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Speaker A: Welcome to the Huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Doctor Karen Parker. Doctor Karen Parker directs the Social Neurosciences research program at the Stanford University School of Medicine. The goal of her laboratory's research is to understand the biological basis of social functioning at any every stage of the lifespan. So this includes the bonds that form between infant and parent or parents, as well as the bonds that occur between children as they grow up, which of course form the template for social functioning when we become adults. Doctor Parker's research is heavily focused on autism and indeed on all forms of autism spectrum disorders. Today, we discuss autism. We talk about the prominent theories and current understanding of the biological basis for autism, as well as what still remains mysterious and unresolved about the causes of autism. You may have heard that the incidence, or perhaps just the diagnosis of autism has dramatically increased in the last ten to 15 years, and today we discuss why it is in fact that the incidence, not just the diagnosis, but the incidence of autism, has so dramatically increased. And perhaps most excitingly, Doctor Parker shares with us brand new research findings from her laboratory that point to a new understanding of what causes autism, as well as a novel treatment for autism. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is element. Element is an electrolyte drink with everything you need and nothing you don't. That means plenty of salt, magnesium, and potassium, the so called electrolytes, and no sugar. Now salt, magnesium, and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electrolytes need to be present in the proper ratios. And we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance. Element contains a science backed electrolyte ratio of 1000 milligrams. That's 1 gram of sodium, 200 milligrams of potassium, and 60 milligrams of magnesium. I typically drink element first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes. And while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot, if you'd like to try element, you can go to drinkelement. That's lmnt.com huberman to claim a free element sample pack with your purchase. Again, that's drinkelementlmnt.com hubermandhe. Today's episode is also brought to us by waking up. Waking up is a meditation app that includes hundreds of meditation programs, mindfulness trainings, yoga Nidra sessions, and NSDR non sleep deep rest protocols. I started using the waking up app a few years ago because even though I've been doing regular meditation since my teens and I started doing yoga Nidra about a decade ago, my dad mentioned to me that he had found an app turned out to be the waking up app, which could teach you meditations of different durations and that had a lot of different types of meditations to place the brain and body into different states and that he liked it very much. So I gave the waking up app a try and I too found it to be extremely useful because sometimes I only have a few minutes to meditate, other times I have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain and body into lots of different kinds of states, depending on which meditation I do. I also love that the waking up app has lots of different types of yoga Nidra sessions. For those of you who don't know, yoga Nidra is a process of lying very still but keeping an active mind. It's very different than most meditations, and there's excellent scientific data to show that yoga Nidra and something similar to it called non sleep deep rest, or NSDR, can greatly restore levels of cognitive and physical energy, even with just a short ten minute session. If you'd like to try the waking up app, you can go to wakingup.com huberman and access a free 30 day trial. Again, that's Wakingupdaily to access a free 30 day trial. And now for my discussion with Doctor Karen Parker. Doctor Karen Parker, welcome.

Speaker B: Thank you. It's great to be here.

Speaker A: This is going to be perhaps one of the longer conversations that we've been able to have over the years, in part because whenever I see you on campus, we're headed in our respective directions. But I'm very excited because the topic of autism is one that is on a lot of people's minds. And I think the first question that always comes up, it seems, is whether or not the frequency of autism is indeed increasing, or whether or not the field of medicine is getting better at detecting what was always there over time. Do we have any clear answers to that?

Speaker B: Well, I think it's a multifactorial answer, so we're getting better at detecting autism. In the past, we were diagnosing kids at nine or ten years of age. Clinicians are able to reliably diagnose kids at two to three years of age. Right. So there's more people. There are, pediatricians have autism screeners now. So when you bring in your baby and over the first couple years of life, you're filling out screeners that are looking for autism symptoms. Right. So there's just a lot more awareness around autism. But the rates have increased to now one in 36 us children have a diagnosis of autism, which is over two years ago it was one in 45.

Speaker A: One in 36. Wow. I feel like it was just yesterday when it was one in 80. But is one in 36 the average across boys and girls? Does it skew differently if you look at just male births versus female births?

Speaker B: Yeah, that's a great question. So autism is male biased and prevalence. So you have, and again, the studies vary. I mean, it's worth noting that autism is a highly clinically heterogeneous disorder, which means that if you've met one kid with autism, you've met one kid with autism. Right. So we have to bear that in mind as we have this conversation. But, you know, different studies show that about, for every one girl, there's three to four boys that are impacted by autism. So there's, you know, differences in the prevalence rate and also there's different monitoring sites. So the way in the US that these data are generated is the CDC has eleven monitoring sites across the country. And so they, they follow children and then that's where we, that's where the prevalence rates come from and they release new prevalence rates every few years.

Speaker A: So if physicians are able to detect autism early, say, in a two year old or a three year old, to imagine that they're working off of tests that don't rely heavily on language, because even though you can get some verbose two and three year olds, most two and three year olds don't have a very extensive vocabulary. And I'm guessing that they're also relying on things like visual gaze, among other things. We've already made clear that this is not a discussion to allow people to diagnose themselves or others. But with that said, what are some of the diagnostic tools that people use? Is it language? Is it vision? Does it present as abnormal auditory processing? Maybe you could give us a sampling.

Speaker B: So autism is a behavioral diagnosis, unlike other areas of medicine where you might be able to take a blood test or there's other sort of tools, it's all a behavioral diagnosis by an expert. So usually a psychiatrist or a psychologist, they look for two core features. So this is based on the DSM five. And the two core features are pervasive social interaction challenges and the presence of restricted repetitive behavior. But there are a lot of people with autism who have anxiety. There are a lot of people with sensory challenges. There are a lot of people with seizure disorders, sleep disorders. So again, it's each person with autism has this sort of unique collection of traits and, you know, that's how they get diagnosed.

Speaker A: We're going to talk a lot today about interventions, but how early are some of the behavioral interventions, and I should just say any interventions introduced nowadays, if someone brings their child to the pediatrician and they take one of these tests and that child is deemed as having autism, will the one year old or the two year old immediately go into behavioral interventions?

Speaker B: Well, so usually you need to have the diagnosis of autism, and then there are behavioral interventions or a variety of different ones that are used. There are some studies where, because autism is highly heritable, you can have one child with autism, and then if you have subsequent children, you're at an increased risk of having subsequent children with autism. And these are called baby sibling studies. So what you're doing is enriching the population of infants that you follow prospectively who are more likely to receive an autism diagnosis. And there are studies where some of those children are enrolled in behavioral studies even when they're quote unquote at risk.

Speaker A: I've heard before that parents in which one or typically both parents are, say, of the engineering, mathy physics, quote unquote hard science type are more likely to have autistic children. Is that true? I mean, did that bear out in the data? If you look at profession or I or undergraduate major, does any of that correlate with the probability of having an autistic child?

