Hi, my name is Dr. Veronica Redpath, I am a general practice psychiatrist and I also practice addiction medicine. Today I'm going to be talking about cannabis use disorder. As far as disclosures, I have no financial conflicts of interest. There may be discussion of off-label uses of medications and other interventions. Discussion of brands, accessibility, or methods of cannabis use should not be considered endorsement but is done for educational purposes and be very helpful for us clinicians to know what our patients are doing, what impacts media and different socialization of cannabis use has on their perception of health. Special thanks to Dr. Moroney who provided much of the material for this presentation. Our objectives today are pretty wide-ranging but hopefully it'll all come together. We're going to review criteria for cannabis use disorder and associated syndromes, explain the neurobiologic effects of cannabinoids, why are they important, what are they doing, discuss the epidemiology of cannabis use, how does it impact different populations and how has it changed, discuss evaluation treatment of cannabis use disorder, identify psychiatric and medical complications of cannabis use disorder and cannabis use in general, and compare current treatment options and potential avenues for treatment in the future. We'll also touch on some changing use patterns, accessibility, and public opinion and how it's impacting cannabis use and the rates of cannabis use disorder. We'll start with a few basics. So cannabis ultimately is a botanical plant product. There are multiple different strains, sativa, indica, ruderalis. These differ based on the geography, the growing conditions, and from these basic strains we have created many, many different hybrids, hundreds to thousands of different strains depending on what your classification is. Certain companies have trademarked certain strains and they are bred for specific purposes. So they're bred to be more bountiful, either more foliage and more fiber for hemp production, increased psychoactive or medicinal cannabinoids so that there is more of an efficiency to the products. They've been made more disease resistant and easy to reproduce. So cannabis is notoriously finicky as a plant, oftentimes has to be grown in specialized grow rooms and so with the transition of these plants getting more specialized breeding, we are seeing more large scale cannabis crops coming up and that is increasing the availability of the product. New cannabis derivatives are becoming available every day. Many of them are based in CBD or use CBD as the base compound, which is then transformed into other compounds and it has gotten quite creative. So when we are looking at cannabinoids, there are over 100 different cannabinoids in the cannabis plant. The ones we generally are talking about, the ones of most medical and psychiatric interest are THC and CBD. So the different cannabinoids impact different receptors. When we're talking about THC, we're talking about the CB1 receptors, which coordinate motor activity, thinking, appetite, short term memory, including some of the hippocampal mapping for moving our short term or working memories into long term storage, pain perception, and there's some immune mediation as well. The CB2 receptors are throughout the body, the gut, the pancreas, adipose tissue, hormonally active tissues, reproductive tissues, skin, central nervous system, and this is where CBD and some of the other minor cannabinoids are more active. When we're looking at the cannabinoids, there are the naturally occurring ones as well as the synthetics. In an attempt to evade some of the legislation, K2 spice synthetic cannabis was created and in some locales can still be purchased relatively easily. There are also semi-synthetics such as Delta-8, which is present in small amounts in the cannabis plant, but most of what is derived now is actually based on CBD and then goes through a pretty harsh chemical process to get to the psychoactive THC molecules. And then we have our pharmaceuticals. So Sativex, Marinol are full spectrum, which means they include both THC and CBD. Sativex is authorized for use overseas. Marinol is what can be gotten in the United States and they have very, very narrow indications. So these aren't things that are used very frequently, but there are a number of different reasons for them, such as cachexia and intractable pain. Marinol in particular has been researched for quite a number of off-label uses. THC is our psychoactive component. It's responsible for the high or the buzz of marijuana. It's relaxant appetite stimulant. When you think of cannabis intoxication, most of it is coming from the THC. This is your euphoria, drowsiness, pain control, or decreased perception of pain, and in high enough doses or in people who are susceptible, there can be paranoia and anxiety as well. CBD is neuroprotective and antipsychotic. So it has anticonvulsant properties, antioxidant properties, anti-inflammatory properties. In some studies, there have been some antitumoral effects. Most of these have been in vitro, not in vivo. So we see these effects in a petri dish, but it's uncertain as to whether or not they have real-life consequences. Minimal to no side effects, however, that's not the full story, and we'll talk about how CBD can be a little bit more impactful. There is some mild anxiolytic effect with CBD, which is why it is promoted so often for anxiety management. All cannabis plants contain both, but with varying ratios. So THC can be high, CBD can be high, they can be equivalent or near-equivalent. And traditionally, they have balanced each other out. Synthetic cannabinoids and distillates of cannabinoids are primarily THC, which increases your risk of paranoia, psychosis, and some of these adverse effects related to THC in particular. For marijuana, it is the most commonly used illicit drug. Orders of magnitude beyond prescription painkillers, hallucinogens, sedatives, or stimulant misuse. And for the number of people that have had past-year illicit drug use, 20% of the population, a very, very large number have used marijuana. And perceived risk of harm tend to be inversely correlated. So when you look at the 1970s, we had a pretty high percentage of marijuana use, up to 40% of 12th graders were using it within a one-year timeframe. The perceived risk of harm was relatively low. So culturally, relatively well accepted, and not quite as much of the education around cannabis use. And in the 90s, we see that there is a spike in this perceived risk of harm, where about 40% of people think that cannabis is a high-harm product. At that same time, we see an all-time low of marijuana use in 12th graders, bordering around 21% to 25%. As we have come from the 90s, we see that marijuana use has had a general upward trend, a little bit of a dip, and