Hello and welcome. I'm Dr. Amy Cohen, a clinical psychologist and director of SMI Advisor. I'm very pleased that you're joining us for today's SMI Advisor webinar, Major Depressive Disorder, Marijuana and Cannabinoids, Disentangling the Research to Help You Guide Your Patients. Next slide. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. Next slide. Today's webinar is applicable to the whole care team, and therefore we are offering one AMA PRA Category 1 credit for Physicians, one Nursing Continuing Professional Development Contact Hour, one Continuing Pharmacy Education Hour, one CE Hour for Psychologists, and one CE Hour for Social Workers. Credit for participating in today's webinar will be available to you until February 19, 2024. Next slide. Slides from the presentation today are available to download in the webinar chat. Select the link to view. Next slide. Captioning for today's presentation is also available. Click Show Captions at the bottom of your screen to enable. Click the arrow and select View Full Transcript to open captions in a side window. Next slide. Please feel free to submit your questions throughout the presentation by typing them into the questionnaire found in the lower portion of your control panel. We'll reserve 10 to 15 minutes at the end of the presentation for Q&A. And now I'd like to introduce you to the faculty for today's webinar, Dr. Edgar Woznika. Dr. Woznika is a board-certified psychiatrist currently working at a federally qualified health center in Chicago, Illinois, also known as an FQHC. He graduated from Brown University's Alpert Medical School and completed psychiatric residency at Johns Hopkins. Following training, he began his years of service in community psychiatry as a National Health Service Core Scholar. He currently directs his organization, Substance Use Treatment Services, and teaches residents about substance use disorder management. He is passionate about serving patients with co-occurring substance use and other mental health disorders. Dr. Woznika, thank you for leading today's webinar. Thank you. Thank you for that very kind introduction. I'm happy to get started. So I have no disclosures to share. In terms of the learning objectives, I hope that by the end of today, you should be able to critically review research by cannabinoid type. You should be able to educate patients on the addictive potential of products with high THC content or high THC to CBD ratios. And you should be able to counsel patients with major depressive disorder on the risks of using whole cannabis and THC concentrates. Before we go into the main body of the presentation, I'd like to give some background to set the scene. So, as I'm sure you're aware, there is a large number of individuals who are expressing support for the use of cannabis. Medical cannabis is now legal in many states. Since I am speaking on a federal platform, I do want to say that it is federally illegal. Patients report improvement when they're using cannabis and chronic pain, anxiety, depression, and the press is often supportive. So, I'm bringing this from a recent New York Times article talking about an elderly cannabis user club. The quote was, the elderly cannabis user club's membership might be higher if it weren't for the stigma still associated with the drug. The highlighted, bolded, and italicized portions saying that this is something that maybe elderly people should move past the reservations around this drug and embrace it as for its medical potential. And so, the key idea in the press is that this is something that you don't need to be afraid of anymore, but instead should embrace for its health benefits. And I would argue sometimes it's being presented as a panacea, a solution to any problem. There's a billboard near my house that says, we have a solution for that. And it's a cannabis dispensary. On the other hand, there are also problems from cannabis. I want to talk just for a second about the concept of medical cannabis. This was something that was created by state legislators. They created the indications. So, it was not the FDA reviewing two randomized double-blind controlled studies, but instead state legislators having some level of review of evidence, but also subject to the political process and all of its inherent challenges, including the addition of a sympathetic population, those with PTSD, for which there is no evidence for cannabis being helpful. In addition, I want to argue or add that you're not giving someone a prescription, but instead a medical card. So, you're not saying, please take 10 milligrams of THC and 10 milligrams of CBD twice daily. Instead, you give them a card. They go to the dispensary, speak with the dispensary salesperson, and are going to purchase, based on how much they can afford and their interest, a product that has an addictive potential that they will self-administer. So, the medical cannabis approach has its strengths, but it's significant weaknesses and vulnerabilities. Additionally, as more people are using cannabis, we are now coming across more consequences related to cannabis use, including cannabis use disorder. And so, this puts us in a challenging situation. What do we tell patients? There are some groups that are supporting use and other groups pointing out the problems with use. Just like lots of things in medicine, there are risks and benefits associated with the use of this product. And so, if you look to the medical literature, you might find it confusing if you're unfamiliar with key concepts. So, as an example for something that was confusing for me, until I learned a great deal about this subject, was that whole cannabis is associated with schizophrenia onset or exacerbation, yet CBD may treat the positive symptoms of schizophrenia. If you are confused by how these two things might be true at the same time, I hope by the end of this presentation, you'll be able to easily separate out a study that looks at whole cannabis from a study that looks at CBD and be able to understand why these two things might be true. So, that's my goal for today's presentation. Here's the overview, then, or the goal, I should say. I'd like to introduce you to the cannabinoid literature so that you can understand the so that in the future, you can review literature on cannabinoids and X blank topic, whatever it is that you're interested in, anxiety, psychosis, chronic pain, et cetera, and make your own decisions with the information you need. And for today, I'm going to use major depressive disorder as an example. It is a serious mental illness. It's very common, and it's one of the reasons why people self-administer a cannabinoid. To achieve that, here's my overview of subjects. I'm going to start off by discussing the endocannabinoid system, so