Welcome, everyone, and thanks for being here. I'm thrilled to be here today and grateful for the opportunity to share some thoughts with you about intergenerational trauma, epigenetics, and resilience. And can you hear me okay in the back there, everyone? Certainly, intergenerational trauma and resilience are relevant topics, given what's been going on in the world today. And what we're going to talk about today is how and whether epigenetics can shed light on how these things work. And again, if people are coming in and there's no room, please tell people that they can hear this lecture in the overflow, because I don't think that people know that. And there's no reason to be uncomfortable. Okay. And as you all know, data on the epigenetics of intergenerational trauma have actually received a lot of attention. And this is true particularly in the public press, with so many people speculating that epigenetics might offer insight into how trauma or traumatic memories are passed across generation. So, today, I'd like to delve into what the findings can and cannot tell us regarding the transmission of trauma effects, and reflect on how what we have learned can contribute to our understanding of human resilience. And we'll talk about this paper that we published in 2015, because this study is often cited as human evidence that trauma is passed intergenerationally through DNA. And I'll explain how people got this impression. And I'll also discuss the findings of replication study, which I think, in some ways, had an even more powerful message, which is that epigenetic changes in the context of intergenerational trauma may be protective. Because indeed, one of the main points that I want to make is that biologic changes in association with intergenerational trauma can aid in coping with the challenges of trauma, and not just compound their effects. So here are the questions that I want us to consider. First, how should we interpret intergenerational epigenetic biology, or really any biology following trauma? What are the implications of this work for resilience? Does what we see in offspring require mental health treatment? And does psychedelic-assisted psychotherapy offer a unique clinical approach for intergenerational trauma effects? And I'm going to talk about this way at the end of the talk. So intergenerational trauma. It's really the idea that the effects of extreme stress can be passed to future generations. And many people think that this means that we're the victim of our parents' or ancestors' history. Isn't it bad enough that we have to deal with our own traumas? Do we also need to be burdened by what happened in prior generations? Now my answer to that is yes. We do need to deal with traumas of past generations. Otherwise, we can't really understand why people react as they do to situations in the present, or why it's not so easy to just forget about past injustices. So society is interested in intergenerational trauma because it justifies efforts to promote social justice and reparations. Individuals care about it because they can understand themselves better in the context of their families and their family histories. But it's actually also a clinical issue because patients may not improve following an intervention to a presenting problem if there are layers of earlier and ancestral traumas. So lots of people are interested in this idea that there might be biologic evidence for intergenerational trauma in DNA. But this is exactly where the conversation gets very, very complicated. Because while the fact of intergenerational trauma may indeed create a mandate to promote healing and resilience and even social equity, the biologic findings don't always support the idea of compounded adversity. And in some cases, they suggest that we develop protective mechanisms, or ones that help us adapt. And I would like to call this the intergenerational paradox, or the idea that parental or ancestral trauma may indeed heighten vulnerability to psychopathology. The epigenetic adaptations may simultaneously facilitate coping mechanisms. Now trauma also increases susceptibility for psychological distress and disorder, but it also produces adaptations or effects that can be protective. And it's very much like how we think about inflammation and the immune response. If you couldn't mount an inflammatory response, you couldn't fight off infection, and you couldn't heal your wounds. In a world full of pathogens, it's good we can mount an inflammatory response. But too much inflammation can compromise your health. So if trauma is a pathogen that causes us to mount a response, some features of that response might be part of how your body mobilizes healing mechanisms. Okay, so I'm going to tell you how our work began, but before I do that, I'm going to remind you that you don't have to stand, and that there is an overflow room in case you want to be more comfortable just around the corner. And so feel welcome to either go there or take one of these three chairs. It's really no problem for me. All right, I'm going to tell you about how our work began and show some data, and then we can return to some of the questions that I raised earlier. Now our inquiry into intergenerational trauma arose in the context of trying to understand the biology of PTSD and develop clinical programming for Holocaust survivors. Back then, intergenerational trauma was just not on my radar at all. In the early 90s, this is a paper actually from 1990, we were trying to understand whether our findings of lower cortisol levels in Vietnam veterans would generalize to other trauma survivors. That finding was counterintuitive. Stress had been linked with elevated cortisol levels and were considered neurotoxic to the brain. Cortisol was also elevated in depression and chronic stress, and it seemed it should also be elevated in PTSD. Now if it were truly low in PTSD, it would absolutely be important to understand why, but was this a universal finding in PTSD? I thought about studying Holocaust survivors because they tended to emphasize their survival and resilience and not their mental health. So we conducted our initial study in Cleveland, Ohio, because I grew up there, and this was the first study of its kind in Holocaust survivors, and there were some sensitivities about participating in medical research, as I'm sure you can appreciate. But eventually, the community got really involved, and we were able to interview more than a hundred survivors and collect biologic data. And here you can see that the results showed low cortisol in those who had PTSD in the red compared to those in the green who were Holocaust survivors without PTSD, and the blue being the Jewish age-comparable controls. Now if you look at the cortisol data side-by-side from the combat veterans and the Holocaust survivors, you might get the impression that these are very similar groups, and they are with respect to cortisol, but they're different in many important ways. About 25 years after Vietnam, about 30 percent of the Vietnam veterans had reported a lifetime diagnosis of PTSD, and many had sought treatment. But in the Holocaust survivors, the lifetime PTSD was nearly 80 percent 50 years later, and more than half still carried the diagnosis, but less than 5 percent had sought any mental health treatment at all. So after doing these cortisol studies as a postdoc at Yale Medical School, I would now be starting a position at Mount Sinai, and the scientist part of me made plans to understand why cortisol levels were low in PTSD, but I also wanted to address the mental health need that we had identified. So we opened a clinic for Holocaust survivors, and as we began publicizing our services, many of the people that called were adult children of Holocaust survivors who expressed to us that they, too, were casualties of the Holocaust and needed treatment. And that is how I met Joseph. Dr. Post? Dr. Post? I have a chair for Dr. Post right here. one of my esteemed teachers. Thank you. That's how I met Joseph. I wrote about him in this article in Scientific American that was published about two years ago, summarizing the work that I'm going to talk about today. And Joseph was a successful professional. He was well dressed and he didn't seem like a casualty of anything. But the first thing he said to me was, don't be fooled by externalities, I'm actually quite messed up. And he didn't use the word messed. He told me that he lived each day with a vague sense that something terrible was going to happen and that he might need to flee or fight for his life. The other shoe is going to drop one day, he said. And lately he was tormented by panic attacks and nightmares of persecution, possibly triggered by reports of ethnic cleansing in Bosnia. Joseph's parents had met in a displaced persons camp after surviving Auschwitz. His father worked 14 hours a day, never talked about the past at all, but woke up frequently from nightmares. His mother talked non-stop about the war and told bedtime stories of how different relatives had been murdered. She was determined that her son succeed and his decision to remain unmarried and childless exasperated her. She said, I didn't survive Auschwitz so that my own child would end the family tree. You have an obligation to me and to history. Sounds familiar