evidence. So one of the reasons for this is that there are many reasons why somebody may respond in a trial. There are concepts like regression to the mean. So people, when they enter a trial tend to have inflated scores and with time they tend to normalize or regress in terms to the mean score. Inadequate blinding can result in some expectancy responses. And there are ones that are called the Hawthorne, the Rosenthal effect, which are seen in the treatment arm. And sometimes when people realize that they have got the placebo and not the actual drug, they tend to have worse responses for the Golomb effect. There may be a strong placebo response. Improvements can maybe because of the nonspecific interventions in a trial. So it may not have to do with the actual drug, but the number of times you're seeing a clinician can also impact the response. There are practice effects, and this is primarily in studies that look at cognition. So when people perform more than once on the cognitive test battery, they tend to perform better with each trial. There may be spurious worsening in the placebo arm, and there may be an inability to actually blind participants because of the side effects of drug and placebo, which is dizziness, orthostasis. And then comes a true drug effect. So you actually need a randomized controlled trial to be able to parse out the true drug effect from all these other reasons why somebody improves in a study. So what is the evidence for cannabis and CBD in anxiety and depressive disorders? This is a meta-analysis that was done in 2019 published in The Lancet. We looked at this in the past and published in Journal of Clinical Psychiatry. There are a few others, newer papers, one by Dr. Hill, which looks at the benefits of cannabis and cannabinoids. And there's also a recent meta-analysis by Bill Barr, which looked at all medical conditions, including psychiatric conditions. So I think it's worth reviewing some of this in terms of the evidence. So the study of the meta-analysis in The Lancet by Dr. Black, this was a systematic review and meta-analysis, 42 studies in depression, 23 were randomized controlled trials. There were 31 in anxiety disorders with 17 randomized controlled trials, 12 in PTSD. There was one randomized control at the time. And since then there's been one more study, which we'll talk about. There's one study in ADHD, two in Tourette's, one in PTSD and six in psychosis. The overall evidence for use in psychiatric conditions was low. They concluded that pharmaceutical THC with or without CBD improved anxiety symptoms in individuals with comorbid medical conditions, primarily chronic non-cancer pain and multiple sclerosis. Again, but the strength of the evidence or the quality of the evidence by the grade was very low. There were very few randomized controlled trials using pharmaceutical CBD or medicinal cannabis and pharmaceutical THC with or without CBD was associated with increased rates of adverse events in these studies and withdrawal due to adverse events in these studies. Again, so this is just a snapshot of those studies in depression. There were studies that looked at a comparator of either an active comparator or a placebo. The criteria for looking at the grade are criteria like risk of bias, the directness of the study or how relevant it is to the population of interest, the consistency across studies in terms of the response, the imprecision in the measure, was there any publication bias. The pooled standardized mean difference, typically a value greater than two would be, well, greater than 0.2 would be thought to be of small effect size, about 0.5 is moderate, 0.8 is large. So most of these studies, so there's at least in depression, there was none of the studies favored THC or CBD and the grade was very low. For anxiety disorders, there was some sense that at least the change in anxiety symptoms was favored by THC or CBD, but the challenge was that the grade or the quality of the evidence was very low. Same with ADHD and with Tourette's syndrome, the overall grade seemed to be low or very low. And again, most of these measures of change in ADHD symptoms or change in tics and Tourette's, it did not favor either THC or CBD. Now, study of PTSD and psychosis as well, the overall grade in these disorders was thought to be low. There was some minor effects seen for like a change in global functioning and change in the frequency of nightmares which favor THC and CBD in at least the PTSD disorders, but then the overall quality of the evidence that we're basing this was low. With psychosis as well, there was low grade of evidence and again, not convincing evidence that it was favored by the THC or CBD. Now, the randomized controlled trials of CBD for anxiety disorders, there were some small studies done. There's one in 24 never treated people with social anxiety disorder. They were allocated to receive either CBD, 600 milligrams of placebo. It's a small sample size, but in the randomized double-blind design, they received THC or CBD and one and a half later, hours later, they had to simulate a public speaking test. And as the figure shows, this is the change from pretest codes. The blue is CBD, the red is placebo and black or the gray is healthy individuals. CBD at least in this small study seemed to reduce anxiety at least before public speaking had no effects on cognitive impairment, no effects on sedation or discomfort. This led to another study. There was another study done looking at the CBD, 400 milligrams in social anxiety disorder and double-blind randomized trial. Again, this was looking at anxiety using a visual analog mood scale. And this study also interestingly