you understand what happens when someone consumes a cannabinoid. I will then go over the major cannabinoid classes. This way, you can organize in your mind the multiple different cannabinoids that exist and their varying effects. Then I will discuss the cannabis plant preparations that exist right now so that you will know the difference between whole cannabis and concentrates. Then I'll discuss cannabis's addictive potential, state laws, and then we'll go into the connection to mood by talking about the role of the endocannabinoid system and mood regulation before wrapping up with, in a sense, the meat of today's discussion, which is what is the role of consumed cannabinoids on mood? To start off with, let's talk about the endocannabinoid system. The endocannabinoid system, or ECS for short, was discovered when researching how cannabis has its effects in the 1960s. It is largely composed of three components, the endo for endogenous cannabinoids, the two main ones being anandamide and 2-AG, multiple cannabinoid receptors, but the main ones being CB1 and CB2, and then the enzymes that synthesize and degrade the endocannabinoid An interesting part about the endocannabinoid system is that it is unusual and that it is involved in retrograde signaling. So all the other neuronal signaling methods are anterograde from the presynaptic neuron to the postsynaptic neuron, but the endocannabinoid system engages in retrograde signaling. So I hope you can see my mouse here. In the image on the right, I'm showing you the endocannabinoid system. So I hope you can see my mouse here. In the image on the right, I'm circling the postsynaptic terminal right now, and inside is AEA, which stands for anandamide, and you can see that it's released into the synaptic cleft and goes to the G-protein coupled receptor, where it has its effects on the presynaptic neuron. And then similarly, coming back down to DAG and the postsynaptic neuron, that goes through change to become 2AG and is released into the synaptic cleft, where it is then taken up by the presynaptic terminal to have its effect. It's thought that this retrograde signaling may play an important role in various homeostatic functions. So to summarize, the endocannabinoid system is fairly different in that it's retrograde signaling instead of anterograde signaling. The endocannabinoid system is also distributed beyond the central nervous system and peripheral nervous system. Let's talk about the distribution. The image on the right has in blue the CB1 receptors and red the CB2 receptors. The CB1 receptors are mostly in the central nervous system, but also elsewhere. And the CB2 receptors are mostly on immune cells, like macrophages, but also elsewhere. I highlight this to say that I'm going to talk mostly about the effects on the brain, but the endocannabinoid system has effects beyond that. And so you might come out with, or there might be medications or drugs or effects of medical cannabis that are on other organ systems, and that's because the cannabinoid receptors are distributed throughout the body. And indeed, as would be expected for a system that is distributed throughout the body, the endocannabinoid system plays a role in various bodily functions. It's involved in, and this is a non-exhaustive list, the immune system, as well as appetite, anxiety, depression, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre and postnatal development. I highlighted this list to say that the endocannabinoid system is involved in a lot of different functions throughout the body. Now I'd like to move on to the major cannabinoid classes with the intention of helping you to organize these in your mind. So to start off with, let's define that a cannabinoid is any compound with affinity or activity at the cannabinoid receptor. And you can split up cannabinoids into two systems. One endogenous, those that the body produces. These are the endocannabinoids, anandamide and 2-AG that we already discussed. And then the exogenous are those that are introduced from outside of the body. And these you can break down into phytocannabinoids and synthetocannabinoids. Phytocannabinoids are those derived from plants. For example, cannabis sativa. There are over 140 of these phytocannabinoids in cannabis sativa. THC and CBD are the main ones. In contrast, the synthetocannabinoids are those that are synthesized in a laboratory. And we can break these down into two main groups. Pharmaceutical meds. These are synthetic THC and THC analogs. And then lab-created recreational drugs, the aminoalkylindole derivatives. And I'll talk more about both phytocannabinoids and synthetocannabinoids in the slides to come. So discussing phytocannabinoids. THC, it is a partial agonist at the CB1 and CB2 receptors. I highlight partial because the aminoalkylindoles derivatives are full agonists. And I'll discuss the implications there. But for now, THC, it's a partial agonist. This is the compound that is responsible for the high or euphoria. That is one of the main reasons why people consume cannabis. It also does reduce nausea, stimulate appetite, and reduce acute and chronic pain. In contrast, CBD is quite different. It is a negative allosteric modulator at the CB1 and CB2 receptors and a full agonist at other receptors. What does it mean to be a negative allosteric modulator? It means that it binds to the receptor at a different site so that the agonist can still bind. But when that agonist binds, it lowers the presence of CBD. And the binding at that receptor lowers the agonist affinity and or efficacy. So put differently, if THC and CBD are both present, then CBD when binding lowers THC's affinity and efficacy. In effect, it moderates the effects of THC. In addition, CBD is anti-inflammatory, neuroprotective, anxiolytic, and antipsychotic. Now, moving on to the synthetocannabinoids. As I introduced previously, there's the pharmaceutical and the lab-created recreational drugs. Within the pharmaceuticals, there is synthetic THC, generic name gernabinol. And this drug has FDA approval for chemotherapy-induced nausea and for appetite stimulation in AIDS wasting syndrome. And the synthetic THC analog nabalone has an FDA indication for chemotherapy-induced nausea. In contrast, there are the lab-created recreational drugs, amino alkalindole derivatives. These were originally designed by chemists to study the cannabinoid system, but are now being created by labs and commercial companies to be distributed as a drug you can purchase in like a convenience store. And these are known as synthetic marijuana, synthetic cannabis, designer drugs, spice, K2, or where I was, Scooby-Doo. And these are full agonists at the CB1 and CB2 receptor. So, by being a full agonist as opposed to THC's partial agonist, it has more