to some people, I think. As we talked to people like Joseph, who called for therapy, it became clear that adult children of Holocaust survivors did suffer from a clear set of symptoms and problems. They felt damaged in a nonspecific way or felt anxious, guilty, shamed, grief-stricken. Some had intrusions of Holocaust-related imagery or had problems separating from parents or feeling the burden of compensating for past losses of parents. They reported dysfunctional, intimate relationships due to fear of loss and they often did meet criteria for mood anxiety disorders or PTSD. And what you can see here is that about the same time we were discovering this, Art Spiegelman published his graphic novel, which really basically said the same thing that the offspring were saying when they came for treatment. But because those who were calling self-selected, we wanted to see if we could find evidence of these and other psychiatric problems in a non-treatment seeking group of Holocaust offspring. So we evaluated the offspring of the Holocaust survivors we had identified in Cleveland, and sure enough, survivors' adult children were more likely to have mood and anxiety disorders as well as PTSD than Jewish comparison subjects, particularly if one of their parents had PTSD. And then we found that many Holocaust offspring had low cortisol levels, particularly if they had PTSD, but also if their parents had PTSD. So the group in the blue had their own lifetime PTSD. We weren't that surprised they had low cortisol, but the group in the yellow seemed like a high-risk group for PTSD, with the risk factor being parental PTSD. And we started to wonder what it meant that cortisol levels were lower in this group. What did it mean if they were lower in any group? So in the decade between first reporting low cortisol in combat veterans and then observing it in the Holocaust offspring, 10 years went by, we conducted a series of studies that looked at the role of the glucocorticoid receptor in PTSD. Now glucocorticoid receptors are the proteins to which cortisol must bind in order to exert its effects in the cell nucleus. Now we did a lot of studies on this, and I won't review those studies, and I'm not even going to read this list, but basically we measured the sensitivity of the glucocorticoid receptors by administering glucocorticoids in vivo, in vitro. We looked at the effect in blood. We looked at the effect on brain activity. No matter what we did, the data all supported the idea that glucocorticoid receptors were more responsive in PTSD. But I do want to mention just this last study that we published a couple of years ago in Nature Neuroscience. Here we injected glucocorticoids to induced neurons that were reprogrammed from stem cells derived from skin cells from people with and without PTSD, and the neurons of the people with PTSD were more responsive. Now neurons that are induced in vitro are comparable to embryonic neurons in their age, so the receptors are different very early on in people who later develop PTSD versus those who don't, and so that is why I want to highlight that. But I'm not reviewing all the studies because I think you'll trust me that the glucocorticoids receptors are more responsive, but what you really want to know, I think, is why this is important. Why would it be important to a conversation about intergenerational trauma or resilience? And the answer to that is that if the cells in the brain or the pituitary or any target tissue are more responsive to the effects of cortisol, this actually has major implications for how our body might respond to stress, and it implicitly addresses why we all don't respond the same way. So I want to spend just one minute on this. Cortisol negative feedback inhibition is like a built-in thermostat for stress hormones. When cortisol levels in the body rise due to stress, they signal the brain in the pituitary to stop making more cortisol. So when cortisol levels are high, the body knows how to put the brakes on this to keep things in check. Now the first panel that you see depicts the normal feedback. The second panel shows you what happens in depression and chronic stress, where the glucocorticoid receptors are less responsive, and the brain doesn't get as good a message to stop producing cortisol, and cortisol levels are elevated. This actually makes people less responsive and less able to cope with stress. But in the third panel, you see an enhanced negative feedback inhibition, and that's when the receptors are more sensitive. Similar amounts of cortisol are needed to signal the brain, and someone with this biology is better at detecting threat and responding to threat more efficiently, but perhaps at a cost. And let me show you what that cost might be during fight-or-flight. If your stress response system is too efficient, when the amygdala signals the brain to activate the sympathetic nervous system or the hypothalamic pituitary adrenal axis to release adrenaline and cortisol in the context of a fight-or-flight response, cortisol may inhibit its own release too quickly. And since one of the functions of cortisol is to help actually contain the high adrenaline levels from the sympathetic nervous system, sending a premature message to the brain to shut off cortisol release will result in higher adrenaline levels. Now that is going to set off this cascade of over-consolidation of the traumatic memory, hyperarousal, hypervigilance, avoidance behavior, and eventually PTSD. So the more efficient threat detector might help you react better to a life-or-death situation in the short run, but you may pay for that a little bit later in terms of the consequences. Now we've been able to demonstrate that cortisol levels are lower at the time of the trauma in people who subsequently develop PTSD, and we've also been able to demonstrate that they're lower in association with PTSD risk factors like childhood trauma. And this you could see, the first study is always, you're very nostalgic, you remember your first. This was published in 1995. It's consecutively admitted rape victims with prior trauma had lower cortisol levels in the emergency room and were more likely to have PTSD at follow-up. But there are really many examples of that, leading again to the important question, why? What is the mechanism for how early experience resets that glucocorticoid receptor, making people respond to stress differently? And it wasn't until we began studying epigenetics that these kinds of questions could be addressed. We were one of the first groups to apply epigenetics in psychiatry and PTSD, but epigenetics proved a critical link to our understanding of how experience could result in long-lasting change and how your cells learn to function differently because of external stimuli. You following me? Yeah? Great. So now let's talk about epigenetics for a minute. Epigenetics is the science of how genes are regulated. Epigenetic marks function as switches to amplify or attenuate gene expression. There are many kinds of epigenetic marks and many ways to influence gene regulation, and one mechanism is DNA methylation. And in DNA methylation, in the presence of specific enzymes on certain genes, methyl groups, which CH3 groups, can attach to key sites on a strand of DNA or in the DNA complex. And by occupying these sites like roadblocks on a highway, methyl groups can alter transcription, which is the basic step in gene expression where a piece of RNA is made from a DNA template. And increased methylation generally impedes RNA transcription, whereas demethylation will enhance it. But the part that's really relevant to our conversation today is this. Epigenetic changes are heritable and they are enduring, so they stick. Unlike neurochemical or hormonal changes, which are generally more transient, epigenetic marks are heritable because they survive cell division, mitosis. That's what that means in biology. Our cells are constantly dividing, creating two daughter cells from one parent cell. And if an epigenetic mark is on the DNA as it replicates, it will survive cell division, and so it will be in the two daughter cells as well. But the marks are also enduring because epigenetic changes require special enzymes for their removal. So in this way, epigenetics provides a fascinating insight into how environmental factors leave lasting imprints on our DNA. And this echoes the enduring effects of traumatic experiences on our psyche, because much like epigenetic marks survive cell division, trauma survivors carry within them the indelible imprints of the past. Their narratives, I'm not the same person I was, or the past lives in me, they seem to parallel with a biologic reality that experience can fundamentally alter our expression and perception of self. So epigenetics provides a mechanism for understanding how the past shapes the present and future. So now you see why we just had to measure it, and why we had to look at it in the glucocorticoid receptor, right? We all see that? Yeah. So a mere 25 years after we had the low cortisol finding, we were able to publish a study showing differences in GR gene methylation in PTSD. And in 2015, we reported lower methylation in PTSD in an important region of the gene, which also correlated with low cortisol and glucocorticoid responsiveness. And these