Welcome to the session today. I'm very pleased to introduce our speaker, who I'm sure you all know, Dr. Nora Volkow. She's the director of the National Institute on Drug Abuse, and she's going to be discussing a topic that's extremely important right now, especially in our times of a very serious overdose crisis and many other social ills. So, Nora, I will turn it over to you. That sounds wonderful. It will be wonderful. Good morning, everyone. I guess I'm coming from here. It's a pleasure to be here at the APA. It always is. Today, actually, it was very good working and preparing for this talk because it forced me into actually addressing and thinking, not that I don't think about it all the time, but in a way that I could communicate why is it that we are living this horrible overdose crisis that Dr. Wise was speaking about, which is the worst we've ever had in the United States, and that started towards the end of the 1990s but really took off in the 2000s. Despite all of the efforts by the government and different agencies, we have not been able to decrease the number of people that are dying from overdoses in this country, predominantly driven by opioids but increasingly by combination of drugs. And we point fingers, of course, in many ways because it is deserved to the pharmaceutical industry that did very aggressive campaigns to oversell opioid analgesics at SAFE and, too, for the healthcare system, all of ourselves, we were included, that actually we became complacent and started to overprescribe opioid medications. And I would also point a finger at the insurances that were willing to cover this. So it's not just one pharmaceutical industry that's responsible, but there are multiple players that allow this to happen. And one of the ones that I think is crucial and fundamental is the neglect of healthcare systems to address the importance of substance use disorder and the fact that in our country we've developed two different systems for taking care of people with substance use disorder, which are the specialized treatments for addiction and then the healthcare system. And these two split systems for taking care of a disease have led one, which is the main one, through which we get our health monitoring and care, basically to divorce any responsibility of doing so. So, yes, the overdose crisis comes because they started to prescribe opioid analgesics and they couldn't even recognize when a person was becoming addicted and they actually couldn't even know who would have been at greater risk to become addicted. So all of these are elements that definitely play a role. It's not just simplistically saying that Purdue's were the ones that were overselling. There are multiple layers. But now that we are almost two and a half decades from the recognition of this trending on increases in opioid overdoses, I mean, the question that emerges to me, and where it's no longer the opioid analgesics that are driving the mortality, but illicit fentanyl that actually is being mixed with multiple drugs, most commonly with heroin, that is responsible for the deaths of most Americans that are dying or whoever is dying in the United States from overdoses. I ask myself the question, what is it that is making our country vulnerable to the overdose crisis? Why is it that this is happening in the United States, which has one of the strongest economies and sort of, I would say, overall quality of life, one would want to say, in general? And that, I think, is where some of the issues start to not go so simple and not so straightforward. And that's where the social determinants of health play an important role. And if we don't pay attention to them, we can figure out ways to improve the prescription of opioid analgesics so that they are done in a much more rigorous and safe way than the way that we've been doing it. And that we can do, and we're starting to do. There's much more to be done. But if we don't address that social determinants of health, we will continue to have that vulnerability of people trying to escape their circumstances by the use of drugs. And in many instances, because they don't seem to have many other alternatives. And that's what I want to do today in my presentation, address that discussion. Now, you may say, well, this is not per se a new discussion. No, it's not per se a new discussion, because we know that addiction emerges, and I'm going to be describing it in addiction, that state when a person no longer has control over his or her intake of drugs. And that's where they end up taking many much higher doses than what they were intending to take. And when they can no longer stop it, even though they don't want to take it anymore. And that compulsive pattern of administration of drugs, despite the understanding that this can have negative consequences, and despite at least the conscious awareness that they don't want to take them, that's what we call addiction. And yes, you need to be exposed to drugs in order to become addicted. But there are people that take drugs and don't become addicted, and others that do. So an extremely important scientific question has been, what is the difference between someone that becomes addicted and someone that does not? And understand those factors that determine one vulnerability versus resilience are crucial in order to be able to do interventions for prevention, and also importantly, for treatment and for recovery. And in that understanding about who's vulnerable and who's resilient, we've come to realize that there are absolutely important biological factors, such as at what stage in your development you get exposed to drugs. And we know that the younger you start taking drugs, this has been shown clearly for alcohol, for tobacco, for cannabis, the greater the risk that you will become addicted to them. We know that. So brain development is very, very important. And the development of the whole individual in its society. But the other element, too, that we've recognized now, also for many, many years, is genetics. And we know this because people have noted more than two decades ago that addiction runs in families. Perhaps initially it was demonstrated in alcohol that people that have a relative, a father or a mother who was alcoholic, were more likely to then have higher risk for alcoholism. So that we recognize. And at that time, I mean, that was described, there is a hereditary disease. But we didn't really understand what genes actually were driving that heredity. We just knew that addiction ran in families. And so there was a lot of concentration of research to try to understand why early developmental exposures to drugs is so impactful in someone's life, and then to how and what genetics and what they are doing to make you vulnerable. And then on the other side, there was also more than four decades of work from epidemiology that showed that there were several environmental factors that make people more vulnerable to addiction or taking drugs, and also environmental factors that make them more resilient. Interestingly, those environmental factors are not related to social structure, such that if you are in an environment where you have strong social networks and support from your family, that provides you resilience. Whereas on the other hand, we knew that if you came from an impoverished environment, and importantly, if you have been subjected to trauma, particularly during early developmental periods, childhood and adolescence, you might have a much higher risk of addiction. So you have these two sides, biological and environmental. And they basically went along like in parallel, separate trajectories. And now with the advent of actually integrated research studies that look across a large number of individuals, it has been possible to create bridges to help us understand how genes, how the environment, how the developmental stage at which you are actually influence the brain in such a way that when that person takes drugs, they are vulnerable to addiction. So in other words, how does environmental exposure affect your brain? How do genes affect the way that you respond to the environment in the way that then translates into how the brain changes? And this is, of course, impossible because the brain, the human brain, or the brain of animals too, but one of the characteristics of the human brain is that its developmental stage is much longer than any other animal that we know of. And this plays an important role because during that developmental stage, what characterizes the brain is a high level of neuroplasticity. And this neuroplasticity allows it to change physically to the exposure in the environment. And thereupon, the longer that that neurodevelopmental stage occurs, the better it is for the complexity and construction of our brain. So when we're born, our brains are actually quite large. But what is different, and they don't grow so much more, but what does happen is on the one hand that we lose a lot of neurons during the early childhood years that are really not being activated, while we form multiplicity of connections depending on what we are experiencing. So one of the main effects of development is the creation of the networks and the connectivity that will allow your brain