of a robust effect. As these are synthetic, there is no CBD to have a moderating effect. So, in total, these lab-created recreational drugs have more potent and enduring effects lab-created recreational drugs have more potent and enduring effects. They're full agonists, there's no CBD. These drugs can be quite potent, and they do have very serious side effects. I had a patient develop a fairly serious rhabdomyolysis from the use of an amino alkalindole derivative. Okay, that was a brief overview of the different cannabinoid classes so that we can start diving into the ways in which people prepare cannabis for consumption. The two major distinctions are on whole cannabis or purified cannabis. And I'm going to start off with whole cannabis. In the upper right, you can have an image of what we're thinking about. We're talking about the plant cannabis, Teva, that is then dried and then consumed through a variety of ways. Some states have legalized whole cannabis for medical and recreational use. And this drug is becoming increasingly potent, both in terms of the percentage THC, with THC being the main euphoria-producing compound, the higher the percentage THC, the more potent it is, and by THC to CBD ratio. Since CBD has a moderating effect, if there's a greater ratio, there's less CBD, THC is going to have more of an effect. So looking at the right graph, this is talking about the changing potency of whole cannabis across time from samples collected by the DEA. And this data set goes from 1995 to 2018. On the x-axis, we have those years. And on the y-axis, we have the potency, the percentage THC or CBD. The blue line represents THC and the red line CBD. And it's very obvious to see that across time, it has become more potent. In the 1980s, the percentage of THC was 2%. When this timeline starts in 1995, it's 4%. And when this stops in 2018, it's 16.2%. I would not be surprised if this trend line has continued. The THC that's locally available here in Illinois, where I am, is between 20% and 30% THC. At the same time, the percentage of THC has gone down by a quarter from 0.28% to 0.21%, meaning that the whole cannabis that's being consumed has a greater percentage of THC and a greater THC to CBD ratio. This is important because these more potent forms are the preferred type. They produce the best high. That's why they're being grown and cultivated, because they're the ones that people like to purchase. But unfortunately, they're also riskier. They're connected with increased risk of psychosis and increased risk of cannabis use disorder. The next slide is about purified cannabis. And here I want to talk about commercial THC concentrates. I have in the upper right an image. This is an oil of a THC concentrate. The examples of these types of drugs are hash, oil, wax, shatter, and dabs. And some states have legalized these substances for medical and recreational use. And similar to the story for whole cannabis, the commercial THC concentrates are becoming increasingly potent, both as a percentage of THC and by the THC and CBD ratio. So going back to that graph on the right, which is the same concept as before, you can see that from 1995 to 2018, the percentage of THC has gone up significantly, and the percentage of CBD has dropped to about a third of what existed before. So this product definitely has more THC in it and has a greater THC to CBD ratio. I apologize I didn't review the numbers in the previous slide, but here the THC to CBD ratio, five-year average from the first five years was 42, and the last five years of this study was 114. So you could see that the THC to CBD ratio is going up. It's going to go back for a second to the previous slide, and you can see the same data again, that in the first five years, the THC to CBD ratio was about 12, and now it's gone up to 78. So we are increasingly creating more potent versions of whole cannabis and commercial THC concentrates. The next form of a purified cannabis is the commercial CBD products. In the upper right, I have an image of a generic CBD concentrate available for purchase. These are commercial products. One unfortunate truth about these commercial products is that the CBD and THC product labeling does not equal the product content, so you cannot trust based on what it says that that's actually what's in there. These are derived from hemp, which is how they're federally legal, but at the state level, it varies. They are legal in my state, but not legal in all states. These are sold over the counter for various ailments. If they're legal in your state, you've no doubt seen them all over. If they're not legal, if you go somewhere else, you will see them for sale in many different locations. The last form of purified cannabis that I want to talk about are pharmaceutical grade extracts. I separated these out because what's important here is the product labeling does indeed equal the product content. There's two pharmaceutical grade extracts. The first is nabixamals. This is a compound that's about one to one THC to CBD. It is not approved in the United States, but it is available internationally for multiple sclerosis, spasticity symptoms, and as an adjunct in cancer analgesia. I just want to give you an example of what this drug would look like. One spray is 2.7 milligrams of THC and 2.5 milligrams of CBD. If we went to the United Kingdom and went by their maximum recommended standards, you would give just 12 sprays a day, which is 32.4 milligrams of THC and 30 milligrams of CBD total. I just want to contrast that with one of my patients who consumes five grams of whole cannabis each day. He says for his anxiety and just for illustrative sake, let's say it was 20% THC and 0.2% CBD, which it very well could be, then that would be a thousand milligrams THC and 10 milligrams CBD consumed each day. I want to contrast that self-administration of whole cannabis with nabixamals. This individual is consuming a vastly larger amount of THC, and even though he's consuming so much marijuana, he's actually consuming less CBD. If we compare nabixamals, which has a high amount of CBD, more than what would be found in whole cannabis that would be moderating the effects of THC, this drug is very different than the whole cannabis that the patients are consuming. The next pharmaceutical grade extract that you probably have heard of is Epidiolex. It's an amazing concentrate that's a lot of CBD, greater than 98%. This is FDA approved for two rare epilepsy syndromes, Lennox-Gastaut and Dravet syndromes. We just went through the endocannabinoid system to introduce you to the major cannabinoid classes to help you organize these in your mind, then the various cannabis preparations. Now I'd like to quickly go through the cannabis's addictive potential and state