findings suggested a potential explanation for how trauma might reset the cortisol levels, because epigenetic changes on the receptor gene might recalibrate the feedback loop. And of course, we could not wait to do this in Holocaust offspring. Now, it turned out that there was a really good rationale, and really specific rationale, to look at the glucocorticoid receptor gene methylation in Holocaust offspring. And it had to do with the work of Dr. Michael Meany, a neurobiologist at McGill University in Canada. Now, Meany had been researching animal models of maternal care, and showing different behavioral and hormonal effects on offspring based on if the mother was, believe it or not, a low licker or a high licker of her pups. Now, either behavior could regulate the hypothalamic pituitary adrenal axis with high licking resulting in low cortisol and increased glucocorticoid receptor responsiveness, and low licking the opposite. Now, when we first became of the work, we believed that parenting was a major contributor to the biology of offspring, and we thought this model was highly relevant to us. And in fact, many offspring did say that their mothers licked them way too much. Now, Meany's findings were very simplistically interpreted by the press and some others in terms of good mothering and bad mothering, but really it demonstrated that different parenting styles prepare offspring for different kinds of environment. We don't always have to put such a judgment on everything. Now, in 2004, Meany reported that the hormonal and behavioral changes in offspring were underpinned by epigenetic changes in this glucocorticoid receptor gene, and so we were beyond excited except for one little thing, and that is, you know, science moves kind of fast and slow. By the mid-2000s, we had begun to look at mechanisms other than parenting to explain the findings in holocaust offspring, because in between 2000 and 2004, you know what happened, 9-11. And 9-11 brought to our attention that there may be a lot more to what we were seeing than parental or maternal behavior, and it taught us that what happens in utero might also matter. Still with me? Okay. So what we do after 9-11, we studied women who were exposed while pregnant on 9-11 and followed them as they gave birth. When we evaluated them seven to nine months later, many of the mothers had developed PTSD and had significantly low levels of cortisol, but so did their babies, and these babies also showed greater evidence of trait anxiety and fear of strangers, even at this young age, which if you've had a baby recently or if you're a grandparent, you know is possible. You see these things pretty early on. Something interesting, though, about the cortisol effect, it was most prominent in babies whose mothers had been in their third trimester on 9-11. Now, we really weren't sure what that meant, but Meany introduced me to Jonathan Seckle, an endocrinologist and molecular neuroscientist at the University of Edinburgh who had been studying the effects of stress on pregnancy, and he was able to explain it. Now, Seckle had been examining an enzyme with a great name called 11-beta-hydroxysteroid dehydrogenase type 2. We can call it 11-beta-HSD2 for short. Now, this enzyme, don't be daunted by an enzyme, it's just chemistry. This is an enzyme that converts active cortisol into inactive cortisol, and during pregnancy, this enzyme is expressed in the placenta and acts like a chemical shield, protecting the fetus from overexposure to excessive maternal glucocorticoids. Now, this enzyme is more active in the first two trimesters when the fetal brain is developing, and protection from glucocorticoids is very desired at this time. But in the third trimester, the enzyme is less active when the fetus needs glucocorticoids to promote lung development and breathe on its own. So, check this out. When something happens to a pregnant woman, it matters to the offspring because literally the offspring is dealing with the effects of maternal stress in a different stress hormone environment, and this can potentially drive different kinds of responses on the part of the fetus. So, with all of this focus on maternal behavior and inuterant effects, I started to wonder about how much of what we had seen in offspring reflected maternal influences, and, I mean, what could fathers really actually contribute to this? Our studies had always enrolled offspring with two Holocaust survivor parents, so we couldn't really dissect it out, and we decided to do more studies, this time enrolling offspring with only one Holocaust survivor parent as often as we could. Now, we hypothesized that we would most likely see effects of maternal exposure or maternal PTSD, right? With very little paternal influence, but, of course, we were wrong, and this is where things started to get very, very interesting. So, what you're looking at here is a paper that we published in 2014, and you're looking at cortisol and glucocorticoid receptor data in offspring. Now, in red are either maternal PTSD alone, or the hatched line is both mother and father have PTSD, and the blue is only fathers have PTSD, and the white are the controls. So, what you can see here is that maternal PTSD gave us the results we had hypothesized and showed patterns consistent with PTSD, but the fathers didn't have no effect. They had an opposite effect, consistent with what we would observe in depression. So, there were really two different stories going on, depending on whether it was the mother, just, or the father that had PTSD, and when we looked at GR gene methylation, we saw the same story. There was lower methylation within the glucocorticoid receptor gene region in the Holocaust offspring mothers with PTSD. These were the changes we observed in PTSD, but in offspring with only a father, we had observed more methylation, and here I should mention that Holocaust offspring did not think that fathers had not impacted them. They just did so in different ways, and in this paper, published in the American Journal of Psychiatry, we also show that there are completely different psychological characteristics and profiles in offspring, depending on whether it's the mother or the father that has PTSD. It's not just biology, but of course, it's not just this one gene either. It seemed to be a general pattern, and when Nikos Daskalakis, then a postdoc in my lab, but now has his own lab at Harvard Medical School, looked at genome-wide gene expression, he saw that many differentially expressed genes are inversely associated with maternal and paternal PTSD. Same genes, directionally different. Same genes that are different from controls, that is. Directionally different. What explains this? Through what mechanism are factors affecting offspring? And why are things different? You with me? Ready for this answer? It's really good. Luckily, we didn't have to figure this out. About a year before we published the study, a really fascinating study came out, concluding that there may be an intergenerational epigenetic pathway that ran through sperm. Doctors Brian Diaz and Kerry Ressler, who were then at Emory University Medical School, repeatedly gave a male mouse a mild electric shock as it smelled a cherry blossom scent. They did this in order to condition the animal to fear the cherry blossom odor. The response was accompanied by epigenetic changes in brain and sperm. Now interestingly, the male offspring of the fear-conditioned mice demonstrated a sensitivity to the smell of cherry blossom, accompanied by epigenetic changes in brain and sperm. Now what is a sensitivity? That's the key to understanding this. OK, it's this. If it took 10 shocks to make dad afraid of the cherry blossom scent through fear conditioning, junior only needed one or two. Junior wasn't born being afraid of the scent of cherry blossoms. Just maybe knowing on, quote unquote, on a cellular level, that adversity might be linked to them. Junior would learn really fast, if cherry blossoms were dangerous, faster than dad. Now these effects were past two generations. Less than the grandfather mouse learned that the cherry blossom scent means danger was transmitted to its son and grandson if they confronted the same stimulus. And this is when the big conversations among scientists and the public started about transmitting memory through the DNA. And it wasn't surprising. I mean, the science was pretty compelling. But how does this work exactly? Sperm, really? Like, what could be going on? OK, it made a lot of sense in concept for there to be an epigenetic pathway through sperm. I showed you before that epigenetic marks survive normal cell division, which is called mitosis. But you know there's another kind of cell division, meiosis. And epigenetic marks can survive that too. Meiosis is a type of cell division that produces reproductive cells, gametes. The marks would be expected to survive in at least half the sex cells. And if the marks are on imprinted genes, they may also survive the process through which epigenetic marks are generally erased and sometimes re-established after fertilization. And if epigenetic information could be transmitted through sperm, well, couldn't it also be transmitted through oocytes, which develop into eggs? So we began to wonder whether this might explain some of the