to properly function. And if you were to simplistically speak about the brain, and I like to sort of say it's probably the most complex network of networks. You create areas of the brain that are connecting with one another, and these patterns are changing. And those interactions and transmissions have different frequencies so that you can communicate at the same time at multiple levels. And understanding how that ultimately influences our behavior is probably one of the most fascinating areas of neuroscience. And also understanding how drugs and how addiction affect that is important. But also within that line of thinking, how is it that our environmental exposures during childhood and adolescence affect that connectivity becomes crucial. So that is where right now all of the research is going, to help us understand that interaction because we can put it very nicely like that in a diagram. But these things don't occur in isolation. It's not that your genes are separated from your environment. Everything is orchestrated in a dynamic way. And that provides us in a way that uniqueness that each person has and why each one of us has a very unique brain that can perceive things in different ways from someone else. And that is ultimately why at the end of a lot of the work that we are doing in science, in medicine, and in psychiatry, is to understand how to optimally personalize interventions for people with mental illness. So where do we start? We start with brain development. And we do know that the risk of addiction can emerge very early on from fetal exposures. And now studies have been actually already being published that show that children whose mothers smoke or whose mothers consume cannabis or whose mothers drank alcohol may be at greater risk of neuropsychiatric disruption and vulnerability of which actually some of it may manifest into substance use disorders. We also know, and this slide actually shows, the ages at which most of the diagnosis for neuropsychiatric diseases are occurring. And this basically occurs very early in childhood, earlier of all for autism spectrum disorder, but also very early on for ADHD, later on for anxiety, but also at a very young age. And then you start to see the emergence of substance use disorders, schizophrenia, bipolar disorders. And this time sequence is not random. It basically reflects the fact that the brain is changing, as I was saying, proceeding in very well orchestrated stages and steps that actually are dependent, interestingly now we know that, on very, as I just described the word before, orchestrated changes in the way that certain genes come into action at certain periods of time. And as a result of that, you can have a child that looks perfectly normal and then at a certain stage you start to see the emergence of symptoms. And this may relate exactly to that very well orchestrated series of events that are happening as our brain grows. Gray matter volume does not change much. White matter volume does increase. And then it stabilizes more or less around 20 to 30 years of age. And then after 60 years of age you start to see a decline in many of the parameters of the brain. So we know that. And we do know that all of the neuropsychiatric diseases actually are strongly tied to these neurodevelopmental trajectories. And I think that when you basically look at that, it's telling us something that also is now emerging in terms of what we're seeing with genetics. Are there specific neurodevelopmental changes that are very unique to one condition and not shared by the other? In other words, to what extent the diagnostic categories that we work with are clearly separate entities. And if you look at it from what we know on neurodevelopment, we see tremendous overlap. And then if you look at what we know from genetics, we also see tremendous overlap. And this slide that I'm showing you here shows the results obtained from the largest genome-wide association study for identifying which are potential genes implicated in addiction. And this study was done in more than a million individuals. And by doing that, you of course increase the power of detecting the genes that are more frequently present in people who have an addiction. And in this case, they were looking at multiple substance use disorders, legal and illegal, and trying to determine two questions initially. Are there specific genes for addiction? And are there common genes across all of the addictions? And the results actually which confirm what other investigators have shown is that the main effect of genetics on the variance reflects a genetic factor for addiction in general. And there are many more genes that are involved in that common genetic factor for addiction in general than there are for specific substance use disorders. There are a couple of genes that are specific for alcohol use disorder, for cannabis use disorder, a couple of them for opioid use disorder. But the big bulk relates to this common addiction genotype. And the issue that leads to creating a polygenic risk score. What's interesting about this polygenic risk scores for the general factor of addiction is that it also explains and is associated with other psychiatric disorders. The most notable that you see there into the right, and they told me that I have here one of these things over here. This doesn't seem to do much. Guys, I'm sorry, and I'm going to not be able to show you. But if you look to the right, those brown dots over there, those are actually phenotypes for mental illness. And you can see that suicide attempts, major depressive disorder, ADHD, all of them actually are significantly associated with this polygenic score for the general addiction. Which is telling us, just like when we were looking at the neurodevelopmental component, that there are commonalities across mental illness. And while there may be specific gene factors or specific sites on development that may say are more likely to result in addiction versus depression, we also see them as highly, highly comorbid. Interestingly, just for those that are very curious about which were the top genes, and I am very curious about what are the top genes that are in this polygenic risk scores for general addiction. And it's the FTO, which is a fat total mass obesity gene, a dopamine D2 receptor gene, and a phosphodiesterase 4B receptor gene. And these, except of course for the dopamine D2 receptor gene, are not genes that we normally think very much associated with addiction, except as we are going along and coming to realize the terms of overlap between some of the vulnerabilities for obesity and addiction. We're trying to realize that the overlap in genetics is also not just limited to psychiatric diseases. Now, how do and what do researchers have shown about this confluence of the genetics I was speaking about and the development? And this is a study that was done 10 years ago, and I like to show it because of its simplicity. And in its simplicity, this becomes eloquent, what it's actually documenting. In the upper part of the figure to your left, you see in colors, coded in colors, the degree of heritability that those areas of the brain actually, where the volumes of those areas of the brain appear to be accounted by genetics. And the way that heritability studies go, as you probably well know, is you compare the concordance of monozygotic twins, identical twins, to that of dizygotic twins. Monozygotic twins basically share the same genetics. So to the extent that those areas of the brain vary concomitantly in the pair of identical twins, much more that on dizygotic twins, you can then determine the degree of genetic inheritance linked with them. And you can see something very interesting. So it shows 5, 8, 11, 14, and 17, that the component of heritability increases, as what is observed as we grow older. And in the lower panel, the researchers do something also that you are able to disentangle between variance due to genetics and variance due to environment. By comparing the differences in the environment exposures that an identical twin may have from that of a dizygotic or of another sibling. And there you can see that the genetic inheritance and the environmental inheritance are particularly strong on both of them at 5, 8, and 11 years of age. And I always, and this is why I like this slide, because if you want to influence right now the trajectory of the brain of a child, we don't know how to change genetics, but we do know how to change environment. And what this slide is telling me, if you look at it in the lower panel, 5, 8, 11, that's where you are seeing the greatest effects on the environment. So prevention interventions targeting to strengthen those early years of childhood and adolescence are likely to be the ones that are more consequential. And nonetheless, it also tells us something very remarkable, which is the extent to which different areas of the brain, it's really a pity that I cannot show you what it is because, ah, yes, now I can show it. Some areas of the brain are more affected by the environment than others. And I want to note this one, this is the superior frontal cortex because this is an area of the brain that actually is crucial, among other things, for cognitive