laws before we move on to mood. I want to recognize in talking about cannabis's addictive potential that indeed cannabis has multiple adverse effects. We know that if you're an adolescent and you start using and you use it consistently for several years, it has an effect in lowering your IQ. We also know that it increases your risk for psychosis and it's a hot area of research as to whether or not that means it increases your risk for schizophrenia. I would have said previous that there was a rare syndrome called cannabis-induced hyperemesis syndrome, but a recent study argued that we should stop talking about this as rare. Using various means of extrapolation, they estimated that two to three million Americans have this condition. That being said, there's other effects from cannabis, other adverse effects, including driving under the influence. That being said, I do want to prioritize cannabis use disorder because when someone has a use disorder, by definition, they have a loss of control. If someone is taking a substance, they're saying for a medical purpose, and it causes an adverse effect, most of the time, the person can stop that without problem. If they are addicted, they have lost control, and by definition, they're going to have difficulty stopping that substance. Also, many substance use disorders are difficult to treat and cannabis use disorder is no exception. I also want to add that when a clinician is talking with a patient about cannabis, I imagine that one of our chief concerns is that we don't want to get the patient addicted is that we don't want to get the patient addicted to the substance. I am privileging addiction over other adverse effects, I think, with reason in this discussion. I do also want to add another reason I'm privileging addiction is that the current high potency products are more addictive. An estimate from 1992 suggested that 9% of people who ever used or tried cannabis would become dependent. That was a DSM-IV definition of a use disorder, our current nomenclature, versus in 2018, an estimate was that 30% of those who use cannabis may develop cannabis use disorder. This drug has become a lot more addictive as it has become a lot more potent. In wrapping up the section on use disorder, I want to share who is at risk. You'll be asking that question, who should I be concerned about in particular? The answer is that we know that those who start younger, those who use more, and those who use more potent versions, such as higher THC content, greater THC to CBD ratios, are at higher risk for developing cannabis use disorder. Now I'd like to discuss state laws, as is the case in 2023. If I give this presentation again next year or two years from now, it may be different, but here are the state laws. I'd like you to think about where you are, what your state has made legal, if anything, and how does that compare to nearby states. At present, 47 states have some form of legal cannabis, 38 states have legalized the medical use of whole cannabis products, 14 states have limited that to only medical cannabis, so the yellow states are those that have allowed only medical cannabis, and then 24 states, those that are in green, have allowed medical and recreational cannabis. I want to contrast that with an interesting case. There's nine states, those in orange, that have legalized only high CBD or low THC products, so just as an illustrative example, Indiana allows you to consume something that is greater than 5% CBD but less than 0.3% THC, so very different than what my patients can easily obtain here in Illinois. I just want to think about, oh, then there's three states, I apologize, for which cannabis is still illegal, and they don't have any color, so I want to think about the reality of someone in Memphis, Tennessee, where there they can only get a high CBD product, but they're near several states that have medical cannabis and several other states that have medical and recreational cannabis. If you're interested in more about this, you can find the data set at the National Conference of State Legislatures. Okay, now I'd like to transition to the example I'd like to go into, which is major depressive disorder, and to start, I'd like to discuss the evidence for the role of the endocannabinoid system, or our own endogenous cannabinoid system, on mood regulation. It's reasonable to think that there might play a role in the endocannabinoid system in mood regulation because endocannabinoid receptors are found in brain structures involved in mood, emotion, and reward regulation. There's also the observation that endocannabinoid system signaling leads to physiologic and behavioral effects seen in major depressive disorder, and so a hypothesis by Hasby et al. in a recent paper is that decreased ECS signaling increases susceptibility to, or directly participates in an individual developing a depressive episode, and they cited the following evidence. Just as a reminder, as I go through this evidence, that the general idea is the hypothesis is that decreased ECS signaling leads to major depressive disorder. The evidence is that depressed animals and depression animal models and depressed humans have decreased ECS signaling. Increasing that ECS tone reduces depressive symptoms. A CB1 agonist, HU210, had an antidepressant effect. A CB1 antagonist, remonibant, increased depression and suicidal ideation. This was indeed a weight loss drug that was available internationally, but never in the United States. When they sought FDA approval, the FDA raised concerns about the suicidal ideation, and that ultimately led to it being pulled from the market internationally. Finally, rodents lacking the CB1 receptor, thereby having a vastly decreased ECS signaling, have a depressive phenotype. So for me, I think there's a reasonable argument that the endocannabinoid system, your endogenous cannabinoid system, is involved in mood, and so then that leads us to the question, what effect does a consumed or exogenous cannabinoid have on mood? There we are. The end of the presentation. The last section, I should say. What effect do consumed cannabinoids have on mood? For the sake of this presentation, I narrowed the conversation to only major depressive disorder, excluding bipolar disorder, and that was just because I had to narrow the scope of my presentation. Coming back to the question, what effect do consumed or exogenous cannabinoids have on mood? We can really break this down into two questions. The first being, let's say a patient does not have major depressive disorder, but they're consuming a cannabinoid. Does that increase or decrease their major depressive disorder risk? The second is, a patient has major depressive disorder already, and they're using a cannabinoid. Does that treat or