maternal effects in Holocaust offspring. Because after all, the pregnancy thing I showed you was kind of neat. But Holocaust survivors had been exposed to their trauma well before conception and pregnancy of the offspring. Furthermore, there's something else. Meiosis in females begins in fetal development. Meiosis actually occurs at different times for males and females. Females are born with all of their primary oocytes. And they're arrested in prophase one until puberty. At this stage, the oocytes are susceptible to epigenetic programming. Now in males, meiosis begins at puberty and continues throughout adult life. So childhood exposures might have very different epigenetic consequences for intergenerational trauma in girls than boys. Now of course, there was no way for us, so many decades later, to be able to confirm any of this stuff that was happening in our particular findings. But we did think it was worth looking to see if the same epigenetic marks would be present in survivors and their own children because we hadn't actually done that yet. That was a lot. You there? Yeah, good. All right. We had collected blood for DNA from families as we enrolled them. Not a lot of blood. We had a precious sample now of about 40 families of parents and at least one adult offspring. So what could we measure? In an ideal world, if we had had unlimited number of samples, what we would have done is look at epigenome-wide methylation to discover new genes and new effects. This is what animal studies did. But we didn't actually have the sample size. We actually had to choose what we were going to measure. Fortunately, the year before, we had just completed the first genome-wide gene expression study in another PTSD cohort after 9-11. And we had identified 23 differentially expressed gene regions that distinguished people who developed PTSD from those who did not. And two of the 23 regions were on a gene called the FKBP5 gene. Now, FKBP5 is a gene that regulates the glucocorticoid receptor gene and importantly, its sensitivity. And we couldn't believe it. We had heard about this gene the year before because we had already known that this gene was implicated in PTSD and PTSD risk. And that's because Dr. Elizabeth Binder at the Max Planck Institute had discovered the importance of this gene in association with depression, childhood trauma, and PTSD. So we asked her to collaborate with us on the study that I opened this talk with that was published in 2015 that I'm going to discuss right now. Now, what we ended up doing was measuring six regions, especially the ones she thought were important for childhood trauma and gene-by-environment interactions across the FKBP5 gene. And I'm not gonna show you the data from all of these regions. You can ask me about it. But here's the intergenerational finding. It was restricted to one site. There was a methylation effect in the same location on a specific region of the FKBP5 gene in Holocaust survivors and their own children compared to controls. Now, the white bars are the age-appropriate Jewish controls for each sample. They're two different groups about 30 years apart in age. The intergenerational methylation effect was not genotype-dependent for this site, but yes, for the childhood trauma site. But if you look closely, and that's what I want you to do, you can see a directional difference when each Holocaust group is compared to their respective control. The methylation findings seem to be going in opposite directions. And we didn't really know if this was important. But despite this, the methylation levels were highly correlated between parents and offspring. And that seemed to suggest that something may have been transmitted, and it was particularly true for the Holocaust parents and children. It's a very strong correlation. And we couldn't really figure out how to account for this correlation. Now, we never said anything about memories as the lay press reported, but since the year before the animal studies had provided us that mechanism through sperm, it was natural that people kind of assumed our data were the human counterpart to the animal studies. But what we showed was a correlation between an epigenetic alteration in parents and children on the same region of a stress gene. We hadn't even yet linked the epigenetic change to the behavioral phenotype associated with intergenerational trauma as we did with the glucocorticoid receptor methylation. And that's what we knew we had to do in the replication study. Now, it wasn't wrong for anyone to hypothesize that the results could be indicative of some kind of transmission through gametes, but we wouldn't be able to demonstrate this, certainly not in a cross-sectional retrospective human study, nobody can do that. But what we could do is see if we could replicate the finding and identify the phenotypic correlation with FKB methylation, and that's why we undertook this replication. And this was headed by Dr. Linda Beer, who's sitting right there, Linda, wave. This time, we could only get holocaust offspring, and we published these findings in 2020. Now, here you can see the replication sample consisted of 156 people, so we now had a total sample of 187 offspring and controls. And we could ask some questions about the data. You see that we replicated the idea, the finding that FKBP5 methylation was lower compared to a new comparison group. But now we had a big enough sample so that we could see what the correlates of the FKBP5 methylation were. And so we looked at variables like maternal and paternal exposure and maternal and paternal PTSD and childhood trauma of the offspring, offspring diagnoses, medications, genetics, all that stuff. And what we found was that FKBP5 methylation associated with maternal trauma exposure in childhood. The effect was independent of whether the mother had PTSD. It was the age of the mother at the time of the trauma that mattered here. And the effect was particularly evident in offspring of mothers who had first experienced the holocaust before puberty. And this made us wonder whether the trauma might have affected the mother's eggs decades before her children was conceived when she herself was a child. Now here's something really interesting though. In this case, the offspring with lower FKBP5 methylation were actually less likely to have lifetime anxiety disorders. So in the purple hatched bars are the prevalence of anxiety disorders and in the light lilac bars that's not having anxiety disorders. And what you can see here is that there was something that really this group had even less lifetime anxiety disorders than controls or people that, yes, in the no exposure group. And so when we thought about this more, we realized that maybe there was something important after all about the directionally different methylation levels in offspring and survivors compared to their respective controls. And the very simplest conclusion to draw here is that maybe there is also something protective to the offspring that occurs when mothers are exposed to trauma in childhood. And I will tell you that that is quite a leap to take for just one study. But then we realized that we'd seen it before. That is to say, we had seen an effect in Holocaust offspring that was associated with maternal age of exposure in the opposite direction of what we observed in Holocaust survivors and that too was associated with perhaps a positive adaptation. Can you bear one more study on offspring? Yeah, okay, you're good, God bless. Okay. All right, also more Dr. Buehrer. What you're looking at here are findings of offspring 11-beta-HSD2. Remember it? Was that placental enzyme that we talked about earlier? Except it's an enzyme that's not only expressed in the placenta, it's expressed in the liver and the kidney, sometimes in the brain also. It was Jonathan Seckel who told us to look at this enzyme. Why? Because this enzyme had been implicated in promoting survival in a very interesting sample of women who were pregnant during the Dutch famine. And it's a long story that I'm not gonna tell you unless you ask me, but what you can see here is that the effects in Holocaust offspring were comparable to the effects that were observed in the offspring of the Dutch hunger. And the enzyme activity is elevated, but the effects were far greatest in offspring of mothers exposed to the Holocaust before puberty. But in Holocaust survivors, the enzyme activity was lower. Why? Because during starvation, enzyme levels decline in order to conserve metabolic fuel in the liver and help sodium be retained in the kidney. So Holocaust survivors faced extreme starvation in addition to the psychological trauma, but this is an instance where having more cortisol will aid your survival. In adults, the enzyme will return to their baseline eventually upon refeeding, but in children, the levels may remain low due to a phenomenon known as developmental programming. Things stick when they change in childhood, and that is exactly what we found. In survivors who were children during the Holocaust, the 11 beta-HSD2 levels remained high well into their old age. So now, take a look side by side. I kind of like the side by side thing. It's working for me with the arrows. What you can see here is that this is very reminiscent of the FKBP5 finding opposite