operations and for a certain level of self-awareness. And this effect is present even into later adolescence. And these parts of the temporal cortex, the superior temporal cortex, and the temporal pole are also areas that are particularly sensitive to environmental exposures. So with this understanding, one of the questions that we've gone all throughout is how do we then bring that developmental stage, those genetics, with the environment? What do we know about the environment and addiction I mentioned before? This has been recognized for a long time. And that is that the social determinants of health are probably, and I want you to think about it because I've been speaking about genetics, genetics, genetics, the largest impact on the vulnerability of someone to develop a substance use disorder, much more than genetics in isolation. What is it that we call social determinants of health? There are multiple variables. One of them that is very important because it's very tractable is poverty, family income, childhood experiences, particularly adverse childhood experiences that can be divided in three different buckets. Abuse, which actually means to, could be something as discrimination or physical violence or sexual violence towards someone. Neglect, lack of caring for someone. Isolation and household dysfunction. The lack of that family support structure that is necessary for the well-being of the child. And the more that you have of these adverse childhood experiences, the greater the likelihood, your risk, for developing a substance use disorder. This increases your risk for a substance use disorder if you have four, five or more adverse childhood experiences by tenfold. Genetics may explain your vulnerability, may increase your vulnerability, and I'm going to be very generous, by 30%. So the question then is that while I can say 30% versus tenfold an adverse environment, that reality is that your genetics will determine your sensitivity to the adverse childhood experiences. And as such, certain genetics may provide you resilience despite the fact that you're exposed to a very adverse childhood experiences. There's also the understanding, and I guess that then this becomes very, very important, that you can have someone with no adverse childhood experience with a strong genetic load that then does develop a substance use disorder. So it's not helpful to just say this is just genetic or this is just social, environmental. It is both an integration of both of these factors. What we do not know, we know this to be the case, but what we do not know yet is, and this is where the research is going, how these adverse childhood experiences, how these social determinants of health influence the development of the human brain. Because I was spending also a lot of time showing how the brain changes from infancy upward into young adulthood. And the brain undergoes very, very fast changes up to your mid-20s. And then it continues to change, but at a much, much lower pace. And that's where basically some of the most exciting studies that we've been funding at the National Institutes on Drug Abuse alongside other institutes like NIMH and the National Institute of Alcohol Abuse and Alcoholism to try to basically disentangle that. The first study that we launched in 2016 is the Adolescent Brain Cognitive Development, an ABCD study. It's a prospective study that aims to follow children that were recruited when they were nine to 10 years old, and they're going to be follow up for 10 years. Every two years, these children get a full brain imaging suite of tests. And every year, they get an evaluation for cognitive, behavioral, and social health factors. And up to now, close to 12,000 children have been followed, I would say, with a retention of more than 95%. That data is deposited in an open access format for researchers to look at that. And that has enabled to carry on studies of a tremendous complexity. Because one of the aspects that has made the ABCD study so unique is not just the large cohort, the largest that there is currently available in a longitudinal study of development, but also the fact that there is an in-depth phenotypic characterization of the social environments of these children. And it has been very successful. We are now eight years into this study. And so last year, we started an equivalent one, but instead of initiating the prospective study when children were nine to 10, this study, which was started last year, basically aims to recruit 7,500 infants, also to understand how fetal exposures and early environments and genetics influence the development of the brain. So this is too early to get your results of what we have learned, but eight years into this study, it basically has illuminated and help us understand right now directly how is it that these social determinants of health are affecting the brain of children. Well, when we speak about social determinants of health, we've come to realize that they have an effect when I speak about substance use disorder is not specific for substance use disorder. It actually has an effect in general on mental health. And studies, because of that diverse set of variables that have been recorded as part of the ABCD study, researchers have started to dissect out the different elements that are important in determining the risk of mental health. For substance use disorders, it's actually early because most of these children are just at the early stages of initiating drug taking. But that data should be available in the next 12 months as they go into the later adolescence where drug use rises. And when they enter all of these parameters, and they do actually in this case a cluster analysis, but the same results emerges when you do factor analysis, you come to realize that these variables that are encoding for different elements of social and economic factors in these children's life, they are categories. And one that is clear is coming from an affluent community. So this is a clustering method that identifies the children that comes from affluent communities whose parents have high incomes and high levels of educations are protected. They are the ones that you see here in blue. They are protected from all of the mental illnesses and they are also having higher cognitive intelligence scores. So coming from an affluent environment gives you a tremendous amount of resilience as a child. And then you have three different clusters. One of them of children coming from high stigma environments that where there's significant discriminating and separation policies. One of high socioeconomic deprivation where families have very low incomes that they don't meet their needs. And a third one here, the fourth one, the high crime, low education, densely populated level. And just as this one is the most protective, coming from high socioeconomic deprivation in brown is the most detrimental. And you can see that, that these children are the ones that actually have higher mental health scores and also have the lower cognitive intelligence scores. What is driving this? And again, it's a question that you say, this is not driven per se by a genetic factor that makes you less intelligent or more vulnerable to have mental illness. This is driving by the circumstances that you live in and are exposed as a child when your brain is developing and responding to the stimuli that are in front of you. So researchers have started to look at it and say, well, how do these factors here, whether you go at them through this cluster or factor analysis, influence how the brain develops? And since poverty, whether it is high income protects or low income makes you vulnerable, this is one of the ones that has been most investigated. And so here you have it. How consequential is poverty in the brain of a child? Well, this is the family income bracket. And this is the total cognitive composite score, which includes average for fluid intelligence and average from crystallized intelligence, the two big factors of intelligence. And you can see in blue boys and in red girls that if you are from a high family income, you have much higher cognitive scores. If you come from a low family income bracket, you have much lower. What does that derive from? Probably children in low income go to schools with a much lower quality of education. But also probably these children whose families have very low income, both parents likely may have to wait multiple jobs and are not there to take care and to push them in school. They may have much more adverse circumstances. Well, family income bracket affects cognitive scores. How does it affect brain volume? And here I'm showing you brain volume. You can look at the same thing for gray volume, which is the measure of the volumes of the cortex. And you see exactly the same effect. Family income significantly influences brain volume. If you have, actually, if you come from a high income, the brain volumes are larger. This is girls. This is boys. Boys have larger brain volumes than girls. And adults have, basically, this is a difference that exists across all of the lifespan. And the brain of women actually has different connectivity patterns and ratios of gray to white matter than that of males, because the body