measured the blood flow to the brain, to the region called the hippocampus. And they found this reduction in anxiety with CBD and also a simultaneous reduction in blood flow to the left hippocampal region. But studies with panic disorder and agoraphobia probably may be related to the dose of CBD or the severity of the disorder. But this was a study in which there were eight therapists and exposure in vivo sessions where people also received 300 milligrams of either CBD or placebo. And the duration was post-treatment, three-month follow-up, six-month follow-up. And this study unfortunately did not show any improvement with CBD or placebo on the fear questionnaire. Either could be because the level of anxiety may be higher in this group than just the public speaking social anxiety groups. What about the general population that uses medical cannabis for anxiety and depression? So this is a study by Dr. Gilman, which is an interesting study because they just did an ecologically valid randomized controlled trial. As patients go to get medical marijuana cards in different, in their state, they randomized them to either get the card immediately. So this was a group of 105. And there was another group that was randomized to a different arm who had to wait for 12 weeks before they could get their card. And the total study duration was 12 weeks. They found that those who got their card immediately had more symptoms of cannabis use disorder. They had fewer self-rated insomnia symptoms, though, interestingly, but there was no change in anxiety, depressive symptoms, or in pain severity. So the overall evidence for anxiety in the meta-analysis by Bilbao, we found that cannabinoids attenuate anxiety levels as a group. The standardized mean difference, again, is less than 0.2, so it's a small effect size. But none of the subgroup analysis of this, this complete analysis combines dronabinol, nabalone, both active in placebo, and cannabidiol, and nabiximol, which is this combination of THC and CBD. So none of the subgroup analysis showed a significant improvement. And again, I think the big challenge was that the overall quality of these studies was low or very low. Similarly, with the evidence for depression, so this is, again, the meta-analysis by Bilbao, they found that there was minor or no attenuation of depressive symptoms. Cannabidiol and nabalone did not modify depressive symptoms. Dronabinol and nabiximol showed a minor improvement. Again, here, the standardized mean difference was minus 0.15, so less than 0.02, less than 0.2. The evidence was moderate only for nabiximol, which is this combination of THC and CBD. So what about PTSD? We've talked about some of the older studies, which did not show an improvement. And this is a more recent randomized control trial, which was looking at smoked cannabis with three different concentrations in US veterans with PTSD. It had a pre-screening or a screening stage, and then it had two different stages. So in the first stage, again, if you just look at the figure, 80 subjects were randomized to 20 received placebo, 20 to receive high THC, 20 to receive high CBD, and 20 got THC plus CBD. Now, the concentration of THC in the studies in the high THC group was 12%. The high CBD group had 11% of CBD. The THC and CBD group had about 7.9% THC and 8.1% CBD, so approximately a one-to-one ratio. Now, in the first stage was for three weeks, people received, were randomized to these four arms. After the three weeks, there was a two-week washout, and then they moved to stage two, where they were then re-randomized to either high THC, high CBD, or THC plus CBD. So there was no placebo group in the second stage. And they had about 26 who completed session two, 23 completers for the high CBD group, and 18 for the THC plus CBD group. And overall, they found there was no significant difference between these three different concentrations of smoked cannabis and placebo. There was no difference also in the concentrations of THC plus CBD. Interestingly, the high THC group, again, not surprising, but they did experience more cannabis withdrawal symptoms. The adverse events report in this trial was tachycardia. There was one case of pulmonary embolism. There was abscess, anxiety, cough, and throat irritation. So the large randomized controlled trial of smoked cannabis in PTSD did not show much of an effect. Now, there's a large population study. This is looking at veterans in the PTSD national program. Evaluation is from 1991 to 2011, about 47,000 veterans who received intensive PTSD treatment. The mean duration, I think, was about 42 days when they're in an intensive PTSD treatment program. And people were classified as those who were never users or never used cannabis, those who stopped using cannabis in green, those who continued using cannabis in light blue, and those who started smoking cannabis. And they compared the change in PTSD scores before and after treatment with, you know, the change in cannabis use. And interestingly, they found that the group that actually stopped using cannabis had the biggest change in PTSD scores compared to the never users and even the continuing users. And those who started using cannabis probably had the least change in PTSD scores. So the overall evidence for use in PTSD is very low. The retrospective studies that suggest that medical cannabis may be associated with improvements in sleep and nightmares, that warrants further research. Studies also suggest that cannabis use was associated with less symptomatic improvement from treatment, both with medication and psychotherapy. There's another meta-analysis of studies with PTSD, panic disorder, bipolar disorder, and