Speaker B: Yeah. Well, what I can say is that there's been some studies. So what we know is that autistic traits are continuously distributed across the general population. And there was a study and there's a couple different instruments that are used to be able to measure these autistic traits. So there's something called the social responsiveness scale. And then that's a us based instrument. And there's an autism quotient that's a similar measure that was designed in England. And what we know from work with the AQ is that individuals that are in intense STEM fields, like engineering, physics, and math, have a greater burden of autistic traits, even if they don't have an autism diagnosis.

Speaker A: Okay, so that leads me to wonder whether or not this whole business of a spectrum is actually multiple spectrims. Is it spectrums or spectri? Someone will put it in the comments on YouTube. We know that for sure. Please let me know. I would like to know what is the plural of spectrum spectrums? Because when we hear the word spectrum, we think, okay, there's a spectrum of severity. In fact, I have some experience with severe autism, not in my family, but where I went to undergraduate university, UC Santa Barbara. Down the way from that school was the Devereaux school, which was a school which has been there for a long time, that parents would send their kids if they were, quote unquote, severely autistic. It was actually where Dustin Hoffman went to study for his role in Rain man. And the kids, who were really delightful, they used to come into town every once in a while to the coffee shop where I'd study, and they would also continue on from there to Kmart, which is why the Dustin Hoffman character would say, gotta go to Kmart. Gotta go to. He would do that repetition, right, that Kmart was down the road from our, you know, our college housing and the Devereux school. Those kids were literally in a away from home facility full time. And I spoke to some of the parents at one point, and they were at that facility, meaning the parents had sent their children away to live there full time. Of course they'd get visits, and they'd get visits home because they were, I suppose we could say, at the far end of some spectrum that made it, at least to the parents idea, impossible for them to be at home. Okay. Now, at the other end of the spectrum, if one is just simply thinking in terms of severity, I know people who have self identified as autistic. That's how they've referred to it. So I feel comfortable saying that. They've said, I am autistic, and they seem pretty high functioning, meaning they have driver's licenses, drive cars, are healthy relationships, and manage life, apparently. Well, they have some traits that, yes, I would agree, are a little bit different. Right. So this is where we get into neurodivergence. But I guess the point is, should we think about autism as on a spectrum? Or given the fact that there are these kind of collections of different traits, could there be a spectrum of severity, also a spectrum of more stereotype behaviors, another spectrum that intersects with that, that has to do with obsession with a particular topic. You could imagine that there are 50 or 60 different spectri or spectrums. I still don't know which one to say. And that when we talk about the spectrum, we're really talking about something that's in multiple dimensions and not just one line that goes from severe to mild. Does that make sense?

Speaker B: Yeah, I mean, I think this is where understanding the biological basis of behavior would then allow us to be able to say, here's these different dimensions, but not understanding the biology you're left with. Okay, are we lumpers or splitters? How do we think about this? Because autism is highly heritable. So there's about 40% to 80% of autism is genetic. Right? So these vary wildly. Right. But the common thinking is that the majority, about 50% of autism is associated with common genetic variants. And so the way that we've always thought about this is that there is this. Autism is largely an inherited polygenic condition. But what I mean by that is that you have a lot of common variants that are additive. And so if you think about this collection of common genetic variants that underlie the spectrum, so if you have less of a dosing of some of these common variants, you might see somebody who's a lot more, who's higher functioning, like you said. And if you end up with one of these single gene, highly penetrant disorders, you might see severe intellectual disability and sort of lower functioning on the other end of the spectrum. But I think that there is a lot that we don't know. And what you're bringing up, I think, underlines sort of an issue with autism, which is common for many brain disorders, which is like, if you don't understand the underlying biological basis, it also gets very difficult to diagnose and treat. Right. And that's where we are with a lot of different psychiatric and neurodevelopmental disorders to date.

Speaker A: Has there been any specific neural network that we can point to and say, ah, that's the neural network that seems to be different in people who are on the autism spectrum? I saw a study published recently that seemed to point to the idea that the genes that are altered in autism at least include a large number of genes that are altered or the proteins that are the consequence of those genes are altered and exist at the synapse, at the connections between neurons. And I'm asking it that way because some years ago, I was at a talk on autism at Stanford, and someone raised their hand and says, do we even know that autism is a brain issue? Couldn't it be an issue of the immune system or the cardiovascular system, which at the time seemed like, okay, gosh, of course. But wait, then you stop and you think, that's a really good question. How do we know? It's a challenge of the brain, right.

Speaker B: I think that's a great question. Right. And there may be people talk about autism, right? And so when you think about where the major player is, you know, we're at the infancy of thinking about this, right? And so maybe for some people it's more of a brain based disorder. Maybe for some people it's, you know, the connection with the gut and the brain. Right. I think what's also really tricky, right. So one thing that you have to ask is, what are the barriers to progress in understanding autism? The way I think about this is that let's just take for a moment that this is a brain disorder. How do you study it in people? It's very difficult to get access to either cerebrospinal fluid, which is a fluid that bathes the brain, brain tissue biopsies. It's very hard to get people, especially children, that are really impacted into a brain scanner because they can't sit still. They may have sensory issues, go into a scanner. So a lot of the tools that neuroscientists or psychiatrists have to think about looking at the brain are limited. Right. And then the other part is, how do you model? So the other way we might think about getting access or thinking about model systems, what we need to do is think about the control animals, and we need to make sure that the species that we're modeling them in has features of control humans, if you will. So we need to have complex cognitive abilities. We need to have complex social skills. We need to have an organism that has vision as its primary sensory modality, potentially sleep consolidating. So we need to think about all of those. And the tricky part, I think, until fairly recently, was that we were doing all of this work in mouse models, and the control mice just fundamentally lack many of the characteristics that are needed to mice model autism with fidelity. Right. And I think that's when we look at drug development pipelines, about 50% of preclinical failures. So that would be something that's tested in an animal that works and then fails in a human clinical drug trial, 50% of those failures can be attributed to poorly selected animal models. And so I think part of where we will be getting traction is picking developing sophisticated models as a sort of point of entry into being able to understand some of these things that are really difficult to study in people.

Speaker A: Yeah, it's such a key point. And for those that have not heard of preclinical models, preclinical models are non human models. So it could be mouse, could be non human primate, could be flies or worms, for that matter. But we're going to talk a lot about non human primate preclinical models and the work that you've been doing, and of course, also the work that you've been doing in humans. The other animal.

Speaker B: The other primate.

Speaker A: The other primate, right, exactly. Remind people that we're primates, old world primates. So thank you for doing that. So you've been talking about the genetic influences on autism, and of course, genes in the environment interact, right? It's never nature or nurture, it's always an interaction. And that isn't just about the epigenome. It's also just about the fact that nature impacts the genome, and our genome impacts the way that we interact with the environment, et cetera. So what is the role of the environment in autism? Both the frequency and the presentation of autism.