of the male is much bigger. When you look at then, what is the correlation to try to see are there links? In other words, do the changes in brain volume, are they associated with cognition? And you can see here, yes, they are. The larger the brain volume overall, the higher the cognitive scores. And it plateaus. It's not a linear association like here, but it does plateaus. And this is for boys, and this is for girls. So in other words, for girls, smaller volumes are associated with equivalent intelligence scores as they are for larger brains in boys. So this is for brain volumes. But I spoke about the brain as this extremely complex network. And now with brain imaging, we can look at the connectivity pattern on the basis of what is the concordance on function between areas of the brain. In other words, if two areas of the brain are basically functioning on the same frequency domains, you can actually assume that they are communicating with one another, that they may be part of an integrated network. And using that, the researchers can actually identify the pattern of connectivity. And in this pattern of connectivity, we can ask the question, what is the association of family income with brain functional connectivity? And you can look at the brain and identify the areas where higher family income is associated with greater density of functional connectivity. And you can look also at the areas where having a higher family income may be associated with lower functional connectivity density. In these maps, I'm showing those areas where the association with high family income and higher connectivity in red is positive. And in blue, the areas where high family income is negatively associated with connectivity. And it is quite notable that the areas that show higher connectivity in children with high family income and are associative cortical areas, those are the areas that are necessary for complex thinking operations, that are also the ones that are more that developmentally are the ones that last to develop. And these areas, in particular, two areas jump at you. One in the posterior part of the brain, which is the precuneus. And the precuneus is a key node of what we can come to describe as the default mode network. And the other one is this anterior one that reflects the anterior part of the default mode network. A medial prefrontal cortical region and a posterior one, the precuneus. The higher the income, the higher the connectivity in these brain regions. And the higher the connectivity in these regions of the brain, the higher the cognitive scores for girls and for boys. And interestingly, and I think it's actually telling us something that we need to look into, the higher the income, the lower the connectivity in these areas of the brain, which are somatomotor areas. And you see it here, the higher the connectivity, the lower, basically, these children coming from lower economic families that have higher connectivity in somatomotor areas. In other words, you have a pattern that is opposite for associative cortices versus primary cortices like the motor cortex. And this gives us now an understanding about why is it that children in low family incomes are actually performing worse at school. For once, whatever exposures they are getting are actually resulting in a pattern of activity that is not optimal for cognitive performance. Now, this becomes also very important when we speak about race and ethnicity, because we also have come to realize that there are tremendous race disparities in our country, that the people coming from underrepresented groups, black, American Indians, to a lesser extent Hispanics, but included among them, have much greater levels of poverty. So children from these races or ethnic groups tend to come from lower family incomes. And as a result of that, if you are to test them on cognitive scores, not surprising, they will tend to score lower than children coming from white backgrounds, from higher economic incomes. So in this particular study, also based on the ABCD study, they actually look at the areas of the brain where the volumes differ between black and white children, and then determine the extent to which those differences were driven by economics. And they found, long and behold, that all of the areas in yellow were areas of the brain where the smaller volume that you were seeing in black children was accounted for them coming from low-income families. As I read this paper, though, one of the things that intrigued me was the areas here that you see in black, which was areas where there were differences between the group on volume that were not easily accounted by family income. It caught my attention, because I call these the dark matter of variables that we're not taking into account. And when I first presented the information on the clustering, I was speaking about income as having the more consequential. But we also come to realize that discrimination and stigma also significantly impair the development of the human brain. And it is likely that that may influence more areas of the brain implicated in emotions. And we will see later on how this is starting to emerge from other studies. So yes, socioeconomic deprivation is one of the main factors that continues to put the children of other racial and minority and racial ethnic groups as a disadvantage. So as I speak about it, one of the things that emerges immediately is what can we do about it? And is it... if there is... I mean, because obviously you say, how can we improve the income for those families with children so that their children can develop better? And is there evidence of this to be the case? I mean, there is. This is an ABCD study that was published last year that actually looked at the cognitive scores and the volumes of the brain of children of different states, children where the cost of living were very high, cost of living very high. But they were comparing those states where the cost of living was very high. But also have high average cash benefits. So even though the cost of livings were high, the state provided cash benefits to those families. And they compared them, those with a high cost of living, with those that do not have those cash benefits. And look at whether there were differences in cognition, in symptoms of internalizing disorders, in brain volumes. And they compared those children that come from low versus high income. Children from high income don't benefit at all. This is internalizing symptoms. Don't benefit at all if you come from a support cash benefit state or not. They already have the money. They don't really need it. But you see that difference when you compare those children from low income that are living in states of high cost of living that have benefits, high benefits versus low benefit. And you can see that delta here versus the delta here. So in this very simple study, it shows that policies that provide cash benefits to children can have a significant impact on the emergence of internalizing symptoms, on the emergence of cognitive scores, and on the emergence of actually larger hippocampal volumes. Indicating, indeed, that prevention interventions to improve the income of these families will have a significant effect. Now, studies are testing this. So these are studies based on the data that is coming from the ABCD study. But investigators have started to do randomized clinical trials to see what about if we improve the income of mothers who come from low income that have economically deprived and give them funds and monitor their children. And this is a study published two years ago. They recruited 1,000 families, poor families. And they divided the families into those that got a cash benefit, $350 a month, which the mothers could use any single way they wanted. There was no strings attached to it, and they had an infant. And the other ones just got $20 as a token for control. And then when they were one year old, they did an EEG analysis on close to 350 of those participants. And what they showed was significant differences in the EEG signatures. In particular, the high frequency signatures, most notable gamma frequency waves, actually were much more prominent in those that got the high cash. On those one year olds, whose mother got $300 a month, have significantly higher absolute values on high frequencies, electrophysiological signals that are the ones associated with cognitive cognition development and cognition performance. Again, indicating that it has a profound effect, the extent to which the mother may be interacting with that child if that mother is stressed by the fact that she does not have enough resources to support that child, and cannot basically put the attention that's necessary. So you see it in a relatively small sample size being very, very consequential. Other studies have also been looking at what other interventions can improve the outcomes on poor families. This is a study that was done in 2002, the Strong African American Families Intervention. It was a study that initially was driven by—it's in the southeast of the United States, predominantly in Atalanta, where there are many black families of low income, and were in some places in the southern part, eastern part of the