Hello, my name is Bertha Madras. I am going to present a very timely topic, which is cannabis and adolescent brain development. These are my disclosures. I'm a consultant for these two firms. My learning objectives for you are the trends in THC potency and delivery systems, high potency marijuana and vaping, what are the risks for marijuana use for the developing fetal brain, although we're going to focus primarily on adolescents, it's very important for us to understand the developmental effects of marijuana from in utero into teenage years, the marijuana risks for the developing adolescent brain, and what you can do with this information. Most importantly, what are the factors that are driving marijuana use and effects in our society currently with the legalization movement in a runaway train, there is much greater access because of the legal status, much more availability, the cost has been reduced and the environment has changed. The perception of harm with regard to marijuana as a medicine and has changed with regard to its recreational use has changed enormously among youth. The doses of THC within the marijuana plant have altered enormously in terms of percent THC and the absolute amounts that are consumed. What has also changed is the frequency of use. There are young people who are using much more than one time daily, weekly, monthly, yearly. The mode of delivery also affects what drives marijuana use and its effects. There are multiple modes of delivery now including inhalation, vaping, smoking, edibles, and even lotions. So we have to recognize that and also be aware that the pharmacokinetic properties are different depending on the mode of delivery. And of course, the most important thing is age of onset. And we're going to try to focus a little bit on prenatal exposure, early adolescence, and what are the consequences to adulthood. The perception of risk of harm for marijuana is at an all-time low. And this is an example for 12th graders. And we can give similar examples for 8th and 10th graders from the Monitoring the Future study. This is a function of year. And what we can see from between 2007 and 2022, there has been a vast drop in perception of harm of marijuana amongst youth. And if you compare that to some of the other drugs, such as heroin, the perception of harm is declining, but nowhere near the values of marijuana. The same is true for cocaine or alcohol, which has remained steady. Five or more drinks, in fact, the perception of harm has increased, but tobacco has also gone down slightly and hallucinogens are also in a downward trajectory. So we have to remember that perception of harm has declined most amongst youth for marijuana, whereas and it's by far the least perceived as the least dangerous substance amongst all the others that are listed here. As a consequence of decreasing perception of harm, there are more youth using marijuana daily and they're using it at higher potencies, which brings us even greater problems in terms of public health consequences. What are some of the trends in THC potency and delivery systems? We're seeing marijuana packaged as sweet drinks. We're seeing it packaged in terms of candy bars that resemble regular candy bars, Oreo cookies and Reese's Pieces and Kit Kats and all of these, which are being packaged to appeal to young people. We're seeing forms of marijuana in Chatter, which is extremely high potency. Some of these range from 60 to 90 and even higher than 90% THC. This is also marijuana concentrates. We're seeing it in lollipops. We're seeing it in gummy bears. All of these, there's make no mistake about it. They're all designed to target young people and even brownies. So new marijuana or cannabis, is it a natural plant? Legalization has resulted in much higher potencies. The percent THC is 15 to 90%. New products are attractive to children and new delivery methods are increasing the rapidity and the acceptability of using marijuana. If we just look historically, what we see is that in the 1970s, THC potency was about 3%. It increased and increased up to 20 to 90% currently. What that does is it produces a greater high for a single puff, for a single vape. It produces greater tolerance, more addiction, and with more addiction, you get more use, more users, and obviously the motive is profit. Does legalization affect the use of highly potent cannabis? Yes, it does, because where there's recreational and medical use, there is much higher use amongst people using. Does legalization affect the use of highly potent cannabis? High potency products are more likely to be used by 18 to 20-year-olds and 21 to 29-year-olds. So what you see is that as the potency in states where there's no legal marijuana versus medical marijuana versus recreational, the use of any concentrate is higher in states that have recreational marijuana or medical compared to no legal. The use of DAP concentrates, the use of vape concentrates, both high and low potency use