exacerbate their major depressive disorder? Unsurprisingly, given that not all cannabinoids are the same, THC is vastly different than CBD, the answers are going to vary based on content. You can look at substances that are THC only, CBD only, or THC and CBD with varying THC and CBD ratios. I wanted to give a breakdown according to the addictive potential. As someone interested in addictions, this is one of my primary concerns. I also think that, for the reasons stated previously, that if someone is having an adverse effect, they can stop it if it's not addictive. I broke down the cannabinoids into highly addictive and less addictive. The highly addictive ones were whole cannabis and THC concentrates, and the less addictive ones were CBD concentrates, THC to CBD in a one-to-one ratio, and then pharmaceutical THC and THC analogs. I want to spend a moment more discussing this breakdown. As we go through the data, I find that this breakdown, I think, has validity in guiding our questions and answers. Though, of course, you might have a different breakdown, a different approach that I think is valuable. In addition, I did put pharmaceutical THC and THC analogs in the less addictive category, not the more addictive or highly addictive one. I did title it less addictive, not addictive, because I can't say that these compounds, including CBD and THC to CBD in a one-to-one ratio, are not addictive. I did put pharmaceutical THC and THC analogs in less addictive because there was a study of dronabinol being given for chemotherapy-induced nausea to individuals, including those with a history of substance use disorders, and there was no evidence that the individual was displaying any evidence of addiction. There was no drug-seeking behaviors, early refills, interactions that left the health staff wondering how they were using the substance. So, that's how I broke it down, and there's probably other ways of validly breaking it down as well. Continuing down, we're going to try and answer, I apologize, the first two questions, but stratify it by highly addictive and less addictive. So, starting off with less addictive cannabinoids and major depressive disorder. Just under the title, I reminded you what the less addictive cannabinoids are. CBD concentrates, THC to CBD in a one-to-one ratio, and then, pharmaceutical THC and THC analogs. Our first question here is, do less addictive cannabinoids increase or decrease the risk of major depressive disorder? Unfortunately, a recent systematic review found that no studies have tried to answer this question, so we don't know. The second question is, do less addictive cannabinoids treat or exacerbate a pre-existing major depressive disorder? In trying to answer the question, treat, there is limited evidence that the three pharmaceuticals, nabixamols, dronabinol, and nabalone, are ineffective, and unfortunately, no studies have been done on CBD. You're asking, do less addictive cannabinoids exacerbate major depressive disorder? Throughout the course of my research for this presentation, I did not identify any studies answering this question and any of the systematic reviews that I read. Doesn't mean it's not there. I just wasn't able to find one. In summary, there's limited evidence that less addictive cannabinoids do not treat major depressive disorder, and that's all we can really say about less addictive cannabinoids. Now, transitioning to highly addictive cannabinoids, again, I want to remind you that we're talking about whole cannabis and THC concentrates. The first question is, do highly addictive cannabinoids increase or decrease the risk of major depressive disorder? I'm going to start off with my summary. I have concluded that the signal suggests that highly addictive cannabinoids increase the risk for the development of major depressive disorder. The evidence for that is that there are cross-sectional epidemiologic studies noting associations, and then recent systematic reviews of longitudinal studies have noted mixed associations, with some finding that it increases the risk and some finding that it does not increase the risk, not that it decreases the risk. None have found that it decreases the risk. Some found that it does not necessarily increase the risk. But what I think is compelling is a recent prospective population-based cohort study where they took the entire population of Denmark and they found that if an individual had cannabis use disorder, their hazard ratio of developing major depressive disorder was 1.84. I can't say relative risk. This is an odds ratio, but in the bad direction, hazard ratio of 1.84. This is not definitive. Whenever we're looking at something where we're not going to be able to do a double-blind placebo-controlled study, a randomized study, then we're going to have to look at lower forms of evidence. These are still valid, but lower forms of evidence. I think that the direction is generally pointing that these highly addictive cannabinoids increase the risk of major depressive disorder. Now to our second question, which is do highly addictive cannabinoids treat or exacerbate major depressive disorder? With the question of treat, there were no available studies in a recent systematic review. I can't say that they do treat. If you're going to ask, do they exacerbate? There are lots of studies on that topic. Again, my summary is that the signal suggests that highly addictive cannabinoids exacerbate a pre-existing major depressive disorder. Here's a summary of the literature on that. Cross-sectional epidemiologic studies show that the association between major depressive disorder and cannabis use has been strengthening over time, meaning that patients with major depressive disorder are increasing likely to use cannabis daily or near daily. Another epidemiologic cross-sectional study has said that that may be explained by confounders. There have been recent systematic reviews that have identified a few longitudinal studies answering this question, and they have found an increase in major depressive disorder illness severity amongst those who use cannabis, as well as an increase in specific major depressive disorder symptoms. Two longitudinal studies of my patients as a psychiatrist, psychiatric outpatients, found that cannabis exacerbated depressive symptoms. Again, this is not a settled issue, but to me, the signal is going in the direction that it's telling me my internet connection is unstable. I hope it's okay right now. We can hear you. Great. Thank you, Dr. Cohen. The signal suggests that highly addictive cannabinoids exacerbate major depressive disorder. I also want to add that a patient who has major depressive disorder who uses cannabis is at an increased risk of developing cannabis use disorder. So to summarize these two