United States. I didn't know this, but close to, between 30 and 100 percent of children live in poverty. Think about it. What are the consequences? And so they—but they saw that not all of the children that lived in poverty had negative outcomes. So the investigators look at a thousand families, and they found out that those children from poor, low income families that did well, one of the characteristics was the control that parents have in those children, the surveillance that they gave them. And so based on that, they designed a study where they did an intervention on 600 African American families of low income, divided the control versus an intervention, where they taught the parents, as well as skills to the children, for the proper oversight and monitoring of activities of these children. And these studies have shown some extremely remarkable results, as it relates to decreasing now—it's two decades—decreasing the risk of these children taking drugs, improving their attainments at school, decreasing the risk of obesity, particularly for girls. And more recently, they did on 100 of those 660 children that were initially part of that intervention, they did brain imaging, and they showed that the reduction in the hippocampus that is associated with greater—or in this case, the amygdala or the hippocampus that is associated with greater poverty, the greater the poverty, the smaller the volumes of amygdala and hippocampus—was completely prevented by that intervention. So indicating how malleable the brain is at that stage, and how we can profoundly influence it, either by providing support to the mothers, like this study showing here, or by actually in terms of economics, or alternatively, by providing guidance on those parents how to optimally oversee their children, so that they can basically protect them and provide them with resilience. So this is at the essence, and it's sort of like in many ways, a non-brainer. So we've identified the factors that make a child vulnerable to substance use disorder, and also to mental health disorders, and the factors that provide them resilience. So yes, prevention interventions—and there are multiple of them, I showed you two just now—work, and there's evidence to show that, and they work by basically decreasing the risk factors, and improving the ones for protection. And what's interesting when you look at all of the evidence-based interventions, that those evidence-based interventions just rely on income, but it's not just relying on income. Importantly, it is relying on creating strong social connections, whether it is by intervening on the child, so that they are better able to navigate the social interactions with their peer groups, or by doing interventions on the parents, so that they can better navigate their parental skills, or by intervening in the school, so that they actually, that teachers can interact in ways that can support their children, or by intervening in a community to create a sense of belonging. All of these strongly, strongly provide resilience, and at the essence of them, yes, there are economic factors, but even more importantly than the economic factors, that creation of those social networks that are necessary for the well-being of the individual, as it goes into childhood, adolescence, adulthood, and later in life. And that pertains not just, sort of why I say later in adult life, it pertains to our whole lifespan, and it pertains for substance use disorder, but also for other mental health conditions, and yet we give it for granted, and it's not for granted. Social meaningful networks are not necessarily present in the life of many people, and this has led, of course, the Surgeon General to declare an epidemic of loneliness in our country. That epidemic of loneliness exists across all of the ages, and it's contributed to an enormous amount of distress and turmoil. And for us as an institute, it is also a key player in this, what we call the overdose crisis, which I started speaking about. Yes, it is economic predictors that are driving, yes, more vulnerable people of low income, but it is also social factors that are driving people from underrepresented groups because of stigma and discrimination or isolations into a higher race. But sometimes it is those underrepresented groups that have stronger social ties and sense of community that actually can provide them with resilience. So how does this overdose crisis look? It looks pretty bad, and actually this is the latest numbers that we have of people that have died from overdoses as of November of 2023. So this is the number of people that died the 12 months preceding this date, 109,527. Slightly less than one year before, but it's basically practical matters, 100 close to 110. That's more than one person dying every five minutes, and every one of these persons should have not died. When we think about cancer or we think about Alzheimer's disease, I mean, these are diseases that in many ways are part of that degenerative, that limited lifespan of our cells. And through science, we can basically expand and come up with treatments, but our biology has a finite lifespan. Not in the case of addiction. These basically tend to be younger deaths. People, that is why it sort of says, if we have prevented their use of drugs, none of these people would have died. Now looking at the numbers, I do want to convey again, these are the number of fatalities where there are increases. And most of those deaths of the 110, as you can see, 76,000 are from fentanyl. And 30,000 and 36,000, close to 90% of these deaths here, there's overlap all of these on cocaine and methamphetamine. The majority of them were combined with fentanyl. So these are polysubstance deaths. And it is rare now to find someone that dies from an overdose that only has one substance. Fentanyl is the substance that's most frequently observed, but regardless of fentanyl, it is frequently associated with other drug combinations. And this is a major challenge. There's a lot of fentanyl actually in the illicit drug market. It is being used and sold as heroin. It is basically used to contaminate cocaine and methamphetamine. It's sent to our country in illicitly manufactured pills that are disguised as pain opioid medications, that are disguised as benzodiazepines, that people may seek out in the web in order to help them sleep better, to treat anxiety, to treat pain, when they cannot get the medications from their doctors, which has basically made everyone of all of the demographics vulnerable to an overdose, but with some groups having a higher risk than others. And so if we look at it from that perspective, and we ask ourselves, actually, how does it look and what are the vulnerabilities? These are the numbers on 2023, as I say, November 2023, and the pattern looks actually for the first time, this is the first time I show this slide, where this number is not red. And red means that it has increased over the past 12 months. Green means it's going in the right direction, it has decreased. It's the first time, and I show this slide every single time, because it's like a record, a report of where we are in the overdose crisis. So it's going down. But it's very, very little. I actually think it's probably this is part of the noise, but it's at least not going up. And it is also interesting when we look at the trajectory, because it points to how important these social factors that I was discussing are for the overdose crisis, to look at what happened during the COVID pandemic, because that was of, it was a pandemic from an infectious disease agent, but it also generated a downstream social isolation experiment, that enabled us to see how that affected mental health and substance use disorder. And as you may imagine, it did not help it. It actually deteriorated very, very severely. And that is shown here in terms of the overdose deaths. We had seen that it looked like, overall, my pointer is sort of dying again, and I'm, it looked like our overdose deaths have sort of stabilized between 2017 and January 2020. And then you see that jump here in overdose deaths, and this is the fentanyl. And this jump corresponded to the COVID pandemic. On March 2020, we closed the country. Basically, we closed a lot of the community support systems that people have, and people became very, very isolated. This also at the same time facilitated the entry of fentanyl. But during the first two years of the pandemic, when we already were at extremely high levels of overdose mortality, the high that we have ever seen, more than 50,000 a year, 60,000 a year, there was close to a 50% increase in mortality over a two-year period. And so that highlights how stress plays such an extremely important role, and how the social structure and how the society as a whole responded to this event and the uncertainties, contributing to a massive accelerate on the overdose deaths. That was one. But it also shifted the paradigm of who was dying at higher numbers. During the initial stages of the overdose crisis, we saw that the mortality was highest in the Appalachian region. And it was highest among middle-aged white Americans that came from economically deprived environments. The Appalachian region, having closed