directions, but positively correlated. What's happening? I will tell you in one word, accommodation. Suppose your mother has lower enzyme levels due to having starved in childhood, or for whatever reason. There would be too much cortisol in utero. It's not an effective placental shield potentially, and this is a problem for the fetus. Now, the mother is not necessarily being exposed in pregnancy, but her past is affecting her pregnancy. It's possible that just as the mother was able to survive trauma by means of a biologic adaptation when she was young, the offspring in utero might also be able to adapt in some situations to the biologic impact of their mother's trauma. This would explain the higher enzyme level, and what this means is really important. Offspring aren't always passive recipients of maternal trauma effects. They are adapting, and they may be displaying the results of adaptation. To me, this means that enduring stress-related genes don't make a stock. They'll fluctuate according to the offspring's needs, and this may reflect a mechanism through which offspring become better equipped to cope with some types of adversity. It might also be inconvenient to have this biology if they don't have the adversity that they have prepared themselves for having. So again, not good or bad, just circumstance that makes it so. What I wanted you to see with all of these studies is that epigenetic inheritance is not the story of how trauma results in permanent damage. It is a story of how effects of parental experiences can be passed in a way that might prepare offspring for challenges because parents encounter challenges. As circumstances change, the benefits conferred by these alterations may wane, or even result in the emergence of novel vulnerabilities. But because the survival advantage of this form of intergenerational trauma depends in large part on the environment encountered by the offspring themselves. Now, I often wonder what would happen to those mice whose dad feared the scent of cherry blossoms if they were shocked to the smell of something else, right? I think that's a good study for someone to do. But offspring can dynamically respond to parental trauma effects, showing, allowing the past to prompt better responses in the future. So essentially, intergenerational effects reflect the ability to adapt. Now, I personally think this is amazing, especially when you consider the alternative to this, which is not being able to adapt. So the fact that epigenetic changes respond to different environments is really important clinically and from the perspective of psychiatry. Several years ago, we discovered that combat veterans with PTSD who benefited from cognitive behavioral psychotherapy showed treatment-induced changes in FKBP5 methylation. And we just replicated the results of this in another sample in response to cognitive processing therapy. And this time, we did it epigenome-wide. This is so important. First of all, it means therapy matters. It means you are changing an environment. It's not a wasted effort. What you do changes biology. And this is a response to psychotherapy. It's not a pharmacologic effect. It's the idea that when you recover, too, that is transformative. Trauma can result in long-lasting change, and so can therapy. And I'm emphasizing this because I think a lot of people secretly believe that the drugs are doing the work. They're not doing all the work, that's for sure. And the mice who feared the scent of cherry blossoms, if the investigators performed fear extinction on the mice before mating, this prevented the epigenetic changes and behavioral sensitivity from being passed to the offspring. And they weren't treated with drugs either. So the fact here is that we're not stuck following trauma. We just have to work very hard on our environments and on optimizing our ancestral gifts to suit our current needs. My colleague Bessel Van Der Kolk says the body keeps the score. But I'm saying to you that fortunately that score can change. So for the last few minutes, I wanna talk a bit about resilience and move into treatment. And what I wanted you to see in this talk is that we're constantly responding to environmental challenges. And so our offspring will respond to our responses to challenge. And there are many ways that we communicate less about survival to offspring. Lessons that can be transmitted in how offspring are raised, how information is encoded in DNA. They can develop as offspring are responding to the maternal environment in utero. And I didn't even tell you about the fascinating work of Dr. Tracy Bale about how trauma and sperm can affect the placenta. There are lots of ways. That information about trauma is communicated to offspring, resulting in biologic change. Now sometimes these responses will be more adaptive, and sometimes there will be a mismatch. But I think it is important to challenge the notion that there is, whoops. No, that's not good. Yeah, that there is something called a biology of resilience versus a biology of trauma or psychopathology. Because I think this prevents us from using biologic changes as assets in our healing journey. And I'm aware that the scientific literature posits that after trauma, there's a PTSD group and a resilient group. And that group somehow escapes the fate of PTSD and to the extent that these groups biologically differ. We have a biology of PTSD and a biology of resilience. And I know this because I've contributed to that literature. Because I used to think this was right. Because I was seduced by the promise of this formulation, that if we can somehow manipulate the underlying biology, we can come up with some fixes. Whoops, having trouble here. Nope. Yeah. Sorry about that, guys. But I don't think that this leads us to the best path. And I think that we need to start really thinking more along the lines of the fact that biologic alterations in trauma, intergenerational trauma, and PTSD can be associated with both symptoms and adaptation. So that's what I'm starting to think about more. That we have to work harder to understand someone's adaptation in the context of their environment. Now, if we thought a specific biologic alteration was the cause of symptoms, then reversing that biology would be a reasonable thing to do. But what if the biologic alteration is providing information that needs to be heated? What if it's a white blood cell? I spent a lot of years thinking about how to develop treatments that would raise cortisol levels and desensitize the glucocorticoid receptor or lower catecholamines for PTSD. But at best, these offer only partial solutions. And now many people are wondering about epigenetic changes. Maybe we should try to reverse them by methylating or demethylating the DNA. And it's really the most asked question that I get when I give these talks. But an alternative is to ask, what is my physiology trying to tell me about my emotional state? To what is my body trying to adapt? For example, we know that the amygdala is overactive, sometimes underactive in PTSD. And that the medial prefrontal cortex, which normally inhibits the amygdala, is underactive. But do we believe this represents a broken neural circuit and needs to be targeted and reversed? Or does it reflect that a person is still afraid and being triggered and needs to explore that fear? And maybe after they engage in that exploration, the amygdala might not be overactive. So don't like this distinction between psychopathology and resilience. But the other thing I don't really like is the concept of resilience as bouncing back. Because I think that it also stands in our way of understanding that resilience is an adaptation. The analogy of the rubber band is often used, as if trauma can result in difficult symptoms that stretch our capacity. But healing will snap us back to where we were. And it is a very well-intentioned analogy. But we don't heal by going back, only forward. And sometimes that rubber band breaks. And so then what, is it game over for resilience? No, of course not. Broken things can be artfully reassembled. Yes, exactly. Kintsugi is this art of making a beautiful pot where the broken parts are filled with gold. And I love this analogy. It's a great metaphor for acknowledging the transformative potential of trauma. And the capacity for growth and adaptation. And just getting to a beautiful new place. Because recovering should land you in a different place, with its own exquisite beauty and knowledge. And sometimes you have to break in order to put yourself back together in a different way. And again, it's not the fact that we can transform to meet. It is the fact that we transform. That is our superpower. The biologic mechanisms for this certainly may be epigenetics, but there's a whole lot more to it than epigenetics. There's neuroplasticity and neural reorganization. And then there are psychological process that are recruited to catalyze biologic change. Not only emotional and cognitive processing, but these things might also include spirituality, acceptance, and self-compassion. So we don't wanna have this narrow view of bouncing back. And we don't wanna have this view of no psychopathology, that's resilience. Because both of those things, while they make for a scientific literature and an easy one, cuz it can be