points, if someone has depression and they're using cannabis, it is likely that that cannabis worsens their major depressive disorder. Because they have major depressive disorder, they're at risk of cannabis use disorder. So they're having a positive feedback in a negative direction. Each condition is getting worse by the presence of the other. This is not surprising, given that the literature on substances that are addictive in general suggests that it worsens mood disorders. If you have a mood disorder, it worsens your substance use disorder. In summary, for the section about consumed cannabinoids and mood, there is limited evidence that pharmaceuticals do not help. There are no studies, unfortunately, on CBD. And the signal suggests that highly addictive cannabinoids increase the risk of major depressive disorder development and exacerbate major depressive disorder. Stopping cannabis will improve your mood. Now, the overall summary for the presentation. I hope that I've been able to convey to you that the endocannabinoid system is involved in multiple bodily functions. And I want to point out that meds will likely in the future target endocannabinoids, the receptors or enzymes. Consumed or exogenous cannabinoids interact with the endocannabinoid system. THC produces euphoria and is also addictive. CBD is anti-inflammatory and moderates THC's effects. Going forward, I hope that you're able to critically examine the literature by which type of cannabinoid did they study? Was it THC only, CBD only, and what was the ratio of THC to CBD? I hope I also conveyed that recreational cannabis is becoming increasingly potent, with higher percentage THC and a higher THC to CBD ratio, which is unfortunately more addictive. The signal suggests that highly addictive cannabis products increase the risk of major depressive disorder and exacerbate a pre-existing major depressive disorder. If a patient is able to stop cannabis, their mood symptoms will improve, and that unfortunately there's an unclear benefit or risk of less addictive cannabinoids. Here is my bibliography. And thank you. Thank you for listening, and I look forward to your questions. Thank you so much. So I learned so much, and we already have a lot of questions, but before we move into Q&A, let's go to the next slide. I want to take a moment and let our audience know that SMI Advisor is accessible from their mobile devices. Use the SMI Advisor app to access resources, education, upcoming events, complete mental health reading scales, and even submit questions directly to our team of SMI experts. You can download the app now at smiadvisor.org forward slash app. So let's go to the next, and let's talk a little bit about our questions that came in. There's some real specific ones, and then there's some more broad ones. I know you're not surprised. So I think when you talked about, when you had the picture of the CBD bottle in your hand, and you said that you don't really know what's in it, right? So a couple people have written in and said, well, if commercial CBD concentrates are legal federally, why is the content not being regulated such that the label accurately reflects its contents? Any ideas on that? That's a great question. I don't know exactly. I don't know the answer. It might have to do with the fact that it's not under the FDA purview. Okay, okay. So I think we were all stunned by your graphs where the potency was going up so significantly. And so there's two parts to this question. One is what's being done to whole plants to change the potency? And then two, the person says you didn't mention indica. I'm not sure if I'm saying it right. Where does indica fit into this conversation? So I am not necessarily an expert on all things cannabis, but I think what is basically occurring when it comes to the whole cannabis plant is genetic selection. So if a strain produces more THC, then we're purposefully propagating that strain, kind of like what's happened with corn. If you look at the original corn product from Mexico, from X number of thousand years ago, Teosinte, I think is the name. It's like a tiny little corn, the flower is tiny, but then we've grown it into this giant corn product. The same thing is happening with THC. It's kind of remarkable to think that that flower is spending so much of the actual structure. It's gone from 2% to 30% of the structure of that flower is a compound that when inhaled is enjoyable to us. We have bred it to be that way. And then obviously with the concentrate, we're purposefully concentrating it to make it stronger. But when it comes to the whole cannabis, I think it's the breeding of it. And then it's also, you can use sinsemia, which I believe is the non-fertilized female flowers produce a higher content as well, but that would not be sufficient if it weren't for the fact that the overall marijuana plant is becoming more concentrated. And as for the second question, is there a difference between cannabis sativa and cannabis indica? Because patients will tell us that the indica has more of a calming effect. And I love that question. I got that question after my first time practicing this. And so I looked into the literature and I don't think that it is seen as valid a distinction in science. That doesn't mean that it's not being sold as different, but the efforts to say, are these actually different species suggested that it's not valid. And in the entire time that I was researching this cannabis or cannabinoid issue, I did not once come across the difference between sativa and indica. And I think it may have to do with the fact that we don't actually know if there is a true difference between the two. Now, I would love for someone that is deeper into the weeds of the science, a researcher on this to give an answer, but I think that's what they might say. Wonderful. Yes, and sometimes we know the marketing is different than the science, right? Yeah, and then I think one thing that's really important to talk about here is the expectancy effect. So if someone expects a drug to have an effect, then that's the effect they will have when they consume that drug. And this has been shown with placebos. We tell someone that they're consuming a product and they start to have the effect even though they're receiving a placebo. And this happens for substances that produce euphoria like cannabis. So I think I can't explain the indica sativa difference entirely, but I wonder to what extent an expectancy plays a role. Interesting idea. So, and I don't know if this is related to the earlier question. So the person says, so the Delta-8 you can purchase at the CBD stores, you cannot believe the label content? How can this be if it's approved federally? Is this the same question that we had earlier? I don't know what