it's going up, but it inversely correlates to this perceived risk of harm, which is going down and is approaching the levels that we're seeing in the 80s and 70s. There's different forms of cannabis as well. So the method of consumption determines the onset, duration, and detectability of cannabis. There's varying degrees of potency as well. The traditional way of using cannabis is smoked flour, bud or flour, joints, bones, kind of all the same concept, which is combustion of the direct flour and then inhalation of the products. There are other extracts of cannabis that are somewhat more potent or are delivered in a different way. So edibles such as cookies, brownies, gummies, candies are much more likely to cause intoxication beyond what the user intends because they are so slow to act. Anything that is absorbed through the lungs is going to bypass that first pass metabolism and hit the brain and the central nervous system much quicker. The edibles and some of the oils have to go through that first pass metabolism. Pills are the same way, and that can lead to a longer time until the onset of effects and a longer time from the consumption to the peak of the effect. And also because it is a lipophilic molecule, transdermal patches and creams, sprays can also be used for cannabis consumption. Now addiction, when we're talking about addiction, the National Institute for Drug Abuse suggests that about 9% of people who abuse marijuana will develop an addiction to the drug in time. Just the use of marijuana does not equal a use disorder. So I see that very frequently that somebody has a positive urine drug screen for THC or endorses use of marijuana. Just because they have that or they don't necessarily want to stop does not mean that they have a use disorder. However, when young people or teenagers are using marijuana, the risk of developing an addiction is in the 17 to 20% range if they start to use in the teen years. And for daily users, this is where we see the highest rates of physical and psychological dependence. 25 to 50% who use the drug every day will develop a problematic use pattern. We can talk about some of the impacts and why we think that is. So we talked about THC and CBD and some of the characteristics of each. The percentage of THC and CBD in cannabis changing has been part of what the suspicion for the increased rates of negative effects or adverse effects from cannabis use are. So if we look at the early 90s, there are percentages of CBD and THC that are in reasonable ranges. CBD percentage around 6%, very, very similar to the CBD percentage around 4%. And as we go on, so they are rising steadily until we get to the early 2000s. Both proportions are rising in an equal fashion. There starts to be a crossover. And when we see that crossover, the rate of THC is increasing while the rate of CBD is decreasing. As we see the decrease in CBD, we see an increase in the adverse effects related to THC. When you have low CBD, there is a decrease in the anxiolytic effect. There's a reduced anti-convulsant effect. So THC is actually mildly pro-convulsant, can induce a seizure. When we talk about cannabis for seizure disorders, we're talking about a balanced product or a CBD predominant product. So when we have high THC products, there is a slightly increased risk of seizure disorders. There's also some reduced neuroprotective effects. So CBD is your anti-psychotic and anti-anxiety portion of the cannabis. So when we get to the point where the CBD is low and the THC is high, that's when we start seeing this increased risk of psychosis, higher risk of developing OCD, PTSD, other substance use disorders. There's an increased risk of both physical and psychological dependence and more severe physical withdrawal, which tends to fuel people using more consistently and at higher rates because there is such a profound physical withdrawal that there is a disincentive to reduce use. There's also more negative impact on memory, both the working memory and the short-term memory, decreased motivation. We see a cannabis-induced amotivational syndrome, which is you're stereotypical, sitting on the couch, not wanting to do anything. There is some neurobiological basis for that is that THC just decreases rate of that motivation or that drive to move or do anything. And that's reproduced even in mouse models. So it is not just a human condition. It really does impact our drive. There is also an overconfidence in abilities. So as THC concentration increases, our ability to have an accurate and realistic appraisal of our abilities decreases. Studies have shown that people who are intoxicated or even just under a very small influence of the THC portion overestimate their accuracy in driving tasks, indicate that they have a greater reaction time than they actually do and are faster and more adept. People who say that they are able to play video games better for whatever reason or the decreased anxiety makes them better at whatever the task is. Subjective reporting does not line up with the objective measures that people tend to do worse with things like hand-eye coordination and discernment of different situations. So it overall has a pretty negative impact. So as we're increasing this THC, the question comes up, is marijuana something that you can overdose on? Because if we are looking at the THC contents increasing, then obviously there's going to be a concern that the marijuana of 30 years ago is not the same as it is today. So we look at the number of marijuana poisoning deaths. These are all that included a fatal dose of marijuana poisoning. All that included a fatal dose of marijuana plus a fatal dose of something else. They have steadily been on the rise. However, when you separate it out, you see that the poisoning deaths to cannabis alone were relatively stable until about the mid-2000s. That was when we started seeing that departure from the THC and CBD tracking at the same rate of increase and started seeing that decrease of CBD and that increase of THC. So from 2011 to 2012, we had about a five-fold increase in the number of deaths from cannabis use alone, and it stayed at that same rate. Now, it's a relatively low number of deaths given the population, however, it is a very striking effect. So medical marijuana is an entirely different subject, but it is important to understand the impact of medical marijuana on recreational use. There's no standard definition or indication for medical marijuana, it's done by the state level, is almost exclusively legislatively advised. So that means that there may be a task force of physicians, there may be people who are informing this, however, it is not necessary at the state level. So there are even some states that legislate medical marijuana for psychiatric conditions that it is known to actually be very detrimental for. In states without