depressive disorder. And across 11 studies, recent cannabis use was associated with higher symptom levels over time relative to the comparison group. And 10 studies suggested that cannabis use was associated with less symptomatic improvement from treatment. So there's this consistent pattern across studies, which seems to suggest that cannabis use may be associated with less symptomatic improvement with treatment. What about, what does, so we've talked about using cannabis as a treatment for anxiety and depression. What about the flip side? So people who are using cannabis recreationally, what are the odds of anxiety and depression in them? The National Epidemiological Survey of Alcohol and Related Conditions, or the NESARC, was this wave of studies that were done 2001 to 2002, and then 2004 to 2005 that captured some of the diagnosis of MDD. So in the first wave, there were about 2,300 people who were diagnosed with MDD, and they looked at the rates of cannabis use in this group as well. About 7.5% used cannabis, and 4.7% had met criteria for cannabis use disorder. Now, 12 months later, when they follow these people up, they look at the rates of remission from all anxiety disorders. And here too, the people who did not use any cannabis, there were about 65% of them who had remission, which is more than that in the cannabis group, which is about 52%, and about 46% in those with cannabis use disorder. This, however, was not statistically significant. So when they compared cannabis use disorder versus non-users, there was a lower mean age of onset for any anxiety disorder in the cannabis use disorder group, they were more likely to break up from the relationship, and more likely to quit school more than once without knowing what to do next. Comparing cannabis users versus non-users, it looked like those who were cannabis users were more likely to report being fired from the workplace, or had a breakup from the relationship. So the mean age of onset of major depressive disorder among cannabis use disorder seemed to be earlier, about 20 years, compared to cannabis users, about 23.7 years. And that was, you know, less than that of non-users, about 29.7 years, and that difference was statistically significant. And comparing cannabis use disorder versus non-users, it was significantly higher greater odds to report anhedonia, change in body weight, insomnia or hypersomnia, and psychomotor problems. In some ways, cannabis use may impact, you know, both depression and anxiety as well. So one of the claims, I mean, again, epidemiological studies are different because there are so many variables that come into play, and there's other things common in substance use, there may be different genetic vulnerability, different environmental stresses. So this is a study that looked at twins, and looked at depressive, major depressive disorders, suicidal thoughts, and behavior, and they looked at the effects of cannabis use among discordant twins, where one twin uses cannabis and the other twin does not. So this is from the Australian Twin Registry. There were three cohorts of samples from 1992 and 93, 96 in 2000, and 2005 to 2009. There was a total of around 13,986 twins, about 6,000 were monozygotic and 7,000 were dizygotic. The cannabis use in the first sample was about 30%, about 69% in sample three, and the prevalence of depression also varied from 20.3% in sample one to 28% in sample two. Now interestingly, when they compared monozygotic twins with frequent cannabis use, was this the discordant twin who does not use cannabis? So in some ways, the genetic factors are the same, and they assume that, you know, some of the environmental factors are the same. The risk was of major depressive disorder was, you know, higher in the group that use frequent cannabis was the discordant twin, and the risk of suicidal ideation as well was higher in those who use cannabis. So moving on to psychotic disorders. So we know that THC is the psychoactive ingredient, can worsen psychosis, there's a lot of interest in cannabidiol for psychotic disorders. The overall evidence for CBD is however mixed, there have been two, I mean three at least randomized controlled trials. The one by Philip McGuire, which looked at 1000 milligrams of CBD per day, they showed an improvement in positive psychotic symptoms, but no improvement in negative symptoms or general psychopathology. There's a study done at Yale by Dr. Ranganathan and Doug Boggs, which looked at CBD at 600 milligrams per day, and that failed to show an improvement in psychosis or cognition. There's an older study by Leveque 2012, which compared CBD and amisulpiride, both at 200 milligrams per day dose, and both groups improved, and there were no differences in treatment between the groups. But the overall evidence again for CBD, again, is not very convincing. I think we still need some work, there seems to be a hint of some improvement in one study, but not in the other. Another area where cannabidiol or medical cannabis has been used is in dementia. This has been studied in at least four randomized controlled trials, they found an overall significant effect, but the evidence for specific cannabinoids was low or missing, but in some ways the effects on agitation are not surprising, given the sedating effects of cannabinoids. Many studies with dronabinol did not reach statistical significance, there was one study with nabilone that showed a significant reduction, and these seem to be fairly moderate effect sizes here as well. There's one recent RCT in dementia, looking at those in the 18-week RCT with a combination of both THC and CBD in a combination of 3 is to 2, or 2.5 milligrams of THC, 