Delta-8 is, but maybe you do. Yeah, so I think there are these other things that are not Delta-9 THC that are getting around this issue. My understanding is that there was a farm bill passed in like 2018 that allowed for hemp. And so then we can derive all these products from hemp that are not technically illegal at the federal level because they're not cannabis sativa or cannabis indica. And so now we have these products like CBD and Delta-8 THC. That said, those are being produced by laboratories that are interested in selling this commercially, but they're not necessarily at the same level of scrutiny as a pharmaceutical company. Pharmaceutical company has to make sure that the product they're selling is the product they're selling, but it has the percentage of X or Y, otherwise they can face significant consequences versus these other commercially available companies. They're not testing each of their products using like, I'm gonna guess gas chromatography, something that's an expensive technique to determine what it is that's actually in there and the amount that's actually in there. Because they're interested in turning a quicker profit, reducing costs. And so when laboratories have assessed these products, they have found that the labeling does not equal the content. Now as to why there's not greater scrutiny, I'm sure that has to do with where it falls into as a product, that it doesn't fall into the same regulatory purview. But I don't know the exact specifics for how that escapes that higher regulation. You talked towards the end of your talk today about exacerbation of MDD symptoms, right? Major depressive symptoms. And a couple of people have written in and kind of said, what does the exacerbation look like? And so I guess, is it on the mood end? Is it on the sleep end, eating end? And what does it look like when you're talking about exacerbation? Right, so the one that talked about the specific symptoms, it was what you would expect, anhedonia, amotivation, loss of ability to sleep, loss of appetite. In my experience, I find that the exacerbation, I don't know that I can say that I've seen the exacerbation. I don't know that I've seen many patients in the beginning when they are using a small amount of cannabis and then they're using a lot more cannabis. I would say that cross-sectionally, I'm seeing patients with fairly severe major depressive disorder and fairly severe cannabis use disorder. And they are my sicker patients, whether that's because they're using cannabis as opposed to a different substance, I can't say, but they do have a comorbid substance use disorder that complicates their major depressive disorder. And so that the exacerbation, I would say, reflects the kind of increased severity that comes from the addition of a substance use disorder. Generally speaking, substances tend to produce exacerbated depression. But I do want to add one point that I think is interesting, specific to cannabis. Cannabis seems to be associated with a particular problem with amotivation. And we don't know yet if that's particular to the drug itself or the loss of motivation towards doing what you're supposed to do that sometimes comes from substance use disorders because the person's priorities have come towards using the substances rather than doing what they're supposed to do. But my suspicion is that the amotivation is more unique to cannabis because my patients with just pure cannabis use disorder and not major depressive disorder have an incredibly difficult time leaving their house. The stereotypical image of someone with a cannabis use disorder is that across time, as they increase the amount of cannabis they're consuming, they retreat more from life and they spend more and more time stereotypically in their parents' basement consuming cannabis, being high, dealing with the effects, not feeling comfortable going outside and not succeeding in job rearing, mating or parenting. And so I'm getting at that retreat from life and connecting with amotivation to say that that overlaps with some of the symptoms of depression where an individual might spend a significant amount of time in bed, they have difficulty motivating themselves to do things that they need to do. We also know that they're less likely, from one study, people with major depressive disorder and cannabis use disorder are less likely to take their medications and less likely to come to appointments. So that might be exacerbating in a sense, and is that pure? It gets complicated, but the idea is generally it goes in that direction. And you seem to say that when the cannabis use disorder is lessened, when that's addressed, the mood improves. Absolutely. So trying to distinguish like which one came first can be hard because people start using cannabis when they're young. If they developed a major depressive disorder before they developed cannabis use disorder, it's easy. If they've had a sustained period of abstinence and they had a major depressive disorder during that period, then it's easy. But generally speaking, it's hazy. And my patients both started using cannabis and developed mood symptoms at the same time and they haven't really stopped using cannabis. And so it's hard for me to determine if they have a major depressive disorder or a substance-induced depression. But what I have found is that when patients are able to stop people who looked severely depressed became completely euthymic and they were not taking medications anymore. Whether or not they got out of the depressive episode and didn't need the medications or I misdiagnosed them as having major depressive disorder when all they had was a substance-induced depression and stopping it led to them getting better, I don't know. But the point is, is that I did give them medications in case and we were able to help them stop and they improved. And I think in the end, what we're looking for is the patient getting better. And I think this is not something somebody wrote in but something we often hear is, which one should I treat first? And it sounds like your answer, which is the one that we usually think about is we treat them both at the same time. And is that kind of your approach, your suggested approach? Yes. I think there's two parts to that. One is it depends on the severity of the cannabis use relative to the severity of the depression. But I would expect someone to not be able to get all the way better unless they've addressed their cannabis use disorder. So, and I think we kind of talked about this before we entered today. We always have folks on here who are practicing and gonna go back to their office tomorrow. And here's a perfect question from one of those kinds of people. So how do we talk with patients who feel like using THC decreases their symptoms