many of its sources of work, the coal mines, left people without job, in poverty, and suffering from pain, and made them very vulnerable to what we call the deaths of despair. Obesity, alcoholism, suicide, and overdose deaths. Then, as time proceeded, and we have the COVID pandemic, we start to see the emergence of a rise in the overdose deaths in underrepresented groups, coming from impoverished environments, but also from cultures that have been very stigmatized. So researchers have started to look at it and say, well, what is it? And there's a lot of work that has gone into trying to understand, how do I predict the risk of a community for overdoses? How do I predict the risk of a person to dying from an overdose? And there are four paths that have been identified that actually increases the risk of a community or of an individual for an overdose death. Number one, resource insufficiency, labor market exclusion, and deindustrialization. And that was at the beginning of the overdose epidemic with regions, rural areas, and the Appalachian regions that put them at high, high risk. Then we see another group that is emerging, and I would say, of all of the groups that we right now know, the highest mortality of all of them emerges in those that are homeless and don't have a house. That mortality is much greater than in any other group, and I'm going to show you groups with extremely high rates of mortality. Homelessness significantly increases that risk of overdose, and that is at the extreme of poverty. Then you have elements that contribute to overdosing, policies, criminalizations, negative interactions with emergency services that lead people not to want to seek help. That is also another entry. And then you have the gender and rationalized dimensions of inequality that relate just to poverty, but also, in addition to that, include discrimination, stigma, lack of opportunities, and very different exposures from early life and higher risk for trauma. So how that, then, is influencing across the racial and ethnic groups? Well, look at this, how the overdose crisis has actually led mortality change over time. We have, speaking of minus 2.5, minus 0.5 mortality this year, that's very much driven by the fact that people are by the general, that's U.S. here, 32.7, and white people, 35.4. They are starting to go down. So we can say we're doing very well. But if you look at American natives, Alaskan American, or black, you can see the curve going steeply up. So the overdose mortality among these two groups has skyrocketed, and has continued to skyrocket even after the COVID pandemic has ended. How bad is it? If you look at the United States, the rate of mortality is 32.7, over 100,000 people. American Indians is 64.4, double the rate of mortality of the United States, double the rate of mortality. And if you think about it, and you have a chance to go into tribal nations, and you can see the devastation that this is having on every single community, where they basically are losing young people to overdoses on a weekly basis. Black people, 50% higher than it is for the rest of the United States. And so this brings to light, yes, we understand that social and economic factors are playing a role in this vulnerability. But how do we tackle? Because one thing is to demonstrate, and that is important. But it does not have consequences. In order for it to have consequences, we need to take this information and act on it. So in respect to the American Indians and Alaskan natives, and I spoke out about the issue of homelessness, how do we tackle these problems in a way that provides resilience and support on these people? And it's not just about economics which help. It's again integrating them into social structures and networks that are meaningful to them. So what we are doing as a result of that, one of the most ambitious projects that we are launching this year, is the Native Collective Research Effort to Enhance Wellness, to actually empower the American native organizations and tribes to be able to conduct research in their communities to address questions and to use practices that are acceptable to them to address the overdose crisis, to actively involve them in the process. So they can provide the interventions that can bring resilience into these really devastated groups. I visited some of these places, and what actually made me aware and touched me in a way that I think I sort of would like to extract something that is so valuable in these communities, is the level of commitment that they have towards one another. They're caring for one another, and that element is probably the most important resiliency factor that we have as human beings. So why is it that despite their having this strength, are they so vulnerable to that vulnerability and the overdoses? So this is a project that we're launching. It's actually a five-year project that started with a pilot that aims to build a structure for the Native Americans to be able to come up with the solutions themselves, as opposed to trying to translate things from cultures that don't speak to them, that actually are felt as an imposing into changing their lifestyles. The other area of research that we are very much starting to, we started three years ago, but it's a relatively new one, is when we speak about treatment. I spoke about prevention and the factors that relate to the social and economic determinants of prevention. And I haven't spoken about the social and economic determinants of getting access to treatment, which also is quite relevant. But I also think it is very important to look at it from the perspective of recovery. So if you go to treatment, we know in the case of opioid use disorder, but also other substance use disorders, that there is a high relapse rate. In the case of people given medications for opioid use disorder, we know that close to 50% of them will stop taking their medications at six months. So how do we build their ability to stay in treatment and to achieve recovery, so that they can integrate into the community in a way that the community itself will help support them? And that is also at the essence of providing a building up, what researchers on the field of recovery science have described as recovery capital. And it basically relates again to building up those social elements at the personal, by strengthening personal skills and capabilities, at the social, by strengthening the associations to positive social networks, and by communities with availability and accessibility of resources, such as jobs and houses, and education in the local community. And with that I want to end up my presentation with this slide. It shows a human from really in total and absolute isolation, in abject poverty, injecting a drug. And it is because when people look and start to think about how addiction looks like, it does not look glamorous. In the severe addictions, what we see are people in total and absolute distress, in really epitomizing what is called diseases of despair. And we now know that indeed addiction accounts for a significant portion of suicides. And we know that people that are shooting drugs, like this woman here, are doing it not because they want to get high. They do it because they don't have a choice. They do it because the addiction themselves has isolated them. Isolated them because of the social rejection by their family and by the culture. But also by the effects of the drugs in their brain that actually make them much more aversive to social interactions. And if we are to solve the crisis, if we are to properly protect people, we need to be able to engage them and to build those social networks that are necessary. And this is relevant not just in terms of achieving treatment and recovery but on prevention. And I show by the side of this very complex picture here, this very simple experiment. And it's an experiment that actually had been shown many years ago by others, but it is shown eloquently in this study by Veniero et al, in which they actually give a rat a choice. The rat can choose to press a lever for a drug or the rat can choose to press a lever for having a social interaction with the other rat. Notice here, you're giving the animal a choice. You have a choice. You can choose this or that. When you're giving a choice, whether it is for heroin, the same results for methamphetamine, the animals don't choose heroin that I might think has died. So you can see in that graph, heroin in red, they don't choose it. They basically choose to do the social interaction. But what happens if you remove that social interaction? Or what happens if when the animal chooses the social interaction, they get an electrical shock, which is the equivalent when someone approaches me and I react aggressively or disdainfully towards them in a sort of disgusting sign, I mean, just discriminative sign. That is an aversive social interaction. And that's what people do with one another all along, particularly for stigmatized groups. And then drug taking goes up. So as I think about it, and I look at it in terms of why is it that we see people in the streets, and as we see in sort of being in New York City, people homeless, and I found myself actually trying not to look at them, and