1.5 milligrams of CBD, and a maximum of 25 milligrams THC, 17 milligrams CBD over two to three weeks. The mean age of the sample was about 85 years, there were no significant differences seen between placebo or the cannabinoid formulation of both behavior, quality of life, or pain. There was a decrease in agitation at the end of treatment in favor of cannabinoids, on one scale, which is the NPI, but not another measure, which is the Cohen-Mansfield agitation inventory. What about medical cannabis and ADHD? There's one randomized controlled trial in ADHD, again, this looked at the combination of THC and CBD, 2.7 milligrams of THC and 2.5 of cannabidiol, so approximately a one is to one ratio. This was two weeks of dose titration, followed by four weeks of safety and monitoring. We found no significant differences in an intent to treat analysis, although the overall pattern of scores were that the active group which received this THC plus CBD had scores that were better than that of the placebo group, but that again was not statistically significant. In terms of other disorders, so insomnia has been studied, there's some studies that suggest there's one recent randomized controlled trial using 150 milligrams of CBD for insomnia, they found no difference in insomnia and severity, self-reported sleep onset latency, sleep efficiency, or wake after sleep onset, but patients who got the CBD group did report greater well-being scores, and that's something that we'll come to in terms of the expectancy response and how sometimes people just feel well when they're receiving CBD rather than placebo. Bipolar depression, there's one RCT using 300 milligrams of CBD as an adjunctive treatment, the Madras scores decreased in both placebo and CBD groups, and then there was no significant difference between the groups. There's one study looking at worry and anxiety among high-trait warriors, and there's a randomized double-blind placebo-controlled trial using 300 milligrams of CBD. They also had a group that got 50 milligrams of CBD and placebo, and they were measuring worry severity, anxiety symptoms. They found no effect of acute dosing of CBD on worry severity or anxiety symptoms, but with repeated administration over the two-week period, they however found that 300 milligrams of CBD reduced anxiety symptoms but did not impact worry severity. So one of the challenges with these randomized controlled trials, of course, is the expectancy response, and this highlights the importance of blinding and making sure that people don't know what they get at least in a randomized controlled trial. So this is a study looking at expectancy response of mood, stress, and anxiety. Included 43 healthy adults who received either CBD-free, hemp seed oil sublingually, and during one session they were incorrectly informed that the oil contained CBD. Another session they said it was CBD-free. They looked at the stress, they underwent what's called a stress test, which is the Maastricht acute stress test. They measured heart rate variability at baseline 90 minutes after the administration of the oil and immediately following the acute stress test and after a 10-minute recovery period. So the expectancy of having received CBD was associated with the increased sedation, changes in heart rate or heart rate variability, and participants who endorsed strong prior beliefs that CBD had anxiolytic properties reported significantly diminished anxiety, although you know both of them, none of the groups received CBD in this study. And that's also been, there are other studies which have similarly replicated that finding. This is another study looking at 48 healthy adults. Again, they were randomly assigned to be informed that they either got CBD-containing oil or a CBD-free oil, except that they both received a CBD-free compound. And following oil administration, they had a laboratory stressor. In this case, it was like a serial subtraction in increments of 13 starting from a four-digit number. So it seems like a fairly difficult task to do, and people were asked to do this as quickly and accurately as possible. And if they, you know, made a mistake, they had to start from the beginning. It's fairly stressful to do this. And they were incorrectly informed that they would engage in a second, more difficult task after a waiting period. Again, subjective states, sedation, energy levels, stress and anxiety, and heart rate versus baseline after the oil administration, immediately after the first stressor, and while anticipating the second stressor. So the expectancy of having received CBD was associated with, you know, increased subjective sedation, and they tended to be associated with a blunted subjective stress response. Although, you know, otherwise, the subjective stress and anxiety were, you know, elevated following the stressor. So this kind of highlights the importance of blinding and, you know, what people expect from CBD and how they're going to respond to it. So one of the questions that comes up is, you know, does cannabidiol make cannabis safer? So we, you know, the preclinical studies suggest that CBD is a negative allosteric inhibitor of the CB1 receptor. So the thought is that just adding CBD may reduce some of the psychoactive effects of THC. So there's an interesting study that was, you know, explored this very question, was done in healthy, infrequent cannabis users, was a double blind randomized trial. People received vaporized cannabis containing 10 milligrams THC and either zero milligrams, 10 milligrams, 20 milligrams, or 30 milligrams of CBD. The primary outcome was a change in delayed verbal memory, but they also looked at change in