medical marijuana, the illicit use rose from about 4 1⁄2% in the early 90s to about 6 1⁄2% in 2013. But in states that had medical marijuana, the rate of illicit use went up even more dramatically, up to about 9%. So much of the argument for legalization of marijuana is that it will decrease illicit use, but time and again, we see that in states with medical programs or recreational programs, the illicit use actually increases. And it drives a lot of the underground trade of black market marijuana, either because there is an increased acceptability of it, so smelling marijuana on the streets is not as big of a deal, people are smoking in public places, there's no way of knowing who has a card, who doesn't, and it generally makes the illicit use more acceptable socially. There's also an increase in the availability of legal cannabinoids. And I do two lectures on each of these over an hour long each, so I'm very, very much just touching on these very big subjects, but cannabidiol or CBD is the extract of the, the purified extract of the CBD compound. At the federal level, less than 0.3% THC can be legal over the counter. So most states, you can buy a CBD product as long as it has less than that 0.3% of the Delta-9-THC, which is the THC that we see in marijuana, and it's very unregulated. So because there's only one that is really FDA-regulated, Epidiolex or Epidiolex, there is such a huge trade in the non-FDA-regulated products and there's been such an explosion. So to get it, prescription is near impossible. There's only two pediatric seizure disorders it's indicated for. It's very expensive, very specialty, but you can get a CBD product at any gas station. The new one in the past couple of years is Delta-8-THC. So back in the 70s, we used Delta-8 to study what we thought Delta-9 was going to do because there was a loophole that allowed for the legal study of this in laboratories to advance cannabis research. It's an isomeric psychoactive structure of the Delta-9-THC. So it is psychologically active just like THC is. It's about 75% as potent when you look at the chemical data. However, my personal experience has been that patients who use Delta-8 will use it at higher rates and more frequently because there's this thought that it's going to be less impactful than the Delta-9-THC. And so people who are using the Delta-8 often will use it daily much quicker than somebody who's using Delta-9 and it's accessible in most states. So this is something that is over the counter, can be bought at a gas station, can be bought at the grocery store, can be bought over the internet, has opened the door to a lot of other cannabis derivatives. So whereas Delta-8 is not particularly potent, the backbone of it and that process through the CBD extraction has led to compounds such as hexahydrocannabinol or HCC that have led to up to 30% more potent effects than Delta-9-THC. And so we have seen quite a few problems with these products. So some of the problems with these illegal cannabinoids is that there is an increased accessibility to minors when there is a legal form of the product and it can be bought by most people at the age of 18, in some states, 21. It makes it that much easier for young people to get it. There's also the frustration that the marketing for CBD and Delta-8 and some of these other THC derivatives outpaces our research. And so people are getting these claims. The FDA sends out hundreds of letters to different companies warning not to make these claims, but it doesn't change that so many of these companies will just market for whatever indication may have some very weak data. A lot of the money drives this because this is a multibillion dollar business. There is a lot of problem with impurity and lack of standard dosing. So because these are not FDA regulated, oftentimes the amount of CBD or the amount of Delta-9 THC in CBD products may be different than what is on the label. From one study of online retailers, 26% were over-labeled for the amount of CBD. So there was a lower amount than was supposed to be there. 42% were under-labeled for CBD. The one that is more concerning is many had more than the legal limit of Delta-9 THC, which means that these could be potentially psychoactive, can cause positives on drug screens, which people are not aware of. I generally tell my patients who are using CBD to just assume that if they take a urine drug screen, it's going to be positive for THC because there is a difficulty in standardization. Cannabis also has a lot of interactions. So when we start looking at these cannabis interactions and the accessibility of these cannabis products, we need to look at the metabolisms. So THC is metabolized by your cytochrome P450 enzymes. We've got the CYP2C19, 2C9, 3A4. And so inhibitors such as fluoxetine and cute cortisol can increase THC effects. But more clinically relevant is the inhibition of different enzymes. So as we have the inhibition by THC or CBD of these different enzymes, these are all of the different medications that can be influenced by it. So when we look at it from the psychiatric standpoint, many of our antipsychotic medications, our SSRIs, some of the anxiolytics and hypnotics can all be impacted by THC. And so there is a, for something like clozapine, when you're doing levels and doing a very careful titration, if somebody is smoking marijuana or using over-the-counter CBD that isn't generally standardized, their blood levels are going to wildly fluctuate and it can make it very difficult to stabilize a regimen. If somebody is taking a, is taking catepine and is at the point where they're at a good dose, they're tolerating it well, and all of a sudden add marijuana into the mix, then we can see excessive sedation. We can see QTC prolongation, cardiotoxicity. We can see mania if somebody is stabilized when they have a high concentration of cannabinoids in their blood, and then we drastically decrease it because it was artificially elevating those levels. So we can see mania and psychosis with that. What worries me as someone who does a lot of addiction medicine, methadone, diazepam, phenobarbital, all of these can have the blood levels increased by cannabis. And so it's very concerning that patients are generally not aware, and it's not going to come up as something that you would think about as adding into a drug interaction calculator. So many times there isn't even a flag on EMRs where you could even consider these. So it's very important to think, if I am prescribing a medication, is there a potential that it could interact with cannabis? So if you're trying to figure it out, is your patient using, are they not? Is this something that you need to take into clinical consideration? There are different detection times for different methods of detection. So blood and saliva, only a couple of hours. That's used generally to assess