Speaker B: Right. So, I mean, there are, again, in lots of different epidemiological studies, so advanced parental age, prematurity, severe prematurity is a risk factor for autism, maternal illness during pregnancy. So there's a bunch of different things that have been associated with an increased.

Speaker A: Risk for autism in terms of environmental influences and how they can intersect with biology. One of the things that I was really struck by in the early two thousands that, at least by my read of the literature, hasn't really gone anywhere, was this idea that was proposed by Pashko Rakesh, who used to run the neurobiology department at Yale, expert in brain neuroanatomy and non human primates, and in humans embryology, really a luminary of our field. And he had a series of papers exploring how the migration of neurons during early development. You and I both know, but most people out there probably don't know because we haven't covered this in the podcast. It's not typical dinner table conversation. When a human embryo is developing, the neurons are born at one location and they migrate out some distance to their final resting place, where then they grow out their connections and connect with one another. That process of neuronal migration is oh so critical for the eventual wiring of the brain. And Rakesh had this idea that perhaps, and I really want to emphasize perhaps, that the more frequent incidence of autism might be correlated with the increase in early prenatal ultrasound. And he had these papers published in a number of really high profile journals, including proceedings of National Academy and Science and elsewhere, showing that in a mouse model, if you do ultrasound, with each successive ultrasound, you got more migration errors. So to me, Washington, an interesting example of the environment frequency of ultrasound and cell migration having some sort of interaction, but it seemed like it never went anywhere. It never got tacked to, okay, you should keep in mind the number of ultrasounds that you're getting for your child. And of course, ultrasounds are critical for pregnant women to get because they can stave off a number of developmental issues and they're super important. But we've heard about ultrasound within the scientific literature, and then occasionally we'll hear other theories about, okay, it's having two parents who are both engineers, and then we'll hear, oh, you know, it's toxicity in the food environment. We've heard hypotheses about vaccines or the adjuvants that the vaccines are contained. And in that large cloud of theories, has anything really emerged from them? It's like, okay, there really seems to be at least one major risk factor, environmental risk factor, because I feel like all those theories come up, get some popular press, a bunch of papers are published, sometimes those papers are retracted, like in the case of the vaccines, and then the theory kind of dies. So is there any specific environmental influence on autism that we can say? Yes, there really seems to be something there.

Speaker B: Yeah. I mean, it's a really spectacularly good question. I think the tricky part about it is that every single person that comes into a trial has a different genetic background. Right. And so until we can have these a priori stratified trials where you could, then, you know, as a good scientist, you would only manipulate maybe one, two variables at a time. Right. But when you're doing these large epidemiological studies, because you can't, it's very difficult to do experimental studies. Right. Especially with developing children. I think that's an incredibly difficult study to do. Right. So there's been a. An interest in this field of, there's these neurogenetic syndromes that have high penetrance for autism, which basically means that you could have a disorder or another genetic condition. Let's say it doesn't have to be a single gene, but that a lot of those kids tend to also get an autism diagnosis. And so there's been work in like. So, for instance, fragile x is a good example where, because autism is so diverse in terms of clinical presentation that, let's say you have a medication that could work for a handful of kids in the trial, you may not be statistically powered to see it. Right. So the way I think about the autism world is there's so little we don't know. So think about being in a dark room, and you have a flashlight, and you only see where you shine the light. Right. And so if you think about a very heterogeneous, genetically heterogeneous study, it's going to be very difficult to tease out these pieces because an environmental risk factor might be a driver for one kid, but not another. Right. And so I think what we need to do is to have these genetically defined subgroups of individuals and then be able to test the gene by environment interactions, or in this genetically defined group of individuals, can we test this certain medication to see if it's beneficial for this subgroup of children?

Speaker A: Got it. So you mentioned fragile x, which we know presents with autism like symptoms in some cases. And then I think of another disease like Timothy syndrome, a mutation in an l type calcium channel, which, for those of you that don't know what these l type calcium channels are, they're not just important for the function of neurons in the brain, they're really important for the function of neurons and other tissues, including heart tissue. Kids with Timothy syndrome have cardiac issues, and they have autism. So I think it's important for us to kind of explore this a bit, because in most people's minds, kids with autism have autism, and occasionally they'll have other issues, gut issues or heart issues or musculoskeletal issues. But we often think that that's the consequence of the autism. But oftentimes they have multiple things going on, and the autism actually could be secondary or independent of. Of the other thing that's going on. So this is what leads me back to this idea of a spectrum. Is it possible that what we call autism is actually 50 different disorders or 50 different conditions, depending on what one wants to call them? I mean, what is autism really? I mean, what does it really center around? And I think here, maybe it's useful. Do we go to the diagnostic criteria? Like, how do we decide if a child has autism, if they also have a bunch of other things that are challenging them?

Speaker B: I mean, I think that that's the $64,000 question. Right. And again, in other areas of medicine. So if you think about, let's think about cancer biology, right? Like decades ago, somebody would come in with cancer and you would hit them with radiation, chemotherapy, and that was the best that we could do, right? But with the invention of a lot of molecular tools, you can remove a tumor and you can do molecular profiling and even have personalized medications made right to attack that tumor. And so what's really tricky, when you have a behavioral diagnosis that's not biologically defined, you see a lot of heterogeneity. So it's incredibly difficult, I think, to answer this question because we don't know how many kinds of autism there are, right? Like there will be people who say if you have a disorder like fragile X or Potter Willie syndrome or Timothy syndrome or a variety of these other conditions, there will be people, I've heard clinicians say, well, that's not really autism, right? That's a piece of fragile x, right? But if it's a behavioral diagnosis and they meet behavioral criteria, it becomes this weird circular argument, right? So, like, until we really understand what autism is, I think that it's going to be very tricky to start, you know, sub defining different aspects of the condition.

Speaker A: I'd like to take a quick break and acknowledge one of our sponsors, athletic greens. Athletic greens, now called ag one, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking athletic greens, and the reason I still take athletic greens once or usually twice a day is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system and basically all the biological systems of our body to strongly impact our immediate and long term health. And those probiotics and athletic greens are optimal and vital for microbiotic health. In addition, athletic greens contains a number of adaptogens, vitamins and minerals that make sure that all of my foundational nutrition needs are met. And it tastes great. If you'd like to try athletic greens, you can go to athleticgreens.com huberman and they'll give you five free travel packs that make it really easy to mix up athletic greens while you're on the road, in the car, on the plane, etcetera. And they'll give you a year's supply of vitamin d. Three, k, two again, that's athleticgreens.com huberman to get the five free travel packs and the year's supply of vitamin d. Three k two. Well this is probably a good time for us to think about the work that you've done in terms of trying to tack the biology of social communication and behavior. Those things interact not just language but also behavior to autism in humans using non human primate models. And then of course to also discuss some of the work that you've been doing in humans. And we can't have that discussion without first having a discussion about two neuropeptides that I think most people have heard of at least one of them. And I think there's a lot of misunderstanding about. But you're going to clarify that for us which are oxytocin and vasopressin. So before we dive into the important work that you've been doing on vasopressin in particular but also oxytocin and autism, what are oxytocin and vasopressin really?