psychotic symptoms and any change in cognitive, subjective, pleasurable, or, you know, pharmacological or physiological effects. So THC alone was associated with impaired verbal memory, it produced positive psychotic-like symptoms on the pants, but these effects were not modulated by any dose of THC. So there was no evidence of CBD modulating the effects of THC on other cognitive, psychotic, subjective, pleasurable, or physiological measure. So although the preclinical studies suggest this negative allosteric effect, this study did not show that. So how do we evaluate the risks versus the benefits of CBD or medical cannabis for, you know, psychiatric indications? So there are some conditions for which there's some moderate evidence for cannabinoids, at least medical conditions like nausea, vomiting, and chemotherapy. There's FDA approval for Marinol for that. HIV, AIDS, cachexia, there's FDA approval for Marinol. There's increasing evidence that cannabinoids can help with pain, so neuropathic pains, spasticity, and MS. There's moderate level of evidence for that. There's some evidence for its effects on ulcerative colitis, Parkinson's disease, but unfortunately when it comes to psychiatric disorders, the evidence for anxiety, depression, PTSD, psychotic disorders, agitation, dementia, and ADHD, at least the strength of the evidence seems to be very little at this time. So in terms of evaluating the risks versus benefits, we also have to pay attention to the possible side effects. So things that we know off as tolerance, we know cannabinoids downregulate the CB1 receptor. So the risk of tolerance or the loss of efficacy is evident. There's the risk of a use disorder, so people tend to use more. There's the risk of dependence or withdrawal symptoms. There are short-lived and persistent cognitive deficits related to the use of cannabinoids. These may be relevant to motor vehicle accidents, driving, and coordination, risks in terms of psychiatric outcomes, psychosis, mania, and depression. We know there's some vulnerabilities, there are some neurobiological vulnerabilities like the GABA deficit, which can make things worse. There's also an amotivational state that's been described in chronic cannabis use, and this in some ways accounts for the poor scholastic performance, high rates of dropouts that we sometimes see in young people who tend to use cannabis for long periods of time. So in terms of tolerance and dependence, this is the SAMHSA's guidance that approximately one in 10 people who use cannabis will likely become addicted, and when they start before the age of 18, the rate of addiction rises to one in six. The more recent data suggests that about 30% of those who use cannabis may have some degree of cannabis use disorder, and people who begin using cannabis before the age of 18 are four to seven times more likely to develop a cannabis use disorder than adults. Unfortunately, one of the challenges with medical cannabis or cannabis being called medical cannabis is that the perception of risk seems to have decreased. So this is a figure which shows the dotted line is the perception that there's no risk with regular cannabis use, and in the black line is the past 30-day daily cannabis use. And this is over the years 1991 to 2015. So it seems that the perception of use of no risk with regular cannabis use seems to have increased over the years. Now relevant to the effects of tolerance dependence is that cannabis use, or the CB1 receptor, is lower in cannabis use disorder. So this is a PET imaging study looking at the CB1 receptor using a PET ligand called 11C-OMAR. The top panel is healthy controls, the lower panel is people with cannabis use disorder, and the brighter, or the redder the color, the more the CB1 receptor is. And what's evident is that the CB1 receptor is lower in people with cannabis use disorder compared to healthy controls. Now DSM-5 has recognized cannabis withdrawal as a separate diagnosis. There are, you know, people need to meet three of seven criteria, which include irritability, anger, aggression, nervousness or anxiety, sleep difficulties, decreased appetite or weight loss, restlessness, depressed mood, and at least one of the following, abdominal pain, tremors, sweating, fever, chills, and headaches. This is a fairly common occurrence now, at least in clinical practice. Now this is a study that was done at Yale by Cyril D'Souza where we scanned people to look at the CB1 receptor on day zero. They had to be inpatient for two days and then continue to be abstinent thereafter for at least four weeks. And they got a scan on the second day and a third scan four weeks later. So this was 11 people with four weeks of abstinence. And what we noticed was that cannabis withdrawal symptoms do appear. There's withdrawal discomfort, irritability, sleep disturbance, strange dreams. The strange dreams seem to persist for as long as four weeks. There's decreased appetite, restlessness, weight change, and some nervousness and anxiety. So cannabis withdrawal symptoms sometimes can be prolonged for as long as four weeks as well. Looking at the brain scans of CB1 receptor changes, so day zero is when people with cannabis use disorder get their first scan, and day two is after two days of abstinence. And you can see that there's some improvement in CB1 receptors just by, you know, the visual appreciation of the colors of it being more red, being more higher density of CB1 receptors. And it tends to normalize or at least approach normalization by week four. So with longer prolonged abstinence, the CB1 receptors can recover. So even with just two days, there's some recovery of CB1 receptors in cannabis use