Dr. Karen Parker: The Causes & Treatments for Autism

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 Dr. Karen Parker. Dr. 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 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. Dr. 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 10 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, Dr. 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 8 Sleep. 8 Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. I've spoken many times before in this podcast about the fact that sleep is the foundation of mental health, physical health, and performance.

Now, a key component of getting a great night's sleep is that in order to fall and stay deeply asleep, your body temperature actually has to drop by about 1 to 3 degrees. And in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about 1 to 3 degrees.

One of the best ways to make sure that those temperature changes occur at the appropriate times, at the beginning and throughout, and at the end of your night when you wake up, is to control the temperature of your sleeping environment. And that's what 8 Sleep allows you to do. It allows you to program the temperature of your mattress and sleeping environment, such that you fall and stay deeply asleep easily, and wake up each morning feeling incredibly refreshed and energized.

I've been sleeping on an 8 Sleep mattress cover for almost three years now, and it has dramatically improved the quality of my sleep. So much so that when I travel and I'm at a hotel or an Airbnb and I don't have access to my 8 Sleep, I very much look forward to getting home because my sleep is always better when I sleep on my 8 Sleep mattress cover. If you'd like to try 8 Sleep, you can go to 8Sleep.com slash Huberman to get $150 off their pod 3 mattress cover.

8 Sleep currently ships in the USA, Canada, UK, select countries in the EU and Australia. Again, that's 8Sleep.com slash Huberman. Today's episode is also brought to us by Element. Elements is an electrolyte drink that has everything you need and nothing you don't. That means zero sugar and the appropriate ratios of the electrolyte, sodium, magnesium, and potassium.

And that correct ratio of electrolytes is extremely important because every cell in your body, but especially your nerve cells, your neurons, relies on electrolytes in order to function properly. So when you're well hydrated and you have the appropriate amount of electrolytes in your system, your mental functioning and your physical functioning is improved. I drink one packet of Element dissolved in about 16 to 32 ounces of water when I wake up in the morning, as well as while I exercise.

And if I've sweated a lot during that exercise, I often will drink a third element packet dissolved in about 32 ounces of water after I exercise. Element comes in a variety of different flavors, all of which I find really tasty. I like the citrus, I like the watermelon, I like the raspberry. Frankly, I can't pick just one. It also comes in chocolate and chocolate mint, which I find tastes best if they are put into water dissolved and then heated up.

I tend to do that in the winter months because, of course, you don't just need hydration on hot days and in the summer and spring months, but also in the winter when the temperatures are cold and the environment tends to be dry. If you'd like to try Element, you can go to drinkElement spelled element.com slashHuberment to try a free sample pack. Again, that's drinkElement.com slashHuberment. Today's episode is also brought to us by Aeropress.

Aeropress is similar to a French press for making coffee, but is in fact a much better way to make coffee. I first learned about Aeropress well over 10 years ago and I've been using one ever since. Aeropress was developed by Alan Adler, who was an engineer at Stanford. And I knew of Alan because he had also built the so-called aerobie frisbee, which I believe at one time. And perhaps still now held the Guinness Book of World Records for this thrown object.

And I used to see Alan, believe it or not, at parks around Palo Alto testing out different aerobie frisbee. So he was sort of famous in our community for developing these different feats of engineering that turned into commercial products. Now, I love coffee. I'm somebody that drinks coffee nearly every day, usually about 90 to 120 minutes after I wake up in the morning, although not always.

Sometimes if I'm going to exercise, I'll drink coffee first thing in the morning, but I love, love, love coffee. And what I've personally found is that by using the Aeropress, I can make the best possible tasting cup of coffee. I don't know what exactly it is in the Aeropress that allows the same beans to be prepared into a cup of coffee that tastes that much better as compared to any other form of brewing that coffee.

Even the traditional French press. The Aeropress is extremely easy to use, and it's extremely compact. In fact, I take it with me whenever I travel, and I use it on the road in hotels, even on planes. I'll just ask for some hot water and I'll brew my coffee or tea right there on the plane. If you'd like to try Aeropress, you can go to Aeropress.com slash Huberman.

That's A-E-R-O-P-R-E-S-S dot com slash Huberman to get 20% off any Aeropress coffee maker, Aeropress ships anywhere in the USA, Canada, and over 60 other countries around the world. Again, that's Aeropress dot com slash Huberman to get 20% off. And now for my discussion with Dr. Karen Parker. Dr. Karen Parker, welcome. Thank you. It's great to be here.

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 heading 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 ready.