I find myself trying not to look at them because in a way it is painful. But in a way too, because I guess in my brain I go with a say of sort of saying something like probably if I were in their shoes, I wouldn't want to be seen. But is that really the case? So what about, I mean, I sort of, one of the things that I sort of says, why not smile at them? Why not make them be aware that they are there? And I think that all of us, and our role as psychiatrists, yes, we interact with patients on a one-on-one, but we also interact with one another. And I think that being aware that kindness and caring is probably the most powerful thing that we can do to prevent substance use disorders, and I do think to basically overcome the overdose crisis. Thanks very much for your attention. Thank you. I think that it is, yes, we have time for questions. Yes. Actually, I'm from India, and it's really a thought-provoking talk, and a very stimulating talk for me as well. And what I was feeling, I'm from a rural, I came up, and then I become a psychiatrist, and now I attend APA. This is the 12th year I'm attending. But my point is, I want to learn from you. As a citizen, privileged citizen, what we can do, how we can work your talk. What you have said is, what way, apart from national policies, apart from state policies, as an individual, as I am a privileged citizen, what we can do. Because whatever you are saying, it was touching me because in my rural area, the marginalized people, the tribal community, they used to die in very early age. Many of them are my friends. Some due to alcohol overdose, some due to nicotine, alcohol, and cannabis, and also they used to have infectious disease like tuberculosis. It was a huge pain when I was a child. Now I've started to work there, and now I want to learn from you how to formulate a care pathway, how to help them, apart from at the state level, at the national level, what we can do as a citizen, privileged citizen of the country. Yeah, I mean, there is not one single solution that addresses the problem. I mean, we're speaking of social and economic disparities that make people vulnerable. To me, as I have been in the field of science, and now also administering science, it's clear, and as a psychiatrist, that the most consequential intervention that we can do is policies because they have a widespread effect. So how can we develop policies that actually improve the quality of education, improve the quality of life of people? How do we develop policies that are not punitive against people that are taking drugs and their families? I think that starting, one of the reasons why I took this job was I was very frustrated on how we criminalize people that take drugs and how we use jails and prisons and put them there with a belief that that will cure them or treat them, when in fact what it's doing is it's degrading their self-confidence even more and stigmatizing it at the level that makes them so much more vulnerable. So changing policies like that one, transforming how we treat addictions and the persons that take drugs from being criminal to looking at it as a public health problem that can be addressed, interventions work, teaching the medical students, the other clinical providers on how to recognize, how to screen substance use, how to actually intervene to help someone with a substance use disorder. They are not inevitable. I've spoken with, they become inevitable when people don't have any choices. So I think that that is the answer. How do we provide alternative choices to people so that they don't take drugs? And for people who are taking drugs or who are addicted, how do we provide them that treatment so that they don't escalate any further? How do we provide the support so they can achieve recovery? And how do we actually, each one of us in our different roles, contribute to actually providing the evidence that can change policies? But also I think, even though it may not be as largely consequential as I said at the end of my talk, how in our everyday interactions can make the life of people that we may encounter that are not as privileged as soft better? Just by smiling at them. Hello, my name is Nicole Knighty. I'm a perinatal epidemiologist. And the lens that I ask my question from is true spots. I lost a partner to overdose and then I now do community-based participatory research with people who use drugs during pregnancy. And so something that I struggle with as an academic is seeing how research on people who use drugs is then used to be weaponized against them in terms of criminalizing them, specifically pregnant people with substance use. So how do we as a research community ensure that the work that we're doing in hopes that it's going to improve outcomes for them doesn't contribute to their harm? Yeah, no, it is an extremely important question and thanks for raising it. And it's sort of among probably the most stigmatized of all people with substance use disorder are women that are pregnant. And there are some states, there are two states that actually can put the women into jail for taking drugs when they are pregnant. And many of the states can send their children to child welfare. And so these punitive practices, as you may imagine, and the majority of states in the United States require that if you are a doctor and your patient is pregnant and has a substance use disorder that you report them. Well, if I were a woman that was pregnant taking drugs, I wouldn't go to the doctor because why would I want to be actually reported or lose my child or end up in jail or prison? And this is contrary antithetical to what the evidence show that we need to provide treatment for women with substance use disorder. And if the substance use disorder is an opioid, we need to be able to provide them with medications for opioid use disorder because it will protect them from overdosing. And this can have a huge impact on the mother and on the infant. So we need to provide the evidence. And one of the reasons of the HPCD study, and so I told you those two large studies, the one that we started last year, we are recruiting at least 15% of those mothers who are taking drugs. And so a big challenge is how do we ensure that we are protecting these women so that they are not penalized by being part of the study. And that is sort of, again, the ability throughout all of our work, because it's not going to be one person, but by documenting the negative effects of penalizing these women in terms of outcomes and documenting how women actually that are taking drugs in pregnancy with treatment do much better. And so their children, showing the evidence in objective way, then that in a way that is so objective that it can change policy. That is right now where we are at with the HPCD study. To gather that data in ways that is so clear cut the advantages that then policies have to change. I'm happy to give you more information, but one of the things that we've had to do with the HPCD study in order not to jeopardize the women who are participating is to devise means by which their information about their drug use goes directly to a data center and the people within the site are not aware of the drug use of the participant in order not to have to report it. We've had extensive conversations about this. Some of the states that we're working in are the ones that Nora mentioned that have these punitive laws. And it's been a very, very complicated process. And I'm happy to provide you with more information if you want. Thank you. My name is Richard Camino from the Medical College of Georgia. One of the things that we do is that we participate with the Georgia PHP, the Physician Health Program. And so my question is the physicians are probably one of the most successful group that go into remission once they are in substance use disorder. I think the rate is about 80, 85%, especially if they're in a very supportive PHP. So my question is, what do you think, and in base of what you're saying, what can we learn from the good response that physicians have to substance use disorder? What do you think are the take up message from that? Well, I mean, what is that legal message? Well, yes, on one the legal message and the other one is, you know, it seems like the social factors that you just mentioned seem to, but I just want, you know, to have an important impact on they being able to return, you know, their connection to others, you know, that. So, but. Yeah, no, from the, within that specific question of the legal impact, I mean, I think that the first thing that jumps into my mind is that it is illegal not to properly provide for treatment with individuals with substance use disorder. It is the law, and that's the parity law, but it's not implemented, not enforced. From the perspective of us as clinicians, I do think that, and again, we all had the, we went to medicine to help others, and I, since we are in the American Psychiatric Association, one of the things that we all need to contend with is that we cannot neglect substance use disorder, and you, they are here, probably recognize this, but it's not necessarily the case, and we do know that in many instances, substance use disorders are not considered concomitantly with the other