disorder. Many of the regions involved with CB1 are also regions that are relevant to the neurobiology of substance use disorders. So, you know, brain regions responsible for anticipation, preoccupation, withdrawal effects, binge and intoxication, like the globus pallidus, the hippocampus, the frontal cortex. Most of these regions are also high in CB1 receptors, and where we see this reduction in CB1 in cannabis use disorder. There are also structural brain changes in cannabis use disorder. There's an earlier study showing alterations in synaptic spine density. We now have the ability to actually map this out by using positron emission tomography or PET. We can look at the ligand that maps on to the synaptic vesicular protein SV2A. And this is a protein that's present on the vesicles. So this schematic represents the terminal, synaptic terminal, and within which is a synaptic vesicle, and the protein SV2A is on the synaptic vesicle. There are about five copies per vesicle, and it's the most monodisperse, so 79 or 97 percent of vesicles have five copies. So in some ways it gives us a quantity to measure of how many synapses there are in the brain. This is what it looks like in healthy people. There's a lot of synapses, nice and red. It has good test, the ligand has good test-retest variability, so you measure it twice and it's fairly accurate in its measure. And this is what we see in healthy controls in cannabis use disorder. The upper panel is healthy people, the lower panel is people with cannabis use disorder, and the visual, you know, there is some reduction in synapses in cannabis use disorder compared to healthy controls. And that is what we see quantitatively as well. There's a general trend towards lower synapses in cannabis use disorder. It was most significant in the hippocampus, and the reduction in cannabis use disorder in hippocampus also seemed to correlate with some of the memory deficits that we see in cannabis use disorder. So the effects in cognition is something that's been well studied. There are effects on verbal memory, attention, recall. Some of these are acute effects. There's a phenomenon of school dropouts that have been described in young people. There's an earlier study that showed a 6 to 8 point lower IQ, and this is the Dunedin cohort study when people used before the age of 18. There's some indication that this may actually be confounded by the socioeconomic status. So when you control for socioeconomic status, you don't see that effect anymore. But it's still something to pay attention to. There are effects on motor coordination, reaction time, driving ability. This at least acutely is relevant, you know, to the acute effects of cannabis. Effects on motivation, like we talked about, the amotivational syndrome is also a consideration. Now in terms of the risk of psychosis, there are large epidemiological studies that show this modest and consistent association. So for daily users, the odds ratio is about 3.2, and this is from the EUGEI, which is a large multi-center study, but the adjusted odds ratio is about 2 in general. There seems to be a dose response. So daily users are at more risk than people who use less than daily. The population attributable risk fraction for cannabis use, that's the number of cases of schizophrenia that is attributable to cannabis, has increased by about 2% in 1995 to 6-8% since 2010. So this is something that we need to pay attention to. Early and chronic use tends to heighten risk. Some early studies suggested some genetic vulnerabilities. These were single genes. I think the field has evolved more now, there's, you know, more advances in looking at polygenic risk scores for cannabis use disorder and how that relates to schizophrenia risk. Now pregnancy is an important period of time where women tend to use cannabis as well, primarily because of the nausea. The cannabis use among pregnant women in California doubled between 2009 and 2016, and nationally rates have increased as well, 2.85% in 2002 to 4.98% in 2016. Now in animal studies, there are some effects that are seen that are similar to what's seen with fetal alcohol syndrome, there's some hyperactivity in the offspring. It's not surprising endocannabinoids are important for placental function, they're present in the embryo even before neurogenesis. So it's, it may have critical effects, again, this has not been well demonstrated in human studies. There's some association studies, like the ABCD study, there's some indication that prenatal cannabis exposure was associated with psychotic-like experiences, lower cognition, lower gray matter volume during middle childhood, but temporarily it seems to be very off, so, you know, there's some hint, but it's not a definitive finding. The other considerations, at least for practitioners, is the drug interaction, CBD is a potent inhibitor of 2D6, 2C19, 3A4, and these are, again, CYP, P450 enzymes responsible for breakdown of antipsychotic SSRIs, so CBD can increase the levels of clobazam via 3A4 inhibition, can alter warfarin levels, and changes in diclofenac levels as well. CBD can also increase THC concentrations, which may also be one of the reasons why, you know, some studies don't show that the CBD inhibits the effects of THC, because the concentration of THC may be increased overall. Now for THC, there's a decreased brain concentration of risperidone as an active metabolite, 9-hydroxy-risperidone, this is by induction of P-glycoprotein expression, so that's something to consider in people with psychosis. Now the other clinical considerations, I think we've talked about some of these, the issues with labeling, we need to pay attention to the total