Is getting better at detecting what was always there over time. Do we have any clear answers to that? Well, I think it's a multifactorial answer. So we're getting better at detecting autism, right? So in the past, we were diagnosing kids at nine or 10 years of age, right? And now 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 in house. 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 44. 136. Wow, I feel like it was just yesterday when it was 180. 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? Yeah, that's a great question. So autism is male biased and prevalent. So you have, and again, the studies vary. I mean, it's worth noting the 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 11 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, you know, few years. 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, you know, 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, you know, is it language, is it vision, or does it present as abnormal auditory processing, maybe you could give us a sampling.

So autism is a behavioral diagnosis, right. So 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. And they look for two core features. So the so this is based on the DSM five and there are 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.

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. So 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. 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 you, 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. I've heard before that, you know, parents in which one or typically both parents are say of the engineering, math, the physics, quote unquote hard science type are more likely to have autistic children.

True, I mean, did that bear out in the data? You know, if you look at profession or or, you know, undergraduate major, does any of that correlate with the probability of having an autistic child. Yeah, well, what I can say is that there has been some studies. So what we know is that autistic traits are continuously distributed across the general population.

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 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. Okay, so that leads me to wonder whether or not this whole business of a spectrum is actually multiple spectra spectrums.

Is it spectrums or spectra? I wait, 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?

You know, because when we hear the word spectrum, we think, okay, there's a spectrum of severity, right? And 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 devoro school, which was a school, which,

it's 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 rainman. Yeah. 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, got to go to Kmart, got to go to Kmart.

We would do that repetition right that came. I was down the road from our, you know, our college housing and the devoro 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 sent their children away to live there full time.

Of course, they get visits and they 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 refer to it.

I feel comfortable saying that they've said, I am autistic. And they seem pretty high functioning, meaning they have drivers licenses, drive cars, healthy relationships and manage life apparently well. They have some traits that yes, I would agree, or a little bit different, right? So 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 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 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. Yeah, that makes sense. Yeah, I mean, I think this is where understanding the biological basis of behavior would then allow us to be able to say, you're like, here's these different dimensions, right?

But not understanding the biology, you're left with, okay, where are we lumpers or splitters? Like, 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 very wildly, right? But the common thinking is that the majority, about 50% of autism is associated with common genetic variance. And so the way that we've always thought about this is that there is this, you know, 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 variance that underlie this spectrum, right? 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, you know, sort of an issue with autism 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, 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 it's a great way to stop and you think, that's a really good question. How do we know it's a challenge of the brain? 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 in 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, right? And so 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, right? So, you know, it's very difficult to get access to either cerebral spinal 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, right?

Because they can't sit still. They may have sensory issues. They don't want to go into a scanner, right? So a lot of the tools that neuroscientists or psychiatrists have to think about looking at the brain are limited, right? And then, 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, right?

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, you know, the control mice just fundamentally lack many of the characteristics that are needed to model, you know, autism with fidelity, right?

And I think that's, you know, 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, you know, 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. 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 worth you've been doing in humans, the other animal, the other primate, the other primate, right? Exactly. I love to 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?

So I mean, there are again lots of different epidemiological studies. So advanced parental age, pre-matured, severe pre-matured 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 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 2000s, that at least by my read of the literature, hasn't really gone anywhere. Was this idea that was proposed by Poshko Rikishu used to run the neurobiology department at Yale expert in brain neuroanatomy and nonhuman primates and in humans and biology, really illuminate of our field.

A series of papers exploring how the migration of neurons during early development, you know, it's 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, you know, when an embryo, when a human embryo is developing that 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.

And that process of neural neuronal migration is oh, so critical for the eventual wiring of the brain. And Rikish had this idea that perhaps, and I really want to emphasize perhaps, that the more frequent incidents 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, processing as a 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, right? So this to me was a, you know, 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, never got tacked to, OK, 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 stay off a number of developmental issues and they're super important.

But, you know, we've heard about ultrasound, you know, within the scientific literature, and then occasionally we'll hear other theories about, OK, it's having two parents who are both engineers and then we'll hear, oh, you know, it's, you know, toxicity in the food environment, we've heard, you know,

there's a lot of similarities about vaccines or the, the adjuvants that the vaccines are contained in, you know, in that large cloud of theories has anything really emerged from them is like, OK, 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.

Yeah, so is there any specific environmental influence on autism that we can say, yes, there really seems to be something there. Yeah, I mean, so 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 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, you know, 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 has 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, so, you know, 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 G by 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? 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 other tissues, including the heart tissue, right? So kids with Timothy syndrome have cardiac issues and they have autism. So, you know, I think it's important for us to kind of explore this a bit because in most people's minds, you know, kids with autism have autism and occasionally they'll have other issues, you know, gut issues or heart issues or

muscular skeletal issues, but we often think that that's the consequence of the autism, but oftentimes that they have multiple things going on. And the autism actually could be secondary or independent of the other thing that's going on. So this is what leads me back to this idea of a spectrum, you know, is it possible that what we call autism is actually like 50 different disorders or 50 different conditions depending on what wants to call them.