Speaker B: Okay so they're these small little peptides. They're nine amino acids long. So very tiny they only differ by two amino acids. And they're these ancient peptides that are hundreds of millions of years old. And in almost any species studied, whether it's the current version you might have vasatocin or other mesotocin which are sort of precursor forms in other species. But they're highly evolutionarily conserved and they're involved in social behavior in pretty much any. It could be egg laying, it could be, you know, but reproduction in social behavior across the phylogenetic taxes.

Speaker A: So house cats make vasopressin and oxytocin. Humans obviously make vasopressin and oxytocin and pretty much every other species that has to interact with and connect with other.

Speaker B: Members of its species, especially mammals. Right. So oxytocin and vasopressin are pervasive.

Speaker A: And mammalian species do the different species tend to make oxytocin and vasopressin in similar brain areas and tissues?

Speaker B: Yes, but not completely overlapping. But I think the thing that, the beautiful mystery about these and the infuriating piece of them is that because they're so structurally similar they can have similar effects and there's four receptors that they bind to. So if you think about a hormone or a neurotransmitter. So oxytocin, vasopressin them like a key and a receptor like a lock and you have to put them together to open a door open behavior. They can bind to these four receptors. So it can be very difficult to disentangle which one is acting and at which receptor and where in the brain.

Speaker A: Oh, so oxytocin, vasopressin are chemically similar.

Speaker B: Yes.

Speaker A: Interesting.

Speaker B: Yes.

Speaker A: And where would you say lies their greatest output? Divergence, which is just nerdspeak for. Is there an example of something that oxytocin does that vasopressin doesn't and vice versa?

Speaker B: Yeah. Okay. So what's really fascinating is these two neurotransmitters, or hormones, were discovered for their peripheral effects, which basically means not in their brain, but somewhere in their body. And so oxytocin's involved in uterine contractions and milk let down, and so was during lactation. So people sort of always thought of it as the female hormone, and then vasopressin, at least in the peripheral system, has been involved in urine regulate, like urinary output regulation, blood pressure. And so we only knew about their physiological roles as their sort of classic hormones for decades. And what was interesting is these, like, naming conventions are fascinating in medicine. Right? So you could name a virus after where it was first found. Right. Or it could be named after somebody who discovered disease, like Alzheimer's, for instance, is a good example. And what was interesting, oxytocin was only named once. Vasopressin was named twice. So it's either called arginine vasopressin or antidiuretic hormone. And so it had two different names. And so, as you can imagine, sometimes genes are named twice. And so somebody in cancer is studying one gene and somebody in autism is studying another, and they're not even communicating because they don't even realize that they've, at least historically, now we have all kinds of gene annotation sites, so it's less likely to happen now. But what was fascinating is these hormones were named. Oxytocin is greek for quick birth. So for decades, people only appreciated their physiological roles. But there were neuroanatomists saying, hey, so these are both made. They're made in a lot of different places, but the action sort of happens in the hypothalamus where they're made. And there were anatomists that said, wait, these sort of project back into the brain. What are these doing in the brain? And one of my favorite historical stories was I had a mentor, a colleague, who I didn't train with, but he was a real source of wisdom to me for many years. And his name's court Peterson. And he told me this wonderful story about this Duke zoologist named Peter Klopfer. And Peter was studying ungulates. So sheep and goats. And he wrote a story, a paper in 1971 called Mother Love, what turns it on. And, you know, one thing about science is I love going back and seeing where do the pearls of wisdom come from? And so he wrote this and said, you know, oxytocin is orchestrating all these events of motherhood. And there are sheep and goats in particular that have offspring that are precocious, meaning they're basically born ready within an hour. They can run with the herd, unlike our species, which is altricial, meaning we have very helpless infants. And mom needs to bond really quickly with that baby if it's going to be running around. And you only from an evolutionary perspective, you want to be investing in the baby that's yours, not somebody else's. Right? And he hypothesized that it was oxytocin that was being co released into the brain. And during milk letdown, that was what turned mother love on. And that was really the beginning of this whole field of thinking. And so that opened up thinking about oxytocin in rodent maternal care and a variety of other instances.

Speaker A: Can I just briefly interrupt you, because I find this so interesting, and I know it's interesting to everyone listening as well, because. Yes, and thank you for making it clear that oxydocin has many different roles. But this role of mother love and bonding to infant has me needing to ask whether or not the idea was that oxytocin is released in the mother when she interacts with her own baby. And that leads me to the question, is oxytocin also released in the baby in reaction to the mother? And how long is that effect lasting? Because in order to have a pervasive bond with that baby and not just some other baby, and of course, we still have visual cues and we know our baby versus another baby in most instances, there are rare exceptions, or perhaps not so rare exceptions. But leaving those aside, the mechanism that would allow for mother infant bonding, an infant mother bonding by way of oxytocin, presumably is something that is literally changing their brains, saying, you are the center of my life. And the baby, of course, is saying, well, you are my life because you are the source of life, certainly for the early part of life. And nowadays it seems that can extend well into the teens and twenties for some people. But how is oxytocin working? Is it working over the course of minutes, hours? Is there some specificity of this baby and this mom that links them in some more pervasive way? I mean, how is oxytocin doing this magic of bonding.

Speaker B: Yeah. I mean, it's very species specific. Right. So I think that. And you need to think about, like, the evolutionary history of the species. Right. So if you think about sheep or goats, the early studies that were done, are you. The passage through the vaginal canal was what, you know, so you activated oxytocin receptors that way. But if you gave an oxytocin antagonist, meaning you would give into the brain something that blocked the oxytocin receptor. So if the oxytocin is being released into the brain, but you have a pharmacological agent blocking its ability to bind to its receptors, these sheep and goats wouldn't bond to their baby, for instance.

Speaker A: So literally, the passage of the baby out of the vaginal canal triggers the oxytocin pathway, the release of oxytocin.

Speaker B: Right. And lactation does too.

Speaker A: Nature is so beautiful because if you had to pick one of to trigger the release of oxytocin, if oxytocin's role is to create bonding with offspring, that would be the event, because that's a tough one to mistake.

Speaker B: But what I will say, because I think you will, to avoid you getting attacked on Twitter or wherever you might get.

Speaker A: I'm going to get attacked anyway. If not for this discussion, then another one. But I'm tougher than I look.