THC content and the content of CBD, there are legal challenges in terms of being a Schedule I drug at the federal level. One of the questions that often comes up is figuring out if symptoms of anxiety and depression are due to withdrawal, or are they, you know, present even before that. And people sometimes, if it's because of cannabis withdrawal, they'll report that, well, cannabis is the only thing that helps my anxiety or my depression. There is this syndrome of cannabinoid hyperemesis syndrome as part of withdrawal, where people have cyclical vomiting and compulsive bathing, the risk of worsening mood and anxiety, the risk of manic episodes and bipolar disorder and of psychosis. There's also emerging concern about cardiovascular risk, there's an increase in, you know, myocardial infarction in young people, and tachyarrhythmias, which is also emerging as a risk. In terms of during the period of COVID, we looked at some of the analysis in terms of cannabis use and the effects on COVID. There seemed to be some increase in the need for ICU care among people with cannabis use, but no real increase in deaths or any other effects. So in terms of conclusions, I think takeaways, mainly cannabis is not just a single compound. We're talking about more than four and 30 different chemical constituents. THC is the main psychoactive constituent. Two main endocannabinoids are anandamide and 2-AG. There are FDA-approved cannabinoids on the market, like bronobinol, nabilone, and epidiolex. The evidence for the use of medical cannabis CBD for the psychiatric indications we covered was low at the present time. We need to consider the risks, such as cannabis use disorder, withdrawal syndrome, the effects on cognition, risk of psychosis. CBD is a potent inhibitor of 2D6, 2C19, 3A4, and interacts with antipsychotic SSRIs. And it's not an easy decision. Medical cannabis is a complex issue and requires careful discussion, documentation of risks and benefits. And with that, I'm happy to take questions. Thank you, Dr. Radhakrishnan, for the thorough presentation. I'd like to remind the audience to submit questions using the control panel. I'm going to read some of the questions. The first question here is, what is known about cannabinoids as a sleep aid? Are there cautions? Many of my patients assume there are no cautions. Can you comment on that? Yeah. I mean, like we talked about, the effects, at least in randomized controlled trials on insomnia, is not very convincing. People do report that, you know, it helps them sleep, and some of that could be the placebo response. Some of that could be a reduction in anxiety. Or if they're already on medications that are sedating, CBD may be increasing the serum levels of these trials. Yeah. So I think at least looking at the strength of the evidence, there's no clear evidence that CBD helps with insomnia per se. If the insomnia is because of other conditions, like, you know, nightmares or anxiety, then it may be playing a role in those situations. And I would add that for CB1 receptors or cannabis, even if there's a sleep induction effect, there's also the REM rebound. Do you want to comment on that, when people stop? Yeah. So again, that's one of the things that, you know, I've seen in cannabis withdrawal as well, that there's this phenomenon where they have a lot of strange dreams. And yeah, like Dr. Dequino said, there's a rebound in REM, so people don't feel as rested when they wake up in the morning as well. The next question is, one of the clinicians in the audience says, some of my patients use a one milligram THC cartridge in three or four days. That is about 280 plus milligrams of THC per day. What can we say about such massive doses of THC? Yeah. So again, I think, you know, one thing that stands out is that this may be an effect of dependence, of lowering of the CB1 receptor. So as people get exposed to more THC, the CB1 receptor is down-regulated, and so now you need more and more. And people become very easily sensitized to this, so the moment that they don't have it, they have cannabis withdrawal effects, have increased anxiety, in some ways they may be self-medicating as well. So yeah, it's unfortunately, you know, that strongly, to me at least, it suggests the development of some form of cannabis use disorder. Thank you. Next question. Can you suggest a standard rubric for assessing well-being in people who use cannabis? So well-being is a very subjective, you know, domain. There are scales of well-being that can be used, but usually for patients, it's what particularly the cannabis seems to be helping them with. So again, it's, I think the key differentiation is trying to see, are we treating symptoms, specific symptoms with the cannabis, or is it just making them feel good? Because people do enjoy the high of THC, and so is the well-being tied to the intoxication, or is the well-being a reduction in distressing symptoms? So I think that would be a framework to kind of tease apart what exactly does the person mean when they say that it's improving their well-being. This is a nice segue to the next question. I think this was covered in the last slide. Is any form of cannabis currently approved for any use in psychiatry? And then there's a comment after that. The comment is on the transitory nature of psychiatric symptoms, and then the person is expecting some skepticism that in those clinical trials, because psychiatric symptoms are transitory, can you really attribute that level of evidence to cannabis without accounting for those confounding variables? So a question and a comment. Yeah. So I wonder if the question pertains to the transient psychotomimetic effects of