acute intoxication, but isn't very reliable if somebody has taken it in the past couple of days. Urine, one-time use, up to 13 days, generally closer to about seven to 10. Part of that is that it takes a while for THC to build up in detectable concentrations in the body, is stored in the adipose tissue. And so with regular or heavy use, it can be up to three months. And for patients with a high degree of adiposity or high degree of fat tissue, it will last for even longer. And in hair, it can be detected in the follicle for up to 90 days. So with marijuana and with cannabis products in general, there are three populations that we really are worried about and that's teens and young folks, pregnant women and people with mental illnesses. So marijuana use and misuse among teens, there's a negative effect, particularly on the developing teen brain. Difficulty with thinking and problem solving, problems with memory and learning. All of this seems to be the most pronounced before about the age of 25, which makes sense because the brain isn't fully done myelinating, it's not fully done setting into what it's going to be. There's negative effects on school and social life, decline in school performance, impaired driving, increased risk of accidents. We see an association with ADHD and cannabis use. There's actually a genetic link. So people who have ADHD, which already has that hypofrontality or that decrease of the executive function, decrease of appropriate appraisal of risk, they are up to eight times more likely to use cannabis and there tends to be an additive effect there. So we start seeing a lot more impairment and impulsivity. There's an increased risk of multiple mental health issues. So for schizophrenia and bipolar disorder, for people who use cannabis before the age of 25, there's an increased risk of substance induced psychosis, which can then transfer into psychotic disorders and there is also an increased risk of mania. The gateway effect is something that has been used almost as a fear technique to the point where many kids and teenagers will roll their eyes at it, but there's actually some legitimate research that supports this hypothesis. Neurobiologically, there are receptors in the brain that get primed by use of cannabis that increases your risk of developing a subsequent addictive disorder for any other substance, whether it be nicotine or opiates or stimulants. There's also increased contact. So I don't know how much this is impactful in a post-legalization environment or in states where there is more legalization, but the contact with people who have access to other substances, that may be one of the benefits of having more legalization is that people don't have to resort to more underground means of getting these substances. And then there's some interpersonal and environmental characteristics. So if you are acclimating yourself to using mind-altering substances, you're acclimating yourself to changing your personal environments. Most athletes are getting drug tested, and so pulling away from some of those supportive environments can all be associated with more isolation and more drug use later on down the line. Marijuana use has actually remained steady from 2010 to 2020. So past year marijuana use, as well as daily marijuana use is steadily staying about the same, which is encouraging, but it doesn't include the Delta-8s or some of the synthetic cannabinoids. So it's uncertain what exactly these rates look like, or if they are shifting from one form of cannabis use to another. With the increase in vaping, there is also the potential that teens are using these higher potency products because that's what's more available. And even in the flower component, if they're smoking it, it's gonna be those higher THC products that are going to be predominant. Pregnant women, I've had some patients tell me that they use marijuana in pregnancy or had used marijuana in pregnancy for nausea. There is a lot of thought that, oh, it's natural, it's not going to impact me. Well, about one in 20 women reports using marijuana at least once or infrequently during pregnancy. Marijuana is also often used in conjunction with tobacco. So there is a little bit of a muddying of this effect, but THC crosses the placenta. So it can impact those neurodevelopmental processes. Studies are very mixed and it's very hard to separate out because the environment of somebody who's using marijuana in pregnancy may also have some of those other socioeconomic impacts or may have other resource poverty. So it's hard to determine just that THC effect. There's very little evidence of pregnancy complications like gestational diabetes or preeclampsia, things that affect the mother. There isn't much evidence for that. Neonatal outcomes, there is substantial evidence for low birth weight, and that does tend to be independent of whether it is smoked or taken in a different route. Postpartum outcomes, there is an increased risk of depressive symptoms and shorter breastfeeding duration for maternal, for women who use marijuana both before and after pregnancy. THC is present in breast milk. It is fat soluble. And so it is something that can be transmitted from mother to child, which can lead to intoxications, decreased respiratory drive. It's uncertain what the child development impacts are. There's a lot of mixed data on it. There can be some decreased academic achievement and some association with later substance use, although it is very difficult to tease out how much of this is a genetic effect and environmental effect and an exposure effect. So when we look at the cannabis use and mental health, marijuana use is widespread among patients with psychiatric diagnoses. And some of this I think is due to the fact that there is so much of this social kind of narrative that marijuana is great for mental health, it helps fear anxiety, helps you feel less depressed, it's natural, it's not one of those medicines like Prozac that takes away your personality. Well, there's an increased risk of schizophrenia, particularly if used before the age of 25. It can worsen psychosis that's already there. Anyone who's worked in an inpatient psychiatric unit will tell you that many times people will be stable, use marijuana, have that psychotic episode, or it is around that time of first break psychosis that we see cannabis actually precipitating the event. There's an increased risk of suicide and depression, possibly due to some of the disinhibition effects of cannabis. And PTSD is one where there's some decrease of in the stress-induced emotional and memory effects. So the acute symptoms of PTSD are suppressed. There is some suppression of nightmares, suppression of REM dreaming, which can be very enticing for people with PTSD. Nightmares, night terrors can be very distressing. However, when the cannabis use is decreasing or if