is still higher among those states that have normalized marijuana, either for medical or recreational purposes. So we can see this upward trend with legal status. With more frequent use, what are the consequences? We have to bear in mind that just statistics alone do not give us the whole picture. With more frequent use, there's a greater risk of addiction. This is a published report that came out last year showing the frequency of cannabis use and development of cannabis use disorder, so that if you compare yearly with monthly, with weekly, with daily use, you find that the more frequently the use, the greater the number of people with cannabis use disorder. Problematically so, the U.S. leads the world in cannabis use disorder among 15- to 19-year-olds. Only Spain comes close and New Zealand comes close to our country's dubious distinction of leading the world with regard to what is increasingly considered a brain disease. So let's look at high potency marijuana and vaping. Why does marijuana potency matter? The higher the potency, the more drug effects, the more tolerance, the more addictive potential and other consequences. We know that alcohol can come in potencies all the way from 4 to 40% with spirits, from beer to wine to spirits. We know that when powdered cocaine was converted to crack cocaine, which is a bicarbonate salt of cocaine that releases a free base, it has three times greater entry into brain than the powder cocaine, and there is strong evidence that the crack cocaine has given rise to people with more rapid progression to addiction. The same is true for powdered meth and crystal meth, and now we have the same principles applied to marijuana, which is to increase the potency, which, as I said, can lead to greater adverse consequences. So what are some of those for adolescents? Higher potency confers greater risk for high frequency. Young people who use concentrates, the odds ratio for them developing continued use and high frequency use is much greater. So the concentrates confer the highest risk for ongoing use and frequent use. Adolescent use of higher low potency can give rise to a more regular use, as I've already alluded to, more drug use problems, the use of other illicit drugs, the use of tobacco and alcohol use disorder, and major depression and anxiety and psychotic-like experiences. So low potency has a reduced risk compared to high potency for a number of factors, and there are others. Vaping as a delivery system is a very significant problem and growing rapidly. One of the reasons is that it disguises the smell of marijuana, it disguises the use of a smokable product, and it can be disguised in writing pens, in backpacks that simply have little tiny vapes attached to them with tubes, with hoses. They can be disguised in hoodies, in smart watches, in iPhones, in USB sticks that look just like regular sticks, and vape pens which are being ordered online by young people that are less than 14 years old. So what are the worries and concerns about vaping? Vaping is rising and it's erasing the gains in smoking cessation. Let's just look at cigarette use. Cigarette use amongst youth dropped dramatically over the past 40 years. It's a remarkable public health accomplishment. But what has happened is that cigarette vaping is increasing and beginning to erase some of the gains that we had in a very concerted effort to stop youth from smoking. Marijuana use seems to have leveled off. It's actually the latest data that came out yesterday from our National Survey on Drug Use and Health implies that marijuana use now amongst youth is rising again. But marijuana vaping is also rising rapidly so that any steady state on smoking marijuana, again, those gains are being erased by marijuana vaping. What are some of the problems with vaping? It's the predominant mode of use amongst adolescents, Delta 9 THC, CBD, Delta 8, Delta 10 are being sold as hemp derived legal highs. They're associated with greater risk for acute lung injuries, for seizures, and for acute psychiatric symptoms. The problem also is that young people who use e-cigarettes are almost three times more likely to use marijuana and young people who vape marijuana are three times more likely to use tobacco products. So the two are intertwined and increasingly one confers a risk on the other. Adolescent use of marijuana edibles and vaping is associated with greater risks for developing psychiatric symptoms. Some of these include conduct problems, depressive symptoms, anhedonia, and sensation seeking. So what are the proportions of young people using edibles versus inhaled and emergency department visits? There have been reportedly in a few years ago that there were close to 10,000 visits for cannabis use. Inhaled cannabis versus edibles. Inhaled is more likely to give rise to cannabis hyperemesis syndrome. It's about a twofold increased risk. Edible cannabis is more likely to confer a higher risk for acute psychiatric symptoms, intoxication, and