operationalized, I don't think they help much when you're dealing with somebody who is really struggling to heal. And the fact that they're in your office is actually a symbol of their resilience. So it's in this context that I wanna introduce psychedelic therapy here, because I actually think it's a promising and powerful paradigm. And as I've become interested in it, it's made me change a lot of my ideas about resilience. I've shared that with you. The purpose of psychedelic therapy is to create a state that's conducive to reflecting, so that instead of running away from painful emotions and memories, which we're all really good at doing, we can develop a curiosity about them and seek to examine the painful material, learn from it, and literally put ourselves back together in a beautiful new vase with gold. Maybe not literally, cuz it's figuratively. But in psychedelic-assisted psychotherapy, it's not only a cognitive learning. It's a deep embodied learning that has emotional, spiritual, and somatic components. And we've been studying both MDMA and psilocybin therapy for PTSD, where it's yielding really encouraging outcomes. And we've just finalized a protocol for intergenerational trauma, because we noticed that many people that are treated with psychedelic drugs report visits from their ancestors that are often very comforting, while at the same time not sparing them of painful realities. So an altered state of consciousness can open up new perspectives and a plasticity of thought. And because of all the preparation and integration that is an inherent part of the process, this really gives people an opportunity to go very deep into a process that is often really transformative for them. Now, obviously, I have to say that these treatments are in a research stage. They're not approved. You can't really go home and do them yet. But it's really one of those things that are promising advances in psychiatry that I look forward to, hopefully in the near future. And it's a very novel use of a medicine. It's not using a medicine to suppress. It's not using a medicine to reverse. It's not saying, you're broken, let me fix it. It's saying, let's see where the more is, and let's see where we can go from here. And everything that's new is old. And so the origins of psychiatry were kind of like that. And as an aside, this paper came out last year in connection with MDMA therapy versus placebo, and we were able to show that there were methylation changes in the glucocorticoid receptor. Now, we also saw this effect with psychotherapy. So because of that, I would hypothesize that the experience of therapy created a different environment for the patient and change was possible. And incidentally, MDMA therapy was also found to decrease amygdala activation, I think, for the same reason. So when you have a different psychological state, the body can recover. It isn't always that changing the biology changes the state. Both things can happen. So I have only two more slides for you, but I have to talk about, when we talk about resilience, we have to talk about the elephant in the room. And the elephant in the room is that often, it's our environments that are broken, not our biology. People sometimes come to mental health professionals not only because they're suffering today because of a wound from the past, but because there's no safe place in the here and now to get the message of safety and turn off the hypervigilance. Which for some becomes part of who they are because their safety is not guaranteed. And we do have to be nuanced about what we want to tell them that they don't need anymore. And sometimes we experience fight or flight because there's still really a threat. And it's not clear that while someone is in an active threat mode, the job is to help people distance from their distress. Maybe the task is to help people find a way through the challenge by helping them listen to what's happening to them and find solutions to make their environments more tolerable or to change their environments, if possible. Depression, anxiety, distress are not always symptoms to eradicate. I hesitate to say this, but it depends on the context. And this brings me back to Joseph, and this is where I really want to end. Joseph is now in his 60s. He spent the first 30 years or so waiting for the other shoe to drop until he received clinical treatment for a few years. He did end up getting married. He did have a son, who became a senior this year at his Ivy League alma mater. And then October 7th happened. And I've spoken to many Holocaust offspring like Joseph in the last few months, and the narrative goes something like this. I knew I didn't have maladaptive cognitions. Luckily, I never believed that we were gonna be safe. And now, I have to tell you I'm extremely triggered by what's going on. I feel paralyzed by my anxiety and distress. What can you offer? And please don't say more CBT. What does the science we have reviewed today offer? And what would you say now to all the Josephs that are gonna call you? And I don't just mean Holocaust survivors or Jewish people. A lot of people are being triggered right now, especially those who are descendants of people that have been victims of violence, racism, slavery, genocide, displacement, and war. This is a very universal talk. Even if I studied a specific population, I really want that to be pretty clear. Now, I'm gonna tell you what I would say, but my full disclosure is that I'm not a psychiatrist. And even though I'm a psychologist, I'm really a research psychologist. But still, I would wanna first understand what was actually happening to the person that has come to see me and in the context of their life to determine. Is this the past resurfacing? Or is there actually a problem in the here and now that, whoops. Sorry, that needs to be solved. Hold on. Whoops. Sorry, I'm not gonna get that to work. But still, I would tell you what I would say to people like Joseph. I would say that it's understandable that you're hypervigilant right now, that there's a threat in anti-Semitism. I think many people are feeling on edge. But because of your background, you can detect it more efficiently, and you can feel it more acutely. And on a bodily level, you know how it might end if you don't act. So maybe you just can't expect your body would function as if the threat is not real, but you can choose to interpret your sensitivity as a call to action. Like you did when we first met, and you got involved in helping Bosnian refugees, and that was actually the beginning of a healing process for him. Think about volunteering, or raising money, or awareness, or becoming part of more nuanced conversations that will help people in need, or fleeing, recruit your resources, your knowledge, your experience, your intelligence to be part of the solution. You've been here before, and you're wiser than you know, because your body has the ancestral wisdom. And most of all, you're here because your ancestors survived. And that is what I would say. And my last slide is an acknowledgment slide, so I really wanna show it, if I can figure that out, good. This is my team at the Bronx VA, and this is actually the staff at the psychedelic center that we have opened in the last few years. Because I do believe that this is the future of psychiatry, and especially for trauma survivors of all kinds. But I want to acknowledge the people that have worked on this talk, both my internal collaborators and my external collaborators. If you wanna have a chance to really review this material in more detail, then please do check out the Scientific American paper, which is on my LinkedIn page, so you could just access it there. And thank you very much for your attention. Thank you. And for people that have questions, if you're in the overflow room, I think you can only come in here to ask them, and if you're here, you can just step up to the mic. Thank you so much, so much information. My name is Bernadette Grougeon, I'm a psychiatrist in Los Angeles, and I'm here to talk to you about psychedelic therapy. Thank you so much, so much information. My name is Bernadette Grougeon, I'm a psychiatrist in Los Angeles. For 20 years, I worked a lot with refugees from many places in the world. And I remember very early in my career there, I heard of this Lakota say that you probably know. When you work with a patient, you work with the seven generations before and the seven generation after. And that was before we knew about epigenetics. And you shared that with us today. I also worked for the last ten years with a lot of autistic women without intellectual disability, like the equivalent of Asperger for women. We have a long history of trauma, which is my experience with the one I've seen. Personal trauma, because of the difficulty to interpret certain signs, a lot of sexual trauma, and family trauma. And I was really curious, because we think of hypersensitivity or anxiety of risk maybe for trauma in the future. If you have any knowledge of research, low cortisol or other in that population, where you have a double genetic sword, I would say. I was curious if there's any research there, it would be great. I don't know any other literature in that population, but I don't think that it would really be much different than what I'm telling