they're not using every day, we start seeing a spike in PTSD symptoms even above their baseline. And so people with PTSD and any history of trauma are much, much more likely to fall into some of these use disorders, addiction independence. Anxiety typically exacerbates. And then there's for even for people who say, oh, it makes me feel better. It helps my anxiety. With cessation, there is a rebound effect. So think of CBD and THC for some people as pressing the brakes on the anxiety response. As soon as we take it away, the car starts moving forward and we start going right back into that anxiety state. Bipolar disorder, there's an increase in rapid cycling, increase in intensity and increase in extremes. And it may lead to dependence. Currently, the evidence is too weak to recommend cannabis-based interventions for a wide range of psychiatric disorders. And that is the stance that most psychiatric and mental health organizations have taken. Let's talk a little bit about the psychiatric diagnoses related to cannabis. Cannabis intoxication, cannabis use disorder, withdrawal syndrome, and other cannabis-related disorders. Cannabis intoxication requires recent use of cannabis, clinically significant problematic behavioral or psychological changes that develop during or shortly after cannabis use. At least two of the following signs developed within two hours. So dry mouth, increased appetite, conjunctival injection, tachycardia, as well as some of that increased nervousness, increased the sense of euphoria and some of the other behavioral changes. But the things that you may see on physical exam, often tachycardia tends to be the presenting symptom. Somebody goes into a primary care office and they have an elevated heart rate, don't have a history of it before. Many times they'll sound a little bit of an alarm. There's a concern of what's going on. And then the patient will say that they've smoked marijuana in the past couple of hours. When we start getting to the cannabis use disorder, so there are specific criteria. First off, it has to be a problematic pattern. So leading to clinically significant impairment or distress or an impact in the daily life as manifested by at least two of the following. And they can't just be tolerance independent. So that can't be your two. It has to be a range of symptoms. So an increase in the amount or longer periods of time, persistent desire, unsuccessful attempts to cut down or control. Great deal of time is spent trying to obtain it, use it or recover from it. Cravings or strong desire. Recurrent cannabis use resulting in a failure to fulfill major obligations at work, school and home. Continued use despite having persistent or recurrent social or interpersonal problems. Important activities are given up or reduced because of cannabis use. Recurrent use in situations where it would be physically hazardous. This includes work, it includes driving, it includes watching children and being the responsible adult. Cannabis use is continued despite knowledge of having a persistent or recurrent physical or psychological problems. So somebody who notices that their anxiety gets worse and yet continues using. And tolerance as defined by either of the following, meaning an increased amount or a markedly diminished effect. One thing that I will count in this as well is using a more potent product. So if somebody goes from smoking the rolled cigarettes or the joints and then goes to a 100% THC pen using in the same amount, that to me would be an increase in the use. Or withdrawal. So there is the classic cannabis withdrawal or we can look at withdrawal. So withdrawal as manifested by the characteristic cannabis withdrawal syndrome or it is taken to relieve or avoid withdrawal symptoms. This includes cannabinoid hyperamnesis which is a cyclic vomiting syndrome that can be associated with cannabis use. And we will see that oftentimes people have a very difficult time reducing their use when they do have that cannabinoid hyperamnesis. Cannabis withdrawal syndrome says it has to have a recent cessation of cannabis use that has been heavy and prolonged either daily or almost daily over a couple of months. Three or more of the following signs and symptoms developing within one week. So cannabis products, THC is a long acting substance. And so about one week to two weeks is where we see the greatest peak of withdrawal symptoms. So somebody may be fine for a couple of days until their nervous system starts to reset. The cannabis is fully out of their system and they start having some of these withdrawal effects. Irritability, anger, aggression, nervousness, anxiety. I've seen anxiety to the point of paranoia that almost looks like psychosis depending on the degree. Decreased appetite, weight loss. Sometimes you can see nausea as well. Restlessness, depressed mood, and then physical symptoms like abdominal pain, tremor, sweating, fever, chills, headache can be pretty profound. And for this, you need three or more signs and symptoms that develop within one week. At least one of these symptoms does have to be physical and they cause clinically significant distress or impairment not attributable to another medical condition or mental disorder. So the timeline, initially you see day one, anxious, irritable, trouble sleeping. Two to three is a peak of some of the physical symptoms. Days four and after the symptoms improve, depression may begin. This is the initial withdrawal. There's almost always a two-phasic withdrawal where there is the initial coming off of the cannabis and having the waning of those intoxication effects. Then we start seeing that ramp up of some of the effects that are related to what somebody was either self-medicating with. So we can see persistence of some of the sleep patterns for weeks on end, sometimes months. And some of the more affective symptoms will be more prevalent after that first week. Things that influence the severity include the current dose, duration, mode of administration, how people expect to experience this. So, you know, was this something that they have a lot of motivation for? Are they expecting these withdrawal symptoms or are they going to be very negative and difficult to tolerate? And then is this voluntary or involuntary? So somebody who goes in for a hospital admission has an abrupt cessation of cannabis use. It's going to be in much more distress than somebody who is voluntarily tapering or has voluntarily had a quit date. The rate of withdrawal, gradual reduction or the sudden cessation. Sudden cessation, like many things, tends to be more distressing. And then how much support? So marijuana has a physical dependence but also psychological dependence. People very often are using it for some other benefit or some other purpose. So do they have something to fill what the cannabis was being used for when it is taken