mental illness, and I think that each one of us has the responsibility to break that stigma against addictions and to embrace substance use disorders like the other mental illness, because the fact is that by doing that, we improve the outcomes of our patients, because comorbidities are so highly prevalent, so us, there's a legal element, but then there's also the one that each one of us as clinicians has the obligation to do. Hello, Ken Thompson from Pittsburgh. You know, I greatly appreciate your description about sort of how the outside gets inside a person and how the inside of that person may predispose them to substance use, but it doesn't necessarily explain what's changing on the outside that may be putting pressure on people. I wanted to just, with your permission, just mention two things that may be of some interest to this audience. One is that Angus Deaton and Ann Case, who wrote the book Deaths of Despair, are actually gonna be presenting today at 1.30 in 1A.17, so there'll be an opportunity there to talk about the actual historical circumstances and the socioeconomic changes that have driven a large amount of what you've been describing. The other is that tomorrow at 1.30, a guy named Alberto Barreto from Brazil is talking about a method of large group social supports where people share their capacities to deal with adversity that developed in the favelas of Brazil, which we are bringing to the United States, an opportunity to show what it means to actually build that kind of social infrastructure that you were describing that people so desperately need. So I wanted to mention those two things as ways to actually instrumentalize what you are talking about. Thank you. Thanks a lot, and I think I unfortunately have to leave, but I would love to hear both of those talks, so thanks for letting us know. Good morning, Dr. Vogel. I am David Gomez from Yucatan Psychiatric Hospital. Thank you for your talk. It's very interesting. I was wondering, you talk about hopeful numbers that were in green when we were talking about the deaths related to drugs, and one of the things I've been seeing, checking the files from my patients in Yucatan, which is in Mexico, and it is a state that has more suicides in the whole country. So my question is, are we being hopeful about those numbers, or are the drugs being shifted to more dangerous drugs? Because one of the things I've been seeing in the files is that patients get their first admissions due to stimulants or particular substances, but then eventually they change the drugs. So what are the perspectives on the future about the situations new drugs are emerging? They are more lethal, more dangerous, so how are we in those situations? Yeah, yeah, I know. And by the way, I was born in Mexico, so I know, but I didn't know Yucatan had the highest rate of suicide. I am hopeful, absolutely I am hopeful, because we can choose to be optimistic or pessimistic, and so in my view, we have to allow ourselves to imagine better circumstances into the future, and that imagining then drives our motivation. I am also not a magical thinker, and what I can foresee is that synthetic drugs are into the future, they are going to become increasingly more addictive and powerful, because that is innovation. At the same time, we can take advantage of innovation to deploy interventions that can provide resilience. So absolutely, I do believe that it is feasible to create prevention interventions that reduce drug taking. We've done it in the past. Look at how dramatically we've reduced tobacco smoking in our country, or in the world, by the way. No, not, I shouldn't say in all of the world, because of some very high rates, but in the United States. I mean, also something that is also very good is we've seen the rates of drug taking among teenagers, the lowest that there have been since we have been surveying them in 1979. The lowest rates among teenagers. That's not among adults, but in teenagers we're seeing low. So there are interventions that we can do to reduce the vulnerability of people to drugs and to addiction. And we know what some of those are. But it's actually the will and the prioritization of providing that support to do it. And it's not going to happen spontaneously, because there are enormous invested interests that are brought up by the billions of dollars that the illicit drug markets produce. That's why we have to be equivalently proactive to counteract that grief from the dollars. I've been looking, of course, at Mexico to try to see how it is being affected by the synthetic opioids. And unfortunately, starting to also negatively affect the border towns of Mexico with deaths from fentanyl, which was not something that certainly we had ever seen. I mean, actually, when I was a medical student in Mexico, where I was born, we didn't see very much injection of heroin. I mean, it was not a drug. And that has changed. And that has to do with the globalization. So we have to contend with innovation on chemistry and the cartels creating these networks of communications and the globalization. But we have also science, and we also have the motivation of the will of many of us to try to make a difference. Hi, thank you, Dr. Volkov. Sofia Mata from Mass General. One comment and two short questions. First of all, thank you for your article on pathology and motivation and choice that you wrote, I think, in 2005. It was something that really shaped my career. Secondly, how do we move the needle to the left? We're always talking about disorders, and you're talking about the social determinants of health. So how do we engage people before the disease has set in, and what can we do to promote post-traumatic growth? Yeah, yeah, no, and that's why, I mean, exactly that question that you're asking me, that's why I show that slide where you can see the effects of environment as a function of the age, how being able to do interventions in children is so, so consequential, because it's going to have the longer-lasting effects. So the issue, how do you ensure that you are motivating them into behaviors and activities that empower them? Because without them, they will seek them out. You know, I was recently in a meeting with people that are taking drugs, and there was this young man who approached me, and he said, you know, you're always speaking about how drugs are so bad. And he says, but let me tell you my story. He says, drugs saved my life. Cocaine saved my life. He says, both my parents were sexually abused me, and the only thing, I would have killed myself if it were not because I had cocaine. And I think that that element shows the lack of options, the lack of choices, and so interventions that can, first of all, identify when there is a toxic environment, social environment, and ideally, you would want to do an intervention that prevents that toxic social environment, which is where a lot of the evidence-based prevention interventions comes. And then if you have that toxic environment, you have to intervene. So otherwise, you are not going to give an alternative to those children or adolescents. Nora, thank you for a wonderful talk, and mostly thank you for your humanity, which shines through, and I think we all appreciate that. I have a question, and I've been following this study, and I'm confused. I do not understand why higher income is protective, because what I see with higher income families is a breaking down of social connection and family connection, and I keep thinking of Peter Fonagy, who developed mentalization. When he teaches mentalization, he talks about the biggest problem that came about in causing all of these disorders was the invention of the steam engine, and I think he was referring to the breakup of these big families and clans, like in Ireland, and coming in to get jobs in faraway places and breaking up the families. And what I see with higher income families is less connection with the children and less of the larger families, the cousins, the aunts, the grandmothers around to provide support. And I just find it very confusing, and I wonder if you could just clarify that a little bit. Yeah, no, first of all, what I, in the bracket, what we call high income are families that have 100K, 100,000K, I mean, $100,000 or more. So, but they are not very rich. They just have a level of income that basically allows the parents not to worry about where the food is going to come, whether they have money for a physician. That is what our high income for the ABCD children is. Are there children that come from very rich families? I am sure there may be a couple of them, but it is really the minority. These are mostly children that come from professional parents, educators. Thank you. And I'm sorry, guys, basically, I'm seeing my people telling me I have to be in, basically, in the Sheraton for another meeting at 10 o'clock. So I really apologize. Can you email me your question? And I promise you, I will answer it. Just saying, yes. Thank you.

overdose crisis

illicit fentanyl

substance use disorder

healthcare system

social determinants

genetic factors

environmental factors

brain development

early interventions

community-based interventions

policy changes

decriminalizing drug use

social support