you. Everybody has something. And I think the population that we studied would have all the genetic risks in the population like everybody else. They're the population that we studied because of, in a moment in time, they were persecuted. But that doesn't mean that they don't carry any of the other genetic risk factors for any of the other things that people have. So a lot of people always ask, well, everything you said, it applies to my specific population. Are there any studies in my specific population? So the answer is, you can generalize from this information. You don't need to create a whole entire literature, I don't think, on a narrow population that you're working with, because I think this is kind of universal, generalizable. Thank you so much. Thank you so much for this wonderful lecture. And actually, I understand that it was a horrible event, that what happened during the Holocaust and the World War. But my question is, is a trauma usually associated with anxiety, depression, and all of these consequences? Or at some times can develop like identification with the aggressor or like displacement as well? Thank you. Well, that's a good question. Yeah, there are lots of different responses to trauma. That's been a little difficult for us as a field, because we really wanna know what trauma does. And we want it to reliably do it, so that we can work with it. But you're very right. In many cases, instead of feeling very victimized, people decide, you know what, I'd rather be a hammer than a nail. And I think that trauma does promote a lot of aggression. And you see it in history, because when you see aggressors, there's usually trauma underneath. And so it becomes a really complicated problem. It's not that there's been, like Michael Meaney's rats, that we've bred for generations, aggressive people and victim people. We're all the same. It's just circumstances that can make us snap. Circumstances that can give us the luxury of being anxious and frightened versus needing to go out there and really defend ourselves. And so I think if we understand that about trauma too, then it can be the beginning of important conversations. There isn't just one response, and you can have multiple responses at different times in your life. It can all be you. So it can be you, and also being an aggressor doesn't mean you don't have anxiety and depression and those kinds of symptoms. And when you deal with combat veterans, who sometimes were also involved in perpetrating aggression, that's often what makes them most symptomatic of all. So I don't think it's binary. I think that all of these consequences live together, which is another reason why I like the psychedelic therapy approach because it really helps unpack some of these complex layers that seem like contradictions within us but that actually coexist within us and make things more complicated for us to understand. But thank you for that question. You can lift that mic, yeah. Thank you very much for your brilliant work and amazing presentation as being a son of the not Holocaust survivor but a parent who was able to run out of Holocaust just a couple of hours before and his family being killed. So I got involved in this work kind of helping people with PTSD and trauma and there is a brilliant work of Bert Hellinger. I don't know if you know about him. He's a German psychologist who has actually been doing this work and he passed away. And there are many other techniques, EMDR, of course, what can be used now, ketamine-assisted psychotherapy. So my question is how can I, in my private practice, can measure the effects of what I do? And I see fourth generation Holocaust survivors and they still have multiple clinical conditions. I mean, you've asked a really important question and I think, you know, one of the wishes for biologic tools is that it will help us, you know, it'll be a good report card for us. It'll help us understand if we're helping the patient. But I think that you know you're helping your patient when the patient makes change. Not necessarily when they feel better but when they can now live in a different way. They'll make, like for Joseph, getting married, you know, that was a barrier. So yeah, we can measure his biology, maybe, but it's not as strong as what decision have you made, what hurdle were you able to cross. Sometimes the changes are small but have a big impact and sometimes the changes are big. So I would always look for change and every now and then if you're treating someone for a long period of time, you can have that conversation like, do we think anything has changed? Because I think that it is an important thing to think about. But because of the biology is often about risk, it may not change in the way that you think or as fast as you think. And you know, so I'm a little bit more careful now about kind of recommending biomarkers of change. You know, we have definitely seen that some things do change following successful treatment, but there's also a lot of variability. So is it like a thermometer that you can precisely measure a degree? No, it's more like, relatively speaking, or a slight index of change. So for now, I think we, for this moment in time, 2024, we don't know what the future will bring. But for now, the best measure is change. Yeah. James Decker. I work for the Diné Nation through the IHS and this gentleman actually asked like part of my question, you just answered that, as far as these being markers. But I think you also spoke very eloquently about the different narratives that surround trauma and how those narratives seem to drive people's both adaption and maladaption to trauma in their own lives. Is there a specific reason that you spoke at the end about psychedelic therapy as being very strong? Do you see a specific reason that that seems to help in that narrative sense for individuals? I think when it comes to the effects of trauma, they're so complicated and layered. And, you know, for most of the time since PTSD has been a diagnosis, we've had this model of trauma that says the person with PTSD is a hundred percent victim and then there's this perpetrator and the symptoms are fear-based. When in reality, people are more complicated than that. There's a lot of shame. There's a lot of guilt. There's a lot of intergenerational stuff. There's a lot of second-guessing of oneself. There's a lot of places along the way where people really second-guess themselves. There's a lot of decision-making at the time of the trauma that's based on what happened earlier in life or what parents did or didn't do. So it just didn't feel rich enough. And then the treatment solutions that we propose are based on, you know, the trauma of that moment and the fear. Let's extinguish that fear. They don't result for enough people in this kind of transformative existential thing that you want to see when somebody comes in pain. You want to really see them get to the other side of it somehow. And, you know, the Japanese art, you know, you want to see that vase come together with the gold. And I just don't think that our current approaches in the current model of fear, the amygdala, fear extinction, you know, even maladaptive cognition, I think we hide a lot from ourselves. We don't often go down below. It's, you know, leave that stuff in the basement. Actually, when I talk to clinicians about psychedelic assistance therapy, they're kind of intrigued. And I say, oh, do you want to try it? Because we have an FDA approved protocol for clinicians and training. No, I don't. Let sleeping dogs lie. I'm not going down that basement. And you're trying to help people go down their basements. Okay, never mind. But I think it's a natural reaction. And what I like about the psychedelic approach is that it doesn't make you go down the basement. It just makes you curious about what's in it. And then if you want, you can go down. And if you say, nah, not today, that can happen too. But it makes you know that there is a basement. Know that you don't have to be afraid of that basement. It's waiting for you. And I think, like, when you talk about pharmacology, you know, that's kind of, okay, problem, I'm going to make you feel better. Let's suppress. Suppress the symptom. You know, reverse the symptom. And, I mean, obviously these are powerful drugs and they do those things. I mean, people do feel better when they take medicine. But when you don't feel good for a reason that has to do with your life, then you might need more. If you have a depression because of a biologic dysregulation, fixing that biologic dysregulation may be great. But I've been working with trauma survivors for, you know, since the beginning. And they just don't have that luxury. And it's complicated. And no matter what happens to someone, you'd be surprised how many ways people find to feel like it's their fault or that they did something wrong. It's like crazy. But it's part of what it is. And so ignoring it or just saying it's a maladaptive cognition, it's not enough. It's not engaging enough of the fact that the person might, first of all, might have actually done something that they are deeply ashamed of and doesn't want it to be dismissed or pacified. They actually want to explore what was that. Because if they don't, then they live in fear that they're going to hurt