cardiovascular symptoms. And the edibles, again, 10.7% of cannabis related ED visits are due to edibles, even though the sales of edibles are much lower. What about the dose? So we've covered route of administration. What about the dose and frequency of use with regard to the risks? This is a tale of three cities, of London, of Amsterdam, and of Paris. It's actually 11 sites, the study was conducted by Marta De Forti and published just a few years ago. And what they showed is that the dose response is a very important measure of a biological causality. There are many, many factors that go into association versus causality, but dose response is one of the six factors. And if people never use compared to, rare use compared to, weekly use, daily use, and daily use, and this is the top one, it's daily use of high potency marijuana, the likelihood is that they are more likely to manifest symptoms of a psychotic disorder. This is true in three cities and actually 11 sites in a number of countries. So that the greatest risk is daily use of potent, of a potent product. The proportion of schizophrenia attributable to cannabis use disorder in Denmark is increasing over time from 1972 to 2022, and males are more susceptible to developing schizophrenia with cannabis use disorder compared to females. The increase of cannabis use disorder for bipolar disorder is believed, cannabis is believed to be a factor associated with unipolar depression and bipolar disorder. The risk of psychiatric disorders are higher for schizophrenia for psychotic bipolar disorder than for non-psychotic bipolar. Is it a psychotogenic effect of cannabis? We don't know, but certainly there is a correlation in this case. So let's just summarize the risks of high potency marijuana products. There's rapid progression from use to marijuana use disorder, more rapid than with low potency. There is more severe marijuana use disorder and withdrawal. There are more adolescent marijuana use disorder in the past year than ever before. There's more, more high frequency use gives more, more potent drug gives use to more daily or near daily marijuana use. There are more psychiatric problems associated with high potency product, including anxiety, depression, psychotic disorders, and there's more emergency care that's related to high potency products. And all the references are given below in the slide. Unregulated marijuana edibles have given rise to an increase in pediatric potencies. They've risen over 1000%. And some of the symptoms for young children, one to three years old are CNS depression, anorexia, agitation, confusion, tremors, seizures, hallucinations, tachycardia, bradycardia, vomiting, and nausea. So quickly, let's go through the marijuana risks for the developing brain. And let's take a quick look at cannabinoid regulation of brain development. These are the endogenous cannabinoids that exist in our brain and the cannabinoid receptors, their targets. THC can affect brain development and THC affects adolescent brain development as well. So pregnant women are using marijuana more and more frequently. If you compare 2002 to 2003 with 2016 and 17, we find that non-pregnant women are using more past month or near daily marijuana use. Pregnant women are using more, more in the first trimester, in the second trimester and the third trimester compared to about 15 years ago. That's a cause for concern, a deep cause for concern for a number of reasons. Because the use increased with normalization, medicalization, commercialization, legalization, and pregnant women self-report lower frequency of use compared to non-pregnant, but it is still a significant number. Marijuana is promoted on social media as effective and safe treatment of nausea and vomiting. There are no current scientific studies showing that there are indications for use during pregnancy, and the American College of Obstetricians and Gynecologists stated this in a committee opinion in 2015. Yet no states with legal medical marijuana laws list pregnancy as a contraindication for recommending or dispensing medical marijuana. So the question is, so what? Is there a problem? Let's take a quick deep dive into biology. THC, the active constituent of the marijuana plant, resembles the endogenous cannabinoids made by the brain. So that when the brain signals through the endocannabinoid signal, endocannabinoids such as 2-arachidonylglycerol and anandamide hit the CB1 or CB2 receptors and transmit a signal. The problem is, when THC of marijuana comes in, it floods the cannabinoid systems in an uncontrolled manner, wherever it can target them, not during signals through its very specific circuits. And the signals that it generates are much, much more pronounced, more prolonged, and much more robust. And the problem is, the reason for this, is that THC when it targets the cannabinoid receptor, it produces a change in the conformation or the shape of the receptor and signaling that is quite