Speaker B: But it's really species specific. If you think about our species and a lot of primate species, we live in these extended family groups, and that's how we evolved. And so, unlike a goat or a sheep that might live in a herd where there's a lot of non relatives, we lived in a community of relatives, right. And so we, and we do all kinds of care of extended relatives. And so you wouldn't necessarily expect in a primate species where you have this long rearing history where help from the family and biparental care, where sort of everybody sort of, of like, it takes a village to raise the baby, we readily adopt in our, in primate societies. Right. And so, you know, like, I had a c section. I mean, I'll tell you something personal. I had a c section and I had a lot of postpartum complications. And so lactation didn't work out that well for me. One of my friends would say I had massive dvts and pulmonary emboli. And so I almost died after my son was born the first time. And so I didn't have a vaginal delivery. I couldn't.

Speaker A: Vein thrombosis.

Speaker B: Yeah. And it was sort of like, welcome to motherhood. And I was in the ICU and had to get a filter put in an inferior vena cava filter to stop me from dying because I had scatter shot clots all over my lungs. And so I didn't really, you know, I didn't do a vaginal delivery. I had a c section, and I wasn't really able to lactate. And, man, I love that baby. Right? So, you know, I can give. You know, what I will say is it's really different in primates, and we don't really understand how bonding occurs. But what I will say is that bonding between a mother, you really need to think about the evolutionary selective pressures. So I was an evolutionary biologist before I found neuroscience, right? And so I really, everything I do, I think about from an evolutionary perspective. But it is. Many people go into the oxytocin vasopressin field because they have a lot of questions about social interactions, right? Like, I think if you think about it, is being social is actually one of the core characteristics of our species, right? So social interactions are rewarding from infancy. They keep us alive, as you mentioned. Right. And so I think it's not an accident that the way we think about disorder in our species is many disorders are disorders because of lack of social connectedness. Right? So it could be something like autism, wherever, where there's these pervasive social interaction impairments. It could be something like drug abuse, where a risk factor for drug abuse is feeling socially disconnected and alone. Right. Social isolation or loss of a loved one is a very strong predictor of the onset of a stress related depressive.

Speaker A: Anxiety disorder in terms of when and how oxytocin is released. You mentioned mother infant bonding, I think you said. Yes, that the infant is also releasing oxytocin. We think so. It's bi directional, we think.

Speaker B: I think most of the work has been done in mom would be. And again, this has not been really done well in primates. So we're extrapolating this information from species that have different evolutionary histories than us. Right? So it's goats, sheeps, prairie voles, mice, rats.

Speaker A: So what do we know about the role of oxytocin in humans? I mean, we know it's there. We presume, based on the animal models, that it's involved in mother infant bonding and presumably romantic partner bonding. At least you hear that a lot. It was unfortunately nicknamed the love hormone. And the reason it's unfortunate it was, is that while that might cue attention to oxytocin, and I'm a big fan of people paying attention to biological phenomena, it discards the other and many roles of oxytocin. But what can we say about oxytocin in humans, if anything, do we know that it does? So we're assuming based on the animal models that it does something. I mean, this is very different than dopamine, where there's tons of animal model data, but we know. But there brain imaging, where we know where dopamine is expressed. And do we even know where oxytocin receptors are expressed in the human brain? Presumably that information is out there recently.

Speaker B: But again, there's a lot of specificity. And I think if you're thinking about disorders, you would then have to study those specific subpopulations. Right. And you need, you know, a lot of this work has been done. So you have to think about how do we study it? Right. So the best way to study it would be to have radio tracers where you could then, which we do have for dopamine and other compounds where you would then go and see where after somebody's performed a task, do we see activation or uptake? There are some imaging studies that are usually done giving intranasal oxytocin. And then you basically ask questions about, okay, we give you oxytocin intranasally, which presumably enters the brain. We could talk about reasons why we think that. And then we have you perform on some task. Right. And so there's evidence if you give oxytocin, it diminishes the amygdala response to fearful stimuli. Right. So that it might have this sort of pro social effect. And it was actually data like that that caused people to start thinking initially about oxytocin.

Speaker A: And those were data in humans. That's right. It reminds me that there was this brief moment where oxytocin wasn't just being discussed as the love hormone, it was being discussed as the trust hormone.

Speaker B: Correct.

Speaker A: Right. Also far too simple heuristic. But again, I think it's cool that the press picks up on these things and at least tells people about what's being discovered. And we just always have to be careful to not have it lead to the assumption that that's the only role of a given hormone. So it can reduce, apparently it can reduce the output of the amygdala in some way, this brain area associated with threat detection. And so you could imagine how that would bias the person toward being more prosocial. Have there been studies exploring the role of oxytocin in making autistic children more pro social? And behind that question, I suppose, is the assumption you can verify or not that autistic children are less prosocial than other children. Is that true? Or is it that autistic kids are just maybe more pro social with the one friend they really, really like? I happen to know some kids with autism, or however you want to phrase it, and they have close friends, and they seem to really like those specific friends a lot. Like, they seem very happy when they show up at the door and like, all the hallmarks of healthy social mind. But it is true that they are uncomfortable in groups and where there's a lot of noise, a busy birthday party is overwhelming for them. But you see them playing with one or two friends, and, like, you could see all that and assume, okay, it's just kind of an introverted kid. Actually, it kind of reminds me of me. I mean, I don't have a problem with crowds, but I much prefer to be with a small group of friends or one close friend.

Speaker B: I hear you. I'm that way, too.

Speaker A: Right. So how do we think about this?

Speaker B: Okay, well, I would say the social features of autism are interesting, right? And so you might have. There was an attempt a long time ago, like 1979, there was a woman named Lorna Wing who tried to subtype the social features of autism, right? And so there could be people that are socially avoidant and really just don't want to have social interactions. There could be kids that are active but odd, which means that they have an interest in being social, but maybe they don't read social cues. Right. And they interact in ways that other kids don't understand or make. Could cause bullying. Right.

Speaker A: Sounds like junior high school.

Speaker B: Yeah, exactly. And that's often why I. Some autistic kids do better with adults. Right. Because adults know how to sort of channel discussions with somebody who might be a little socially awkward. Right. But there's different phenotypes. I mean, people having a disinterest in social interactions could be that they're highly socially anxious. Right. That making eye contact makes them anxious. You could have somebody who maybe is relatively, let's say, socially intact, if you will, but they have overwhelming sensory abnormalities that make it very difficult to interact with other people. Right. So let's just say again, that's another caveat. There have been some studies administering oxytocin to individuals with autism. And again, these are these single dose studies. So the first studies that were done were looking at single dose oxytocin in males, because some of the. And we can talk a little bit about why oxytocin versus vasopressin which vasopressin actually would have been my choice based on the animal literature, and we can talk about that. But vasoxytocin was given to males partly because it wouldn't. The idea would be that the off target effects in the peripheral nervous system, that is, milk let down uterine contractions, are not gonna happen in males. Right. And so that it was deemed that they might be safer subjects. Males are often also the go to for research studies, as you may have talked about on your podcast before, too.