of depression and anxiety without any side effects? So how do we start that conversation with them? So first I wanna say that I start off by saying that it's not exactly natural, that this is not the wild type cannabis that's growing in Central Asia, but instead something that has been engineered. And so that is a point against the natural concept. And then one thing that's always helpful to start is to ask permission. Because if you start talking without asking permission, then you elicit defensive guardrails. But if you say, can I ask you, or can I share with you a couple of things about cannabis, then that opens up them listening to you. And one of the main things I share is that there's a difference between what you experience when intoxicated or feeling the acute effects and what happens over the long run. So the acute effects of cannabis consumption is euphoria, which seemingly helps. But if we look at it across time, the overall depression scores get worse. So the acute effects are different than the chronic effects. I think that's intuitive for many patients based on like alcohol consumption and major depressive disorder. And then I also add in that if someone has major depressive, let me switch for a second. If someone is drinking alcohol on a weekend, it's actually still a toxin and it's not good for them, but we don't really think of it as being a problem for them in the same way as if they're consuming alcohol all day, every day, then there's not really much of a question that that person has a problem with alcohol. But when it comes to cannabis, if someone consumes on weekends, that's one thing, but we had this idea that somehow consuming all day, every day is not a problem and it's somehow medicinal. And I don't think that's accurate. I think that reflects a problem in how we have been discussing cannabis in our country, because that amount of intoxication, like my patient who's consuming five grams of cannabis every day, that leads to disruption and dysregulation of various bodily functions, not to mention severe cannabis use disorder that affects them. So my point there is that I started off by saying, I think we can talk about this more like alcohol, where use all day, every day is likely to make you worse versus recreational use. I'm not sure how much I can comment on that. And so you might feel like it's helping because the acute effect is euphoria, chronically it makes it worse. And then ask what they think about that. Hmm. And like you said, a lot of the things that you've just said probably resonate with them. Like they're like, I can kind of see that and that opens up the conversation to get going. Yeah, there's certainly some patients that deny it and those are the sicker patients, but most people can see it. Right. So someone wrote in and said, can the pattern of using cannabis be stopped with time? Specifically, I'm thinking about people who start at a young age. So I'm not exactly sure. I mean, obviously at any point we hope with treatment it can be stopped, but I think she's kind of asking like, do people ever kind of grow out of it, especially if they started young or is treatment always kind of needed? So I think we have a pretty good, like if I'm gonna draw an analogy to alcohol, we have pretty good data that if you look at across the age span, like the number of people that meet the definition for alcohol use disorder, the peak is actually at 18 to 24 when there's so much binge alcohol consumption, but then it goes down. I don't think there's a second peak. I don't know that, I mean, maybe the like latest studies on cannabis have something akin to that for cannabis, but I don't know that that's the case. And I think one thing that is a challenge is it's constantly changing because of the strength of the cannabis that's being consumed and who has access to it. And I think we're starting to see more and more problems amongst the elderly, people 65 and above, because they're starting to consume this and their brain is at risk for delirium from the use of the substance. Well, wow, it's been a great conversation. There are more questions, but I know we're running out of time. I think it's pretty clear to me that this is a hot topic and you are definitely an expert who's brought a lot of information to us today. I'm so appreciative and I learned a lot. So I really am glad that I was here to be part of this with you. So let's move on to the next slide. If there are any topics covered in this webinar that you would like to discuss with colleagues in the mental health field, post a question or comment on SMI's, you can post a question or comment on SMI advisors discussion board. It's an easy way to network and share ideas with other clinicians who participated today in this webinar. If you have any questions about this webinar or any other topic related to evidence-based care for SMI, you can get an answer within one business day from our SMI advisor national experts. This service is available to all mental health clinicians, peer support specialists, administrators, anyone in the mental health field who works with individuals with SMI. It's completely free and confidential service. Next slide. So I just want to point out that SMI advisor offers more evidence-based guidance on cannabis, such as the basics on substance use and mental health, I'm sorry, and serious mental illness cannabis. This is a great actually resource that I hope you will take advantage of. This fact sheet provides an overview of relevant background details, reviews basics on screening, interventions, treatments, and more. You can access the fact sheet by clicking on the link in the chat or by downloading our slides. Next slide. Don't forget to claim credit for participating in today's webinar. All you need to do is to meet the requisite attendance threshold for your profession, which you have after the webinar ends, please click continue, complete the program evaluation. And the system verifies your attendance, the time that you've been in the session for credit claim. It sometimes takes up to an hour. It really varies on the local regional national web traffic on Zoom. So be patient, but within about an hour or so you should be able to claim the credit. And lastly, last slide. Join us on January 11th in the new year as Dr. Douglas Nordsee presents Self-Report Scales for People with Serious Mental Illness. Introducing the Inspire Self-Report Scale. This free webinar is on January 11th at 3 p.m. Eastern. That's a Thursday. Thank you for joining us all of you today. And thank you, Dr. Woznika so much for your expertise. Until next time, everyone take care.

webinar

Dr. Edgar Woznika

major depressive disorder

marijuana

cannabinoids

endocannabinoid system

THC

CBD

cannabis preparation

potency