different than what the endogenous cannabinoids do, the ones that are made by the brain. So the ones that are made by the brain are very important for brain development. They promote the birth of new brain cells. They tell cells what type to become. They guide them to their targets. They help them form connections. And they prune and control signals. And in each stage of development, these endogenous cannabinoids have influences from gestation to birth to infancy, childhood, adolescence. They all have influences on how the brain develops and how the brain functions. So THC signaling is very different than the endocannabinoids in your brain. THC binds much tighter to the CB1 receptor. It interferes with normal function to produce unwanted side effects. It may reduce effects that override regulatory processes for brain development and function. The CB1 receptor can adopt distinguished shapes, more than one. Each unique shape can trigger different signals. But THC binds the receptors differently and activates its own set of unique signals. So THC can interfere with the developing fetal brain. It can change signaling systems. It creates mistakes in the migration of nerve cells. It can reorganize brain circuitry and change the type of neurons. What are the consequences? We haven't drawn direct links yet. But marijuana use in pregnancy increases the risk of preterm deliveries, neonatal intensive care unit admission, it decreases mean birth weight, and it decreases head circumference of babies. All the references for these are given below. Prenatal cannabis exposure increases the risk for psychopathology. This is a longitudinal study, the Adolescent Brain Cognitive Development Study, otherwise known as ABCD, of 11,000, approximately 500 children. Some studies were done at the age of nine, and others were done as they were growing up to the age of 13 and 14. And what we've seen is an increased risk for psychotic-like experiences with exposure in utero. There's a reduced white matter and gray matter in terms of brain structure. There is an increased risk of attentional cognitive function. And there's also an increased association with sleep disorders. Prenatal marijuana exposure is associated with psychosis proneness during childhood. There's an increased risk of pre-symptomatic psychosis in terms of self-reports by the children. Prenatal marijuana exposure increases the mental health burden of children exposed. There's more rule-breaking behavior, more conduct problems, more social problems, more aggressive behavior, more psychotic-like behavior, so that in summary, there are brain changes that are related to THC exposure, and these are all done in preclinical studies. One can hope they don't extrapolate to humans, but they are very clearly evident in animal studies. At birth, we've seen already what some of the consequences of exposure. There are deficits in function in terms of attention thinking. There are social problems associated with it, behavioral problems, psychosis proneness, and sleep problems. What about the risks of marijuana for the developing adolescent brain? The developing adolescent brain increases grain white matter. It prunes connections. It strengthens some connections. It changes function regionally. This would take probably two hours to excavate each one of these. I'm just summarizing them now. So, as we said, endocannabinoids regulate brain development through all these phases, and we've already seen, and I'm just refocusing the fact that they're critical for brain development. The adolescent brain is undergoing very rapid changes, and these are the changes during adolescence that could affect synaptic pruning, transmission of signals in the brain, and the final steps in brain maturation. So, what do we know about altered brain development during adolescence? THC accumulates in brain. It's released into the bloodstream, and it could persist days to weeks with heavy regular use in the brain. It can affect brain development in terms of its molecular and cell biology, in terms of maturation of circuits and behaviors, and the neurodevelopmental changes may persist weeks to years after use. I'm going to just do a quick deep dive to the bottom to a very fundamental study that has been done in two labs that I think are quite critical in terms of transcriptomics, which means RNA expression from DNA, and also proteins. So, one of the studies that we did was in the amygdala. It's a very fascinating part of the brain, which contributes to Darwinian survival. It controls behavior to find the necessities of food and water. It assesses resources in terms of threats and safety. It responds to stimuli externally as well as internally, and the signals can be manifest as anxiety, stress, fear, aggression. Damage to the amygdala impairs these functions. So, what we did in our lab was find, in three labs, in fact, at the University of Toronto with Susan George, my lab with Dr. Sarah Withee, and Dr. Miriam