away? Other cannabis-induced disorders. Unspecified cannabis-related disorders. So if cannabis is creating the amotivational syndrome or if there's cannabis-related tachycardia, these would be the codes that you use. Cannabis-induced psychotic disorder, a brief psychotic disorder that is related to cannabis use, can progress into other psychotic disorders. Anxiety, sleep, and then there is an intoxication delirium depending on the degree of use. The other one I want to really touch on because it is very clinically significant is e-cigarette and vape-associated lung injury or EVALI. Approximately 3,000 EVALI cases were reported to the Centers of Disease Control by November 2019, with 68 deaths confirmed by 2020. The reporting drastically decreased with the pandemic because EVALI looks very similar to COVID pneumonia. The big difference is that this is very, very responsive to steroids, and oftentimes people can be kept out of the hospital and out of the ICU if caught early enough and given appropriate steroid treatment. But this has led to deaths and lung transplantation considered to be an autoimmune response, maybe in part due to the vitamin E acetate that is used in some of these vapes mixing with the THC causing an autoimmune reaction. It's still in the infancy of the research, and because of the COVID-19 pandemic, there has been a lot of difficulty sorting that out from some of the COVID pneumonias, which almost identical on x-ray. So for cannabis use disorders, screening assessment diagnosis, there are multiple different screening tests. There's a cannabis use disorder identification test, which sometimes I will use. I like the Cannabis Problems Questionnaire because it really looks at the negative impacts. Marijuana Screening and CRAFT Questionnaire. And then there are two instruments that assess change, the Marijuana Problem Inventory and the Marijuana Withdrawal Checklist. So pharmacological approaches, what do we do with this? So cannabis withdrawal is generally mild, self-limited, don't generally need medical intervention. Potentially helpful studies have shown oral THC decreasing marijuana craving and withdrawal symptoms. Obviously, THC is what you're withdrawing from. So replacement as using it as a more concentrated distilled product and being able to taper can help. Lithium was shown to reduce depressive symptoms and cannabis related problems up to 87.5% in one study and had no effect in another. And you'll see this pretty significantly because of changes or differences in between the studies. So are they self-report? Are they double-blinded? Are they based on urine cannabis concentrations? There are so many different ways of doing these studies that you'll see a lot of conflicting reports. Potentially harmful, which was interesting to me, is that bupropion almost invariably worsened withdrawal symptoms, including increased irritability, sleep disturbance, and depressed mood. Considering that bupropion is used for motivation and cannabis has a lot of amotivational symptoms, it is something that often gets used. Divalprex or Depakote increased ratings of anxiety, irritability, sleepiness, distress, and worsened performance on psychomotor tasks psychiatric and mental health organizations have taken. Let's talk a little bit about the psychiatric diagnoses related to cannabis. Cannabis intoxication, cannabis use disorder, withdrawal syndrome, and other cannabis-related disorders. Cannabis intoxication requires recent use of cannabis, clinically significant problematic behavioral or psychological changes that develop during or shortly after cannabis use. At least two of the following signs developed within two hours. Dry mouth, increased appetite, conjunctival injection, tachycardia, as well as some of that increased nervousness, increased the sense of euphoria, and some of the other behavioral changes. But the things that you may see on physical exam, often tachycardia tends to be the presenting symptom. Somebody goes into a primary care office and they have an elevated heart rate, don't have a history of it before. Many times they'll sound a little bit of an alarm. There's a concern of what's going on, and then the patient will say that they've smoked marijuana in the past couple of hours. When we start getting to the cannabis use disorder, so there are specific criteria. First off, it has to be a problematic pattern. So leading to clinically significant impairment or distress or an impact in the daily life as manifested by at least two of the following. And they can't just be tolerance-independent. So that can't be your two. It has to be a range of symptoms. So an increase in the amount or longer periods of time, persistent desire, unsuccessful attempts to cut down or control, great deal of time is spent trying to obtain it, use it, or recover from it, cravings or strong desire, recurrent cannabis use resulting in a failure to fulfill major obligations at work, school, and home, continued use despite having persistent or recurrent social or interpersonal problems, important activities are given up or reduced because of cannabis use, recurrent use in situations where it would be physically hazardous. This includes work, it includes driving, it includes watching children and being the responsible adult. Cannabis use is continued despite knowledge of having a persistent or recurrent physical or psychological problem. So somebody who notices that their anxiety gets worse and yet continues using. And tolerance as defined by either of the following, meaning an increased amount or a markedly diminished effect. One thing that I will count in this as well is using a more potent products. If somebody goes from smoking the rolled cigarettes or the joints, and then goes to a 100% THC pen using in the same amount, that to me would be an increase in the use. Or withdrawal. So there is the classic cannabis withdrawal or we can look at withdrawal. So withdrawal as manifested by the characteristic cannabis withdrawal syndrome, or it is taken to relieve or avoid withdrawal symptoms. This includes cannabinoid hyperemesis, which is a cyclic vomiting syndrome that can be associated with cannabis use. And we'll see that oftentimes people have a very difficult time reducing their use when they do have that cannabinoid hyperemesis. Cannabis withdrawal syndrome says it has to have a recent cessation of cannabis use that has been heavy and prolonged, either daily or almost daily over a couple of months. Three or more of the following signs and symptoms developing within one week. So cannabis products, THC, is a long-acting substance. And so about one week to two weeks is where we see the greatest peak of withdrawal symptoms, so somebody may be fine for a couple of days until their nervous system starts to reset, the cannabis is fully out of their system and they start having some of these withdrawal