I mean, what is autism really? I mean, is it, it's, what is it really center around what I think here, maybe it's useful to go, like, 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? I mean, I think that that's the $64,000 question, right? And, and again, in other areas of medicine. So if you think about, let's think about cancer biology, right?

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, you know, have personalized medications made right to attack that tumor.

And so, you know, 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's there are, right? Like, there will be people who say, if you have a disorder like fragile acts or prodder willy syndrome or timidly syndrome or or a variety of these.

Other conditions, there will be people people, I've heard clinicians say, well, that's not really autism, right? That's a piece of fragile acts, 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.

As we all know, quality nutrition influences, of course, our physical health, but also our mental health and our cognitive functioning, our memory, our ability to learn new things and to focus. And we know that one of the most important features of high quality nutrition is making sure that we get enough vitamins and minerals from high quality, unprocessed or minimally processed sources, as well as enough probiotics and prebiotics and fiber to support basically all the cellular functions in our body, including the gut microbiome.

Now, I like most everybody, try to get optimal nutrition from whole foods, ideally, mostly from minimally processed or non-process foods. However, one of the challenges that I and so many other people face is getting enough servings of high quality fruits and vegetables per day, as well as fiber and probiotics that often accompany those fruits and vegetables.

That's why way back in 2012, long before I ever had a podcast, I started drinking AG1. And so I'm delighted that AG1 is sponsoring the Hubertman Lab podcast. The reason I started taking AG1 and the reason I still drink AG1 once or twice a day is that it provides all of my foundational nutritional needs. That is, it provides insurance that I get the proper amounts of those vitamins, minerals, probiotics and fiber to ensure optimal mental health, physical health and performance.

If you'd like to try AG1, you can go to drinkag1.com slash Hubertman to claim a special offer. They're giving away 5 free travel packs plus a year supply of vitamin D3K2. Again, that's drinkag1.com slash Hubertman to claim that special offer.

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 with those things interact, not just language, but also behavior to autism and 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? Okay. So there are these small little peptide, they're nine amino acids long, so very tiny. They only differ by two amino acids. And there are 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 vasotocin 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 the reproduction and social behavior across the phylogenetic taxes.

So how 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 members of its species. Especially mammals, right? So oxytocin and vasopressin are pervasive and mammalian species. Do the different species tend to make oxytocin and vasopressin in similar brain areas and tissues?

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, if you think about 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? Oh, so oxytocin, vasopressin are chemically similar. Yes. Interesting. And where would you say lies their greatest output divergence, which is just nerd speak for. Is there an example of something that oxytocin does that vasopressin doesn't and vice versa?

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 oxytocins 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 has at least in the peripheral system has been involved in urine, like urinary output regulation, blood pressure.

And so we only knew about their physiological roles as sort of classic hormones for decades. And what was interesting is these like naming conventions are fascinating medicine, right? So you could name a virus after where it was first found, right? Or it could be named after somebody who discovered the 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 antidioretic 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 but what was fascinating is they were, these hormones were named oxytocin is Greek for quick birth. So for decades, people only appreciated their physiological roles, but but there are no anatomists saying, hey, so these are both made, they're made in a lot of different places, but the the actions 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 like, you know, who I didn't train with, but he was a real source of wisdom to me for many years. And his name is court Peterson, and he told me this wonderful story about this Duke's aologist named Peter Klopfer. And Peter was studying ungulates, so sheep and goats.

And he wrote a story of 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, you know, within an hour they can run with the herd, unlike our species, which is all traditional 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, you know, from an evolutionary perspective, you want to be investing in the baby that yours not somebody else's right.

And he hypothesized that it was oxytocin that was being co-released into the brain and during milk let down, 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.

Can I just briefly interrupt you because I find this so interesting and I know it's interesting to everyone listening as well because you know, yes, and thank you for making it clear the oxytocin 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 you know, our baby versus another baby most instances their rare exceptions or perhaps not so rare exceptions, but leaving those aside, you know, the mechanism that would allow for mother infant bonding and infant mother bonding by way of oxytocin presumably is something that is literally changing their brains saying it's 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 right and certainly for the early part early part of life and that nowadays it seems that that can extend well into the teens and 20s for some people. But you know, how how is oxytocin working is it is it working over the course of minutes hours is there some specificity of this baby in this mom that links them in some more pervasive way.

I mean, how is oxytocin doing this magic of bonding yeah, I mean it's 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.

And the passage through the vaginal canal was what you know, so you would activate it 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.

And the sheep and goats wouldn't bond to their baby for instance, so literally the passage of the baby out of the vaginal canal triggers the oxytocin pathway the release of oxytocin. As in lactation does nature is so beautiful because if you had to pick one event yeah 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 right.