cannabinoids, like in terms of the anxiety or the psychosis that THC may be associated with. So in terms of what's approved, so the one FDA-approved compound is, there's a version of cannabidiol that's approved by the FDA that's for epilepsy in both temporal sclerosis and in Dravet's and Lennox-Gastaut syndrome. As far as I know, there's no other cannabinoid. And so there are nabiximols, like a combination of THC and CBD, what's called Sativex, which is approved in Canada. There's nothing else that I know that's been approved here. There's Pronabinol, there's Marinol. There are some cannabinoids that are FDA-approved in the US. So in terms of the transient effects, so although people report, you know, adverse events as being anxiety, and although it feels like it's transient, sometimes the severity of the anxiety is, you know, way out of proportion, that people sometimes have to go to the emergency room because they have a panic attack or they're very paranoid. So the intensity of the anxiety sometimes makes people, you know, count it as an adverse event in these clinical trials. Thank you. Another comment. I am interested in finding out people's thoughts about prescribing controlled substances such as benzodiazepines and stimulants to people who are on medical cannabis for some reason or the other. Yeah, no, that's a challenging issue. There's some epidemiological evidence that cannabinoids will reduce the total dose of benzodiazepines and opioids. Again, this is in large population-level data, which seem to suggest this effect. There's at least one laboratory study showing that cannabidiol will lower opioid CT scans in people with opioid use disorder. So it's a fairly complex issue. In terms of stimulants, I think, you know, it's more, there's less controversy because there doesn't seem to be an effect on ADHD symptoms per se. Sometimes ADHD is comorbid with anxiety, so people may be using cannabidiol or cannabinoids to treat the anxiety that comes along with it. So I think it's still, yeah, it's controversial. I don't think there's a clear answer, but I think it's about checking with your patient about what exact symptom they're trying to treat. If it's the inattention of ADHD, it's unlikely that cannabidiol may work for that. Yeah, thank you for that. As an addicted psychiatrist, I would just add that it's hard to extrapolate evidence from one population to the other. So a lot of these early drug development human lab studies are done in healthy people. It's hard to extrapolate things like abuse liability of a medication to people who already have a substance use disorder. And it's natural that first it's done in healthy people, only after that you have a high quality data in populations who have opioid-induced neuroadaptations or benzodiazepine-induced neuroadaptations. Any suggestions for helping heavy users stop or reduce use? Anything to help withdrawal? And then there's some comments about gabapentin and mirtazapine. People have had a positive experience prescribing those drugs for cannabis withdrawal syndrome. Yeah, so there are no FDA-approved drugs for the treatment of cannabis use or cannabis withdrawal. People have tried mirtazapine. They've tried trazodone. They've tried dronabinol. They've tried CBD. It may treat specific symptoms, such as sleep. If the major reason for somebody to start using again is the sleep disturbance, which lasts as long as four to six weeks, then some of those targeting sleep symptoms may help. But there's no specific treatment. Yeah, people have tried these gabapentin as well. There are anecdotal reports. There are clinical trials which do not show that these are effective. And we're almost at 4.30, so you might have time for one more question. The question is, we'd love to hear tips on risk reduction and advice for patients about doses and routes of administration. PO, is it safer than inhalation? Some medical cannabis clinics help patients transition from inhaled to medical, including calculating weekly doses used, et cetera. What are your thoughts about this? Yeah, I think this, again, is a very interesting question. You know, a goal in many ways is harm reduction. We know some ways have greater effects, like, you know, with the oral route gives you very unpredictable absorption, may give you very high levels. We know that smoke sometimes affects lungs. So there are challenges in terms of choosing the route. There are now patches that come that people can use subcutaneous, you know, cannabidiol as well. So there are different formulations. I think the goal should be to reduce drug interactions, which I think is usually overlooked, that people are already on medications, then they are using cannabidiol to get a certain response or an improvement, but you may have got that same improvement just by increasing the dose a little. Because what CBD may be doing is increasing your serum level or whatever medication they're already on. So that would be, you know, one thing to consider is, is the current medications optimal that they're on? But again, yeah, I think, you know, non-oral, non-smoke routes, you know, subcutaneous routes may be less, you know, have less negative effects compared to the others. Okay. And with that, we unfortunately have time to address all the questions. Thank you so much, Dr. Radhakrishnan. Thank you everyone for joining the webinar today. Please claim credit for the webinar in the APA Learning Center.

Medical Cannabis

Psychiatric Indications

Dr. Ranjith Radhakrishnan

Phytocannabinoids

Endocannabinoid System

THC

CBD

Psychiatric Disorders

Adverse Effects

Cannabis Usage Trends

Research Efforts

Cannabis Use Disorder

Harm Reduction Strategies