Speaker A: Something that, fortunately is changing.

Speaker B: Yes.

Speaker A: Thanks to a mandate by the. By the NIH. Correct. I had to just kind of smile, raise my eyebrows a little bit at the idea that the assumption that oxytocin administered to males. Yes. One can see why it wouldn't cause milk letdown or uterine contractions. But, of course, there could be other peripheral effects of oxytocin in males, but they had to pick one, so they went with males. Okay. And there is this higher incidence of autism in males, so it's not a terrible place to start. You just would hope that they would also do the experiment on females. So they're doing this by nasal spray.

Speaker B: So, intranasal, one dose. Correct. And for reasons that I don't understand, it's 24 international units. And I think maybe somebody did the first study using it, and this is how science happens. Right. And it worked. And so then everyone uses that protocol. And so then there's been a lot of studies looking at, you know, there's one reading the mind and the eyes. So can you look at pictures of somebody's eyes and then ask, what is the emotion that they're feeling right after receiving this? Where is your eye gaze going in a picture? Right. So one of the theories is that people with autism may, at least a subset of them, lack social motivation. So maybe they're not looking in the places like eyes, where you receive a lot of social cues that are relevant to social communication. And so some of these early studies showed that a single dose of oxytocin in people that had high functioning autism, so they were verbal, like you said, they could come in for studies, and that it looked like it had some potential effectiveness. And so there became a really strong interest in the field to think about oxytocin, potentially as a therapy for autism.

Speaker A: And is oxytocin available over the counter? Does it require a prescription? I mean, you see sites that are selling it, but that doesn't mean anything these days, right? Yeah, there's gray market. There's all sorts of stuff going on. But I know people that have used oxytocin there's actually a market for. And by the way, folks, I'm not suggesting, but someone the other day told me that they've been regularly taking oxytocin ketamine nasal inhalations as part of their work with their licensed therapist on PTSD type stuff relating to, let's just call it relational trauma. So that's happening. But let's just think about oxytocin alone for the moment. Are parents of autistic kids able to buy oxytocin nasal spray?

Speaker B: No. So it would need to be written like, the prescription would need to be written by a physician, and it's not on the market. Right. So there's one thing we should say is there's only two drugs that are approved by the FDA to treat autism, and they're both antipsychotics, which they treat associated features like irritability, and they have off target effects like weight gain. And, you know, so we. We don't have any medications that are currently approved in the US or anywhere else, for that matter, to treat the core features of autism.

Speaker A: Interesting and unfortunate, and hopefully that will change in the not too distant future. Do we know that children with autism, people with autism. Cause I'm gonna just sort of assume that autism is stable over the lifespan. Like, if a child is diagnosed with autism, are they going to be an adolescent and adult with autism?

Speaker B: So I would say that in a lot of cases, autism has lifelong impact, but there are people who outgrow their diagnosis. There are people who respond well to behavioral therapy. I mean, obviously it's not the cure all for everybody. There's lots of people who go through intensive behavioral therapy and probably see minimal benefit. But, I mean, it's certainly something that occurs in childhood, for the diagnosis occurs in childhood, and for most people will then be present across the lifespan. So we could say people with autism, because each study sometimes will have adults, sometimes you'll have teenagers, sometimes you'll have kids.

Speaker A: Is it known whether or not people with autism, assuming they meet the criteria for being autistic at that moment, have lower natural circulating or active levels of oxygen? Because it's one thing for a nasal spray of oxytocin to improve social functioning, it's another to know that the effect is addressing an underlying biological deficit.

Speaker B: Yeah, it's such a great question. Okay, so we should unpack that because there's been a lot of work in this area. So the first question is, where are we measuring the oxytocin? Right. So we mentioned oxytocin has all kinds of effects in the body as well as the brain, and it's released into the blood, but it's also released directly into the brain. And there's variable evidence about, if you measure it in blood, is it a readout of the brain or not? Right. Or should you be looking at something like spinal fluid that's maybe a better biochemical proxy of the brain? Most studies. So what I will say is there were, there's been a handful of small studies where there has been some, you know, there's been some benefits, maybe no benefit, small effects. We did a study that was a small study at Stanford, and it was based on mouse genetic data. And I'll sort of walk you through what we did. So there's multiple mouse models of these neurogenetic syndromes where people have social impairment. Right. We can quibble about whether that's autism or not, but that they have social impairment. And so that there are this fragile x mouse. There's a potter Willie syndrome mouse, which is the magile two gene that gets manipulated, and then there's a catnap two mouse. And in all of those instances, when you genetically modify those mice, you see a reduction of oxytocin in the hypothalamus. And what's interesting is that in those instances where you see this genetic modification, you do see lower blood levels in these genetically defined models. What's really cool is you can give oxytocin across development in those models, and at least in the catnap two mouse, you can restore oxytocin, neuron number two equivalent of control animals, suggesting that oxytocin is doing something in these oxytocin deficient animals. These are not an oxytocin gene manipulation, but these are these syndromes where you see, as a consequence of manipulating genes for these syndromes, that oxytocin gets knocked down. Right. And so our thinking when we went into our clinical trial was, what if its blood oxytocin levels, that there were going to be a subset of individuals that just make less oxytocin?

Speaker A: Humans.

Speaker B: Humans. And that maybe those are the individuals who could, who stand to benefit the most from treatment. And so we were the first group to ask, you know, across this range of individuals who showed up, and we did in all the trials that we'll talk about today. These are done with my colleague Antonia Hardin at Stanford, who's a child psychiatrist. And we always have double blind, meaning that the investigative team is blind and that they are unaware, I should say they're unaware of treatment, and then the families and the children are unaware, and then they're randomized, meaning there was an equal chance you could get either drug or placebo. And they're controlled. Right. Okay. So we asked if we know what your pre treatment blood oxytocin level, who's gonna benefit from treatment? And we found a couple really interesting things. One was that the lower your baseline, so your pre treatment blood oxytocin level, you showed much greater benefit from the oxytocin intervention. These are children.

Speaker A: One intervention, one nasal spread.

Speaker B: This was four weeks. Sorry, I should have clarified, this is four weeks of treatment being administered oxytocin twice a day.

Speaker A: Okay.

Speaker B: And so we saw effectiveness there.

Speaker A: May I? Sorry to interrupt so much, but just male and female subjects.

Speaker B: We did. But again, because autism is male biased and prevalence, even if you make this heroic effort to over recruit, try to get more girls in. In the study, we usually try to aim for the prevalence rate because it's difficult to get girls just because there's fewer of them.