Hyman at MIT, that exposure of primates, adolescent primates, to THC at doses that are very similar to what adolescents are exposed to, and daily. These are daily doses. We found a very large increase in a marker for inflammation. This increase was only found, only found in adolescent amygdala, not in the adult. We were shocked. Now, the amygdala has very robust endocannabinoid signaling. It's implicated in the consequences of cannabis use. It's implicated in depression, anxiety, compromised cognition and psychosis, and sleep disturbances. And Dr. Yasmin Hurd at Mount Sinai, New York, found exactly the same thing, this increased influent marker for inflammations. And there was a strong correlation of this increased marker with behavioral deficits, which even persisted into adulthood. So, the new, there's new level of insight and new targets that are emerging of the effects of THC in the adolescent brain. They change the supporting cells of the brain, and they could alter brain development, inflammation, toxicity. Are these changes a newly recognized form of brain toxicity, which may persist into adulthood? Others have done brain imaging in human brains, in human adolescents to see whether or not there are changes using magnetic resonances in imaging, or diffusion tensor imaging, or spectroscopy, a whole, and using tasks with functional MRI and so on. And they have found that there are many, many, in fact, there are many publications of changes in the frontal and parietal lobes of the brain that are associated with adolescent marijuana use. These changes are robust. Some have found brain changes that correlate with impaired function. So, what are the effects of adolescent marijuana exposure? There's effects on psychosocial functioning, educational achievement, employment, addiction, psychiatric symptoms, use of other drugs. Just an example of psychosocial function. People with cannabis use disorder, these are the light blue bars, non-users compared to non-disordered, which is infrequent use or not daily use associated with a use disorder. And the prevalence of deficits in psychosocial function are even present with non-cannabis use disorder, but with cannabis use, and they're greater, above all, for cannabis use disorder. And these include suicidal ideation and major depressive disorder, both. So, we also see deficits that depend on whether or not one uses cannabis as an adolescent, or uses it to an extent that is characteristic of cannabis use disorder. Slower thoughts, difficulty concentrating. Again, more truancy, a lower GPA, grade point average in school, in terms of academic performance. And once again, greater episodes of aggression, of fighting, of arrest. There's also increasing suicide exposures in which cannabis is suspected. And this is as a function of age, and as a function of year. So, as the years increased from 2009 to 2021, there was greater suspected suicidal cannabis exposures reported to U.S. poison control centers. The most vulnerable group were the 14 to 18-year-olds, but it did not dissipate between 19 to 24, 25 to 39, and so on. There's also increased cannabis-based hospitalizations of adolescents, and they are increasing. The increase is in post-legalization in states, and we need to identify, intervene, and treat at-risk adolescents. There's the famous study by Madeline Meyer, which showed that if one uses cannabis early in adolescence, and persists on using it until the age of 35, there is an eight-point IQ loss from an average of 100 to 92. It predicts, the IQ predicts, access to university education, to lifelong income, to access to a good job, to performance on the job. And the persistent cannabis users had less skilled jobs than their parents. They had poor memory and attention. It was not explained by tobacco, alcohol, other illicit drug use, or a family history of substance use disorders. And so, we can also see it in terms of high school grades. Every used marijuana, the correlation is greater if you ever use marijuana to getting mostly Ds and Fs, compared to never using. And the correlation to getting mostly Ds and Fs is if marijuana was by the age of 13. And there's also a correlation with prescription drugs by academic grades earned. So, teen marijuana use can affect a host of behavioral and social functioning. It affects adult motivation and drug use. This is a function of how many times marijuana was used as a teen, and whether or not they graduated from college, whether or not they were on welfare, unemployed. And there's also a correlation with use of other illicit drugs, alcohol, smoking daily, less likely to be in relationships. Adolescents are much greater risk for marijuana use disorder. In the first year with heavy marijuana use, about 11% of teens have self-report traits that are consistent with a marijuana or cannabis use disorder. For the adult, half that amount. After four years of heavy use, they're double the prevalence of cannabis use disorder compared