effects. Irritability, anger, aggression, nervousness, anxiety, I've seen anxiety to the point of paranoia that almost looks like psychosis depending on the degree. Decreased appetite, weight loss, sometimes you can see nausea as well. Restlessness, depressed mood, and then physical symptoms like abdominal pain, tremor, sweating, fever, chills, headache, can be pretty profound. And for this, you need three or more signs and symptoms that develop within one week. At least one of these symptoms does have to be physical and they cause clinically significant distress or impairment not attributable to another medical condition or mental disorder. So the timeline, initially you see day one, anxious, irritable, trouble sleeping, two to three is a peak of some of the physical symptoms. Days four and after the symptoms improve, depression may begin. This is the initial withdrawal. There's almost always a two-phasic withdrawal where there is the initial coming off of the cannabis and having the waning of those intoxication effects. Then we start seeing that ramp up of some of the effects that are related to what somebody was either self-medicating with. So we can see persistence of some sleep patterns for weeks on end, sometimes months, and some of the more affective symptoms will be more prevalent after that first week. Things that influence the severity include the current dose, duration, mode of administration, how people expect to experience this. So, you know, was this something that they have a lot of motivation for? Are they expecting these withdrawal symptoms or are they going to be very negative and difficult to tolerate? And then is this voluntary or involuntary? So somebody who goes in for a hospital admission has an abrupt cessation of cannabis use is going to be in much more distress than somebody who is voluntarily tapering or has voluntarily had a quit date. The rate of withdrawal, gradual reduction or the sudden cessation, sudden cessation, like many things, tends to be more distressing. And then how much support? So marijuana has a physical dependence but also a psychological dependence. People very often are using it for some other benefit or some other purpose. So do they have something to fill what the cannabis was being used for when it is taken away? Other cannabis-induced disorders, unspecified cannabis-related disorders. So if cannabis is creating the amotivational syndrome or if there's cannabis-related tachycardia, these would be the codes that you use. Cannabis-induced psychotic disorder, the brief psychotic disorder that is related to cannabis use can progress into other psychotic disorders. Anxiety, sleep, and then there is an intoxication delirium depending on the degree of use. The other one I want to really touch on because it is very clinically significant is e-cigarette and vape-associated lung injury or EVLI. Approximately 3,000 EVLI cases were reported to the Centers of Disease Control by November 2019 with 68 deaths confirmed by 2020. The reporting drastically decreased with the pandemic because EVLI looks very similar to COVID pneumonia. The big difference is that this is very, very responsive to steroids and oftentimes people can be kept out of the hospital and out of the ICU if caught early enough and given appropriate steroid treatment. But this has led to deaths and lung transplantation. Considered to be an autoimmune response, maybe in part due to the vitamin E acetate that is used in some of these vapes mixing with the THC causing an autoimmune reaction. It's still in the infancy of the research and because of the COVID-19 pandemic, there has been a lot of difficulty sorting that out from some of the COVID pneumonias which look almost identical on x-ray. For cannabis use disorders, screening assessment diagnosis, there are multiple different screening tests. There's a cannabis use disorder identification test which sometimes I will use. I like the Cannabis Problems Questionnaire because it really looks at the negative impacts, marijuana screening, and CRAFT questionnaire. And then there are two instruments that assess change, the Marijuana Problem Inventory and the Marijuana Withdrawal Checklist. So pharmacological approaches, what do we do with this? So cannabis withdrawal is generally mild, self-limited, don't generally need medical intervention. Potentially helpful studies have shown oral THC, decreasing marijuana craving and withdrawal symptoms. Obviously THC is what you're withdrawing from, replacement as using it as a more concentrated distilled product and being able to taper can help. Lithium was shown to reduce depressive symptoms and cannabis-related problems up to 87.5% in one study and had no effect in another. And you'll see this pretty significantly because of changes or differences in between the studies. So are they self-report? Are they double-blinded? Are they based on urine cannabis concentrations? There are so many different ways of doing these studies that you'll see a lot of conflicting reports. Potentially harmful, which was interesting to me, is that bupropion almost invariably worsened withdrawal symptoms, including increased irritability, sleep disturbance, and depressed mood. Considering that bupropion is used for motivation and cannabis has a lot of amotivational symptoms, it is something that often gets used. Divalprex or Depakote increased ratings of anxiety, irritability, sleepiness, distress, and worsened performance on psychomotor tasks. Cotiapine can be tempting to use because of the increase in sleep quality and appetite during cannabis withdrawal, but it also increases cannabis cravings and self-administration. So ultimately not something that we would recommend. Gapopentin is interesting. It's one of the ones that shows the greatest reduction in reducing distressing withdrawal symptoms. So people tolerate withdrawal more consistently. This is used by many substance disorders units as a way of managing patients who are undergoing cannabis withdrawal and are very physically or emotionally, mentally uncomfortable. There is somewhat of an adjunctive effect with cannabis and Gapopentin use. So Gapopentin can promote some of the euphoria with cannabis. So it's not generally recommended to be used long-term or to be used in patients who are at high risk of abuse or dependence. The Gapopentinoids in general have come under a little bit more scrutiny. Gapopentin and Pregabalin because of that euphoric effect that can be felt. Cannabis use disorder does not have any FDA approved treatments. All of this is anecdotal. My personal approach is to figure out what cannabis is providing to a person and then figure out what we need to address. Is it anxiety? Is it sleep? Is it a decreased sense of purpose in some untreated depression? So that tends to be my perspective. When you look at potentially helpful, Buspirone in