Speaker A: Got it. Okay. But boys and girls were included. They're taking oxytocin over the period of several weeks. And if they started off with lower baseline levels of oxytocin, you observed a benefit of the oxytocin treatment in those individuals. What about the individuals who had normal to high levels?

Speaker B: They didn't see much benefit. Right. And so that was a cue to me to think that there may be a subset of individuals that, you know, for whatever reason, they have lower oxytocin, and they may stand to benefit more from treatment. And none of the prior had looked at blood oxytocin levels. And so what we had thought was that, well, maybe if everybody had measured baseline blood oxytocin levels, maybe some of these, you know, maybe there would have been more positive outcomes. So. But there's a lot of controversy in this field about whether oxytocin is a treatment for autism. Right. So after we completed that trial, there was a large multisite, what's called a phase three oxytocin treatment trial that was done at, I think, five sites, and they gave oxytocin for an extended period of time, and they showed no benefit.

Speaker A: Were they looking to see who started off with low levels of oxytocin pre treatment?

Speaker B: So what was interesting about that study, and there were a lot of issues with it, was that oxytocin is something where you, if you look at it, it degrades. That's kind of what I joke about. Right? So you need to take it. When we go in, we have, like, these really intense protocols, right? So you go in and we have vacutainer tubes that are cold, and we put them on ice, and then the phlebotomist takes the blood from the child.

Speaker A: So a lot of technical gymnastics, and.

Speaker B: Then we make sure we spin it in a centrifuge cold, and then we pipe head it onto dry ice. So we have very many minimal loss of the signal. And so if you don't adhere to those rigid protocols, which is very difficult to do across multiple sites, it can be very difficult to get an accurate read of oxytocin. And so I think, for me, it's still an open question. They didn't see that blood oxytocin predicted response in that study. The data weren't provided in the paper. It was just said that they didn't. But it's still an open question to me. Like, what if there was a group of children who had low oxytocin levels and they could benefit, right? There's other people where they'll say, no, no, no, we don't think that chronic oxytocin is a good idea, that what you really should be doing is just giving it before a behavioral therapy session. Right? And so that maybe that is the way. So if you give it acutely, like in those early studies we talked about, that maybe oxytocin diminishes fear. We know that oxytocin decreases the stress axis, the hypothalamic, pituitary, adrenal axis, and then it can diminish anxiety in animal models. So that's well established. And in a former life, I was a stress researcher, so I've spent a lot of time thinking about this. But it's sort of. The sad thing is that once you have a negative trial, there isn't a lot of interest in funding the work going forward. Right. And so I think it's still really an open question about. There is a subset of individuals that could benefit from oxytocin replacement therapy. Right. And it's. And until there's money to do that work, we may not ever know the answer.

Speaker A: Well, it will be important for that work to be done eventually. Hopefully, the field will return to it, despite whatever trends might be happening. Now, I think it's important to know, for the parents of autistic children, whether or not there were any negative effects, effects of oxytocin administration, in particular in the children that did not benefit from oxytocin treatment. The rationale is the following. Well, of course, these things require a prescription if a parent has a child with autism, especially if they're young enough that the behavioral interventions could possibly stand a good chance of inducing neuroplasticity, rewiring of the neural circuits that underlie social connection. Well, then there's this time limited window in which those parents presumably are willing to try most anything, provided it's safe. So let's assume, and I'm making up these numbers now because I haven't seen this study, but according to what you told me, that, let's say a third of the autistic boys and girls that come in have low baseline levels of oxytocin. They're the ones that are going to benefit from this oxytocin intervention. The other but two thirds don't. Well, given the difficulties of measuring baseline levels of oxytocin, most people don't have access to those kind of resources. Um, if it's safe to give oxytocin no matter what, well, then if I were that parent, I'd be knocking on my physician's door saying, hey, give me an oxytocin spray, because my kid might fall into that one third category if and only if it turns out that oxytocin is safe to give. But if there's a risk profile that doesn't justify that kind of shotgun approach, well, then I wouldn't do that. So is oxytocin spray safe? And if so, why doesn't every physician who has a patient with autism give them oxytocin nasal spray?

Speaker B: Right. It's a great question. And I know that I'm a parent of three children, and I know this sense of, like, you would do anything to help your child. Right. And so I think the tricky part is that one thing I will say is that all of the studies, and there's been many of them, have shown that oxytocin is relatively safe in a pediatric population. Right. The tricky part is, I don't know, there's physicians that really pay attention to clinical trials, and if they don't see a benefit, they may not be willing to write the prescription. Right. So until we could identify a group of children that could benefit, you know, we need to create the opportunity for physicians to recognize that this could potentially still be a treatment. Right. Work. You know, but I think the tricky part, and what I will say is, and we can maybe talk a bit about vasopressin, which, you know, my feeling is that if I was placing bets and having to choose between these two, my money would be on vasopressin.

Speaker A: Well, we are definitely going to talk about vasopressin in detail. I mean, the reason I mentioned that hypothetical scenario is just the sense of urgency and in some cases, desperation that parents feel, and time's ticking. And if oxytocin's safe, then I guess I'll put in my vote that parents should at least talk to their physician, maybe even hand them the study to consider. But I can also understand the perspective of a pediatrician who says, well, listen, it was a small number of kids that benefited. You're welcome to try it, but it doesn't seem like the results are that impressive. But this gets to a bunch of larger issues about medical care and randomized controlled trials and the desperation of parents and kids to treat neurodevelopmental challenges. I just want to ask because it feels relevant in a real way, if ultimately the goal of improving symptom profiles in autistic kids is about improving social cognition and social behavior, and that process involves rewiring of brain circuits. Neuroplasticity. Is there any reason to think that other approaches to inducing neuroplasticity would be beneficial, even if they're not in the biological pathways that are disrupted in autism? I think, for instance, about the now extensive use of SSRI's for the treatment of depression. Some cases it works, in some cases it doesn't. Side effect profiles are a serious concern, as discussed on this podcast before. But ultimately, we know that depression is not a serotonin deficiency. In most cases, SSRI's or atypical antidepressants like proprierone, wellbutrin, and things of that sort. When they work, they probably work because of their ability to induce or assist neuroplasticity. Also, the trials on psilocybin are not really about psilocybin. They're about neuroplasticity, at least the trials for depression. There may be other uses of psilocybin that relate more directly to the effects of psilocybin. Ultimately, what we're talking about here is the attempt to rewire the brain in a specific way, whether or not it's assisted by oxytocin or some other mechanism. So the question is, are there trials happening where people are exploring, say, psilocybin MDMA, which, by the way, we know increases oxytocin, I was going to say, and serotonin dramatically, as well as things like atypical antidepressants, antidepressants in kids that have autism, not because we think that those autistic kids are deficient in any of the neurochemicals that these drugs would target, but that these drugs can help rewire the brain. And ultimately that's what these kids need.