to the adult. And so, again, the teen is vulnerable. Adolescent users of marijuana are much more likely to use other substances. They're more likely to smoke, to binge alcohol, to drink alcohol heavily, and use illicit drugs. The same is true for the other substances. If they use alcohol, they're more likely to use marijuana or tobacco. If they use tobacco, they're much more likely to use alcohol and marijuana. So, basically, using none of these three during adolescence is associated with much more favorable outcomes. A study by Adway Watiker, which was published in a high-quality journal, showed that marijuana use before age 18 is the highest risk for opioid use disorder. It's a greater risk than having a mental illness, encountering a drug seller, age, health, easy access, income, education, employment, greater risk than alcohol before 18, obesity, race, disability, gender, risk of trying. In other words, all these risks are lesser than if a child starts to use before age 18. Adolescent cannabis users are much more likely to use hallucinogens. If they use 100 times more marijuana, they're much, much more likely to use. But 40 to 45 percent are using hallucinogens. There is a much stronger association of cannabis use disorder with schizophrenia. And as I said before, it's stronger in males than in females. 20 percent of schizophrenic cases in young males may be prevented by averting cannabis use disorder. And it may be 20 to 25 to 30 percent for males. Early detection, treatment, reduced cannabis use access is critical, particularly for 16 to 25-year-olds. And the use of the drug is associated with more substance use and problems later in life. By mid-30s, young adult, adolescent onset, regular users are more likely than minimal or non-users to have used other drugs, to be a high-risk alcohol drinker, to smoke daily, less likely to be in relationships if use began in teens. And so there are so many physical effects in terms of sleep problems, in terms of lung injuries, in terms of reproductive health. There's no known safe amount of cannabis in the context of fertility, pregnancy, and breastfeeding. This is adolescent cannabis use disorder. There's a greater risk for myocardial infarct, atrial fibrillation, stroke. There's a greater risk for GI problems in terms of hyperemesis, nausea, pain, appetite loss. And there's a greater risk for disruption of endocrine function and decreased stress reactivity and cortisol function is disrupted. And once again, in the Child and Adolescent Psychiatric Clinics of North America, this is the citation that one can look for the primary data. So adolescent marijuana users are just more susceptible to brain changes, to addiction, to deficits in cognition, to amotivation, to psychiatric symptoms, and to functional and health problems and safety. So what can you do? The most important thing is to screen for marijuana use amongst youth. Discuss the possible consequences of cannabis use with youth and their parents. And I'll show you why parents are invoked in this case. And it's so critical to get youth who are using cannabis and have developed a cannabis use disorder to be treated. It is so important for you to disseminate the trends in THC potency and delivery systems. Marijuana is no longer a low dose natural plant. It is so important to disseminate information that high potency marijuana products are associated with greater risks of adverse effects. It is so important to disseminate that current teen use patterns are highly risky. There's more daily use. There's the use of more potent products associated with higher risk for consequences. It is so important to disseminate that THC affects the developing brain of the fetus and the adolescent. It is so important to disseminate that the adverse effects of THC may start in adolescence and persist later in life. It is so important for you and parents and caregivers to be aware that if mothers or fathers use marijuana, the offspring from 12 to 30 years living in the same household, they're much more likely to use marijuana. And the offspring use is a function of whether or not parents use for both mothers and fathers, but more extreme for mothers. So the percent of youth that are 12 to 17 that use marijuana is much lower amongst them if their parents never used. If their parents had a lifetime use, it's higher. And if they have used less than or greater than the past 52 days, their offspring are much more likely to use. And even among 18 to 30-year-olds, again, if parents never use, lifetime use, daily use, or less than, their offspring that are 18 to 30 are much more likely to use. And so I just close by saying the brain is the repository of our humanity. This is not a war on drugs. It's a defense of our brain, the repository of our humanity. Thank you very much.

cannabis use

adolescent brain development

high potency marijuana

vaping

pharmacokinetic properties

prenatal exposure

adolescent marijuana use

harmful effects