pretty high doses reduces self-report of cannabis use and reduction in anxiety which can drive the use of cannabis. N-Acetylcysteine has reduced self-report of cannabis use and reduced cravings. More significant in adolescent populations. Gapopentin reduced cannabinoid UDS levels so people are using less and some improvement in the cognitive function as well. Lithium tends to reduce cannabis use and Topiramate has an association with reduced cravings in adolescent populations. Has not shown as robust of an effect in adults. Potentially harmful, interestingly enough, is Naltrexone. So the medication we go to for pretty much every addiction or behavioral addictions, there are multiple studies that show that it enhances the effect of THC. I'm uncertain about the reason behind that or the mechanism, but it is enough that it may be something to avoid. Atamoxetine or Stratera, there's no effect or an increased risk of adverse events. When we look at the other new effects for cannabis use disorder, Mirtazapine, Baclofen, and then Divalprox, which we had previously discussed, there can be some benefit for withdrawal. So I will often use Mirtazapine for the sleep and mood appetite at the beginning of cannabis withdrawal, but there is no sustained effect for the cannabis use disorder. Baclofen can also help with some of the physiologic effects. Fluoxetine, no effect, and synthetic Tranavinol does not have any effect after the withdrawal period. Psychotherapeutic approaches are going to be the mainstay of treatment. So motivational enhancement therapy or motivational interviewing, designed to help resolve ambivalence about quitting and strengthen the motivation to change. Techniques include exploration of pros and cons of use, rolling with the resistance, really treating the patient as a partner. And this is probably my preference for most patients. Cognitive behavioral therapy focuses on coping skills that are relevant to quitting marijuana use. So what are some of these triggers? How do I manage when somebody's offering this to me? If my family members use and I'm trying to cut back, how do I deal with that situation? Thoughts and behaviors as they relate to actions and looking at that cycle. So contingency management is the systematic application of the reinforcing consequences and rewards in order to achieve the therapeutic goals. Positive reinforcement to increase the abstinence, facilitate other therapeutic changes, improve retention. And then family and system intervention looks at the reciprocal relationship between family functioning and substance use. So if we look back in all of the studies on substance use, one of the core features is a lack of connection or a lack of what we call recovery capital. And that is the number of positive connections that we have in our lives. I'm a huge fan of harm reduction. Harm reduction is often used in terms of things like opioid use and medication-assisted treatment. However, for my preferences, cannabis use lends itself very, very well to harm reduction principles. So can we reduce the amount, duration, or circumstances that somebody is going to use? Can you say, okay, I'm not going to smoke inside my house anymore. I'm going to have to go outside every time I use. If I am vaping 100% THC product, can I go to using a pre-dosed edible knowing that I'm only going to use these a certain number of days? Can I decrease the amount I use per setting? So can I extinguish that bowl that I'm smoking after just a couple of puffs and then leave it for later? Or can I skip a day? If I'm smoking every day, can I go to every other day? I'm not likely to have that withdrawal if I do it that way. So it's a way of kind of testing recovery. If somebody is continuing their use, I am very insistent on controlling our variables. So if you are using marijuana and on some of these medications that have interactions, I need to know as the physician, is there going to be a difference in the amount, the method, the duration, or the supplier? Because that changes the amount of THC and the amount of CBD that is being delivered. I also encourage all my patients, particularly if they're using waxes, oils, other concentrates, to test products or verify the purity of the products that they're using so that they are not getting anything that has certain substances that can be tainting it. So I had a teenager at one point in an inpatient psychiatric unit who was convinced that she was smoking DABS, which is a waxy substance that is a concentrate of THC, generally extracted with butane and some pretty nasty stuff, but she was convinced that this is what she was using. And her urine drug screen came up negative for THC, and she was saying that she was a daily user. So we looked a little bit at some of her other labs, did the extended tox screen, and she had a positive result for mephedrone or bath salts. So her concept and her understanding of what was normal for cannabis intoxication was very different because she was using by herself, she was using to manage her anxiety, and didn't know that hallucinations and hearing voices, and seeing things and a significant amount of anger and distress was not typical of cannabis intoxication. So it's really important to make sure that people are well aware of some of the risks and benefits or perceived benefits. So when I look at the psychotherapeutic approaches for motivational interviewing some of the things I say very frequently are do you feel like you use marijuana recreationally or are you relying on it? What happens if you don't use it? Ask questions. It's very important that people feel that they are being listened to and that there are some understandings of what the substance is doing for them. What would need to change for you to feel like you wanted to use it Some people say I don't want to quit it helps with this, it helps with that it helps my pain, I can't sleep and then it leads to some level of reliance and so I ask what would go from daily use that daily dependency to recreational use? How can we get you to recreational use? Which often leads to a little bit more of an opening up. If you're increasing let's explore why and see if there's anything else we can do to support you Why are you using more? Are you more stressed? Are you having more panic symptoms? How can we support that? If you're decreasing what's leading to that? Can we enhance that even more? Is it being more social? Is it having more important things in your life? Do you have drivers for that? And then bolstering those to look at what's working and helping it work more and then what would have to change for you to feel like you wanted to use versus needed to use?

Cannabis Use Disorder

Addiction Medicine

THC

CBD

Psychiatric Disorders

Screening Tools

Withdrawal Symptoms

Treatment Options

Cognitive Behavioral Therapy

Harm Reduction

Patient Engagement