Speaker B: Right. It's a really great point. And there might be subsets of kids. Right. There might be kids where there would be a medication that would target other pathways, but that potently releases oxytocin. Right. But there might be kids that have an oxytocin deficiency. Right. That. That circles back to your point at the beginning, or our point is that autism is a very heterogeneous condition. And being able to know before you begin a trial. Right. Like, who am I gonna put into it and what is my primary outcome? Like one measure that I think is gonna move the needle. Right. Like it kind of requires a crystal ball. So there's a lot of guesswork that goes into this, but I would very much like to see, I will say one other thing that I have a colleague named Adam Gustala who's at the University of Sydney, and he published a paper a year or two ago now suggesting that oxytocin may be most effective in kids at younger ages. And don't quote me, somewhere between two and, you know, two and five or three insects or something, we'll find the.

Speaker A: Paper and put it in the show notes.

Speaker B: But, you know, so it could be, to your point about neuroplasticity, that oxytocin may be maximally beneficial in younger ages. Right. And if these studies are these hodgepodges across ages and across sort of different social phenotypes, finding that signal is really important. Right. And maybe age is a driver or maybe low blood oxytocin, regardless of what age you are. Or maybe in Adam's case, if you recruit really young children, you're likely to see a benefit just because the brain is wiring up and it's more plastic at younger ages.

Speaker A: Yeah. That's also a vote, in my opinion, for early examination of kids. Parents really need to get autism screening. And perhaps, maybe the most important thing is to make autism screening as available and as inexpensive as possible for everyone because of the importance of early intervention. Even if it's purely behavioral intervention? Certainly if it's behavioral and drug intervention.

Speaker B: But the clinic wait times are really long. Right. So you have to have a specialist who's capable to diagnose autism. And so you could have a clinic where you're showing troublesome features and a parent wants to get their kid into a clinic. And you could have a twelve month or 18 month wait time. Right. And so there are a lot of people that are thinking about, are there laboratory based tests that we can develop, maybe either for detection or clinical referral. Right. So could we come up with a biomarker panel, for instance, where we might be able to say, wow, here's a panel where we think this child is at reasonable risk for developing autism. Can we make sure they're prioritized for getting a diagnosis right so we can get them an early intervention, but right now, we don't have that. Right. So having some sort of laboratory based test, whether it could be biological or if we could do something with eye gaze, and there's a lot of companies working on these things now to say, this may not work. And also, obviously, again, autism is always controversial in this field. There's so many different stakeholders. A lot of clinicians will say, well, I don't want a 32nd video clip replacing expert clinical opinion. There's good reasons for them to feel that way. But I think if there was a way to prioritize people that are in this line, you know, we could get diagnoses faster.

Speaker A: Well, you wouldn't want false positives, but I would think that a 32nd video clip, provided it's of something useful, is going to be more valuable than nothing. Given the time sensitivity, what are some of the barriers to getting this behavioral testing to be not just more prominent but pervasive? Like, it seems to me that, well, I recall in school they gave us the hearing test. We all marched on the bus. We get the beep test, you know, for hearing challenges. We get vision tests. You get the Babinski reflex test, not the moment you come out of the womb, but pretty soon after. I mean, why isn't this stuff happening for autism for every kid?

Speaker B: Yeah. It's not scalable. Right. So these interviews with parents and the tests that you do can take hours. Right. And any given clinician, even if they're working really long hours, there just aren't that many people that have the extensive training needed to make these expert diagnoses. Right. And so I think that there's, you know, clinicians that are doing the absolute best they can, but they can only see a certain number of people a week. Right.

Speaker A: Does it have to be a physician? Sorry to interrupt. Or could a well trained technician do this?

Speaker B: Yeah. Well, I mean, I think technically it's a DSM diagnosis, right. So it's usually somebody who has a clinical degree. So it would be a clinical psychologist. It could be a behavioral pediatrician. It could be a child psychiatrist or child neurologist. But again, that requires years and years of training. And if we look in areas where people have fewer access to resource, I mean, particularly in impoverished areas, the mean age of an autism diagnosis is years later than in wealthy areas where there's many different medical specialists with parents that aren't working three jobs and can sit waiting around and really lobby and really advocate for their kids, because if they don't show up for work that day, they're not going to get fired from their job. Right. And so I think that if there's some sort of solution that allows there to be a more democratic approach to saying we need a really quick way, like you said, to be able to identify at risk children, especially if it's a blood test or something like that, it could be incredibly impactful.

Speaker A: Are there human trials exploring MDMA, methylene dioximethetamine, also referred to as ecstasy and or psilocybin, for treatment of autism.

Speaker B: So I was aware that maps had an MDMA trial in autism. I don't know what's happened with that.

Speaker A: Yeah, perhaps it's still ongoing. I'll check the map site. I'm in communication with them from time to time. I mean, the reason for asking it, of course, you know, but maybe in case some of the listeners don't, is that MDMA causes these massive increases in serotonin. That seems to be the major source of the MDMA effect, so to speak. Based on the work of our colleague Rob Malenka and at least one human study comparing MDMA to very high dose oxytocin treatment ruled out the oxytocin spike that's induced by MDMA as the source or the only source. But of course, these chemicals can synergize, but based on its chemical profile, oxytocin release, massive serotonin release, dopamine release, and a propensity to enhance neuroplasticity. Assuming all the safety protocols calls were there. Seems like not the perfect drug, but not a bad choice if, of course, it's inducing the kind of plasticity that someone with autism would be seeking.

Speaker B: Right. I mean, I think the tricky part, especially in children, is there's going to be a reluctance to potentially give them psychedelics. Right. And so is there a way to modify the chemical compound to, you know, be something that parents might be more willing to give to their children? Right, right.

Speaker A: And I totally agree with that, I guess, to play devil's advocate, not against you, but. Well, I'll just state it very directly and then I'll take the heat as necessary. I mean, I've done two episodes about the drugs that tens of millions, if not hundreds of millions of parents are already giving their kids for ADHD, which include amphetamines, including dioxine, methamphetamine, is actually a prescription drug for a very small subset of kids with ADHD. But things like Adderall, vivance, even methylphenidate, Ritalin, I mean, these are amphetamines. They induce dopamine release and norepinephrine release. And again, I'm not suggesting people give their kids MDMA to try and ameliorate symptoms of autism, but something chemically similar to it ought to be developed or at least explored in a human trial, in my opinion. Well, time will tell. I'll reach out to the maps group and see what's happening. Let's talk about vasopressin, because there's a lot to discuss there. So you told us this is a molecule that chemically is very similar to oxytocin. Is it manufactured in the human brain and body?

Speaker B: Yes.