people that they love because they know they have this, like, monster in them that they think of. And this just takes all the sting out. So I like it. And so if I like it, I'm going to spend my time studying it and making, trying to make it available. Because I've been around for a while and I've liked other things before, not nearly as much, and not seen the kind of outcomes that we're seeing now. Personal choice. Thank you so much. For a number of years, I've been following the American Psychological Association's reports, the stress in America. You've probably seen those. And the levels that they're reporting today are like the highest I've ever seen. They're off the charts. And so, you know, I'm wondering if you could just comment on, you know, what does that mean for our future? Taking your research and kind of combining that with these incredible high levels and in really in the younger people is where it's like showing up. Half of the people are saying they're so overwhelmed they can't even function in life. Thank you for that question. I try to emphasize the environment a lot in this talk, way more than I usually have. Because what's happening in the world, it's not just a mental health problem and it's not just for mental health providers to solve. Society needs to create a kind of society that doesn't leave everybody stressed out of their minds and unable to kind of have any kind of a dialogue or tolerance of something that is different from what they think or feel. I'm not even sure how we got here, to be honest. I mean, I guess I could do, I guess other people are doing these analyses all the time. But at some point it doesn't matter how we got here, it just matters that we clean it up. And it's not only a mental health problem, although mental health providers can strategically be part of a solution. So yes, it doesn't end well when people are functioning in a way of being stressed out of their minds. And I agree with you and I'm very, very concerned about it. So again, how do we kind of dial back some of the stuff that has led people to feel the way they feel? I don't really have all the answers to that or maybe even any, but I think that it's the kind of conversations that we need to start having when we come together as mental health professionals. We have to leave the unit of the individual patient and really start to figure out how we heal our societies and how we make this a better, more comforting and comfortable place for people so that they won't need to be operating in full fight-or-flight mode all the time. Because that's what's happening. Thanks for your talk. It's not easy to keep people listening and be clear for a solid hour, so kudos to you. I have a question about mourning and the role of mourning in this, and it goes back to the 2015 annual meeting when I heard my first talk on epigenetics given by a Professor Ziff from McGill, and he was talking about translational research and models that involve rhesus macaque monkeys who were traumatized by separation from their mothers and there was massive methylation of DNA throughout their bodies, and he was talking about his search for a drug that would lead to demethylation, and he made a sort of a throwaway commentary, and I never got the reference for it, and I don't know whether you know anything about this. He said, you know, what did lead to demethylation in these monkeys was to put them in periods of quiet reflection in their cages, cued by the scent of the lost mother, and that sounded a lot to me like mourning, and it reminded me of what one of my psychoanalytic supervisors had taught me, and beginning in my training, you know, it's wrong, but it's very useful that all psychopathology is loss, all psychotherapy is mourning. So I didn't know if you had a perspective on the role of mourning in this or whether it's just orthogonal to what you're studying. Thank you for that. Yeah, I often use the metaphor that trauma work is like sitting Shiva for your former self, because that person's just gone, but there could be a different person, and you do have to mourn kind of the loss of innocence, or you have to mourn something. I don't know if I would say all of psychopsychiatry is like that, but I think a lot of it, and certainly with trauma work, there is a part of it, a part of saying goodbye to something that used to be that isn't, and I think it's hard when, you know, as people age and the world changes very rapidly, and you kind of like a lot of the things, and they're not there anymore, and things change, and you don't know what's really happening, but you're mourning. You're mourning something that was. So, you know, I take what you say. I think it's very valid, and what you don't want to do is, you know, Shiva is seven days, and I think that the art of this is really to keep it in a container. Go wild during the time that you've allotted for it, and then, you know, you get up from Shiva, and then you have another 30 days, but then you have a year, and then okay, and you just visit it once a year, and so you have to be able to change the state of mourning also, but yes, it can certainly start with mourning. And it may well be that psychedelics, in some way, open up a kind of a blocked mourning that is what keeps people frozen, but that's... Yeah, yeah. I mean, it opens up, so whatever is in there, you can look at, and if it's the need to mourn, you can go do it. Thank you. Thank you so much for your talk. Thank you for bringing up the topic of intergenerational trauma. I am a psychiatrist that's been practicing about 17 years now, so mostly outpatient setting, and I've worked with a lot of trauma patients, people suffering from PTSD, anxiety, and so on and so forth. So my question is to you, in terms of other modalities, in terms of, you know, dynamic psychotherapies, in terms of EMDR, in terms of hypnosis or meditation, yoga, prayer, all of these modalities I've seen has been useful in the practice of working with people to help them calm their emotional states and to become reflective, meditative, and to see more. So I'm curious as to what you've seen with these other modalities, and curious as to how your mind psychedelics compares to those, because I've seen those help people reach altered states of consciousness as well. Yes, I think, thank you for that. That's that's a really important point. You don't need a psychedelic to achieve kind of an altered state of consciousness. It can be done with breath work. It can be done, I think, I think what you're really talking about is engaging your body, engaging your spirit, and engaging more than just your cognitive self. And I think that that's very, very important. And since we can't use psychedelics yet, except in research right now, these are great things. And you might have to try different things for different people, because something that, you know, everyone can figure out how to meditate or breathe. But they might be able to control their breath in yoga, right, while they're moving. And then it achieves very much the same thing. So yeah, I think that, I think those things are great. I don't, there's not a lot of research on them. That doesn't mean they're not good. It just means that some things are harder to study. And I think what I'm hearing from you is you're fighting really hard to help your patient any way you can. And I think that is wonderful. And that's the spirit, to not just be locked into traditional things, but just try to find them more, because they need them more. Thank you for that, because I've seen, like, even in the moment, breath work and pacing people, and just helping them through that panic attack, helping them through that moment. It builds rapport, and it leads to a better therapeutic alliance. And that then leads to other avenues. So, absolutely. Thank you. Thank you. Hello. Slightly different direction. Do we know if there are epigenetic changes for positive things that happen to humans? That's one question. And a related question is, do we know if epigenetic changes happen in all different other receptor systems, or, you know, neurocircuitry systems, you know, endocannabinoid systems, or is it only basically trauma that causes epigenetic changes? Thank you for your question. Epigenetics is the study of how genes are regulated. So, I imagine they're regulated under all sorts of circumstances, be they adverse or be they non-adverse. You saw epigenetic changes in association with positive outcomes in psychotherapy. What you need to understand is that epigenetics is happening all the time on the relevant genes. Sometimes it's from a genetic program, and sometimes there's an environmental influence. But these things don't happen randomly. There's a precision around what genes, what enzymes, what things are present. So, I would imagine that this is just a basic mechanism of life, and that's how I would understand it. But it would be kind of cool if people studied epigenetic changes following extremely positive events. So, I think that would be very nice. Thank you, everybody. You've been great. Thank you.

intergenerational trauma

epigenetics

resilience

biological pathways

DNA encoding

cortisol levels

glucocorticoid receptors

PTSD

Holocaust survivors

epigenetic changes

psychotherapy

psychedelic-assisted therapy

mental health