But but what I will say because I think you will you know to avoid you getting attacked on Twitter or wherever you might get attacked anyway, if not, if not for this discussion in another one, but I'm tougher than I'm. So, but it's really species specific right so 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 and by parental care where we're sort of everybody is sort of like it takes a village to raise the baby we readily adopt in our in primate societies right and so.

So you know like I had a cease I mean I'll tell you something personal I had a cease section and had I had a lot of postpartum complications and so lactation didn't work out that well for me one of my friends would say my massive DV's T's and pulmonary embolite 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.

And so I had a lot of DV's a deep vein from thrombosis 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 kiva filtered 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 I didn't do a vaginal delivery I had a cease 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 pressure so I was an evolution biologist before I found neuroscience right and so I really everything I do I think about from an evolutionary perspective.

So 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 is being social is actually one of the what are 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 as a survivor is that we have a certain kind of a mental integrity and a sort of a very difficult perspective.

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 where, you know, there's these pervasive social interaction impairments. It could be something like drug abuse where, you know, you, you, a risk factor for drug abuse is feeling, you know, socially disconnected and alone, right?

So social isolation or loss of a loved one is a very strong predictor of the onset of a stress-related depressive 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, it's bidirectional. We think, I think most of the work has been done in mom would be, and again, this has not been really done well in primates, right? So we're extrapolating this information from

species that have different evolutionary histories than us, right? So it's goat, sheep, purrivals, mice, rats. So what do we know about the role of oxytocin in humans? Do it, I mean, we know it's there. Yeah. 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.

Yes. And the reason it's unfortunate it was is that while that might cue attention to oxytocin and I'm, you know, a big fan of people paying attention to biological phenomena, it, it discards the other and many roles of oxytocin. But, yeah, what can we say about oxytocin in humans if, if anything? Like, do we know that it does, I mean, is it, we're just, so

we're assuming based on the animal models that it does something. I mean, this is very different than like dopamine, where there's tons of animal model data, but we know, but there are 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, is out there. Recently, 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, 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, you know, activation, right,

or uptake? There are some imaging studies. They're usually done giving intranasal oxytocin and then you basically ask questions about, okay, we give you oxytocin intranasally, which presumably enters the brain. There's, we could talk about reasons why we think that. And then we have you perform on some task, right? And so, you know, there's evidence if you give oxytocin, it diminishes the amygdala's response to fearful stimuli, right? So that

it might have this sort of prosocial effect. And it was actually data like that that caused people to start thinking initially about oxytocin. And those are 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 hormonose, it was being discussed as the trust hormone, right? Also far too simple, heuristic, but again, I think it's cool that the, you know, 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, 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. Right. Have there been studies exploring the role of oxytocin in making autistic children more prosocial? 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, you know, autistic kids are just maybe more prosocial 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. They seem very happy when they show up at the door and like all the hallmarks of, you know, 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 see them playing with one or two friends.

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, you know, 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. So I hear you. I'm not way too. Right. So, you know, how do we think about this? Okay. Well, I would say the social features of autism are interesting, right? And so

you might have there were, there was an attempt a long time ago, like 1979. There's 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? And yeah, exactly. And that's often why, you know, 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 has 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? And so like, 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 vasopressin was given to males partly because it wouldn't, the idea would be that the off target of facts in the peripheral nervous system, i.e. milk, like down, uterine contractions are not going to happen in males, right? And so 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. Yeah, something that fortunately is changing. Yes, absolutely. Thanks to a mandate by the, by the NIH.

Right. I had to just kind of smile slash, raise my eyebrows a little bit at the idea that, you know, the assumption that oxytocin administered to males, yes, one can see why it wouldn't cause milk, like down, or uterine contractions, but, but of course, there could be other peripheral facts about oxytocin in males, but they had to pick, they had to pick one so they went with males. Okay, so, 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. Right. So they're doing this by nasal spray. 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 you know, 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

in 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. Oxytocin or placebo. Where's your eye gaze going in a picture, right? So one of, 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 were 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. And is oxytocin available over the counter? It is it

require 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 that there's actually a market for and by the way, folks, I'm not suggesting this, 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

and like PTSD type stuff relating to, let's just call it relational trauma. Okay. So that's happening. Yeah. But let's just think about oxytocin alone for the moment. Our parents of autistic kids able to like bioxytocin nasal spray? No. So it would need to be written like the prescription

would be need to be written by a bi of 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 anisocotics, which they treat associated features like irritability and they have off-target effects like weight gain and and you know, so we don't have any medications that are currently approved in the US or anywhere else for that matter, I should treat the core features

of autism. Interesting and unfortunate. And hopefully that will change in the not too distant future. Do we know that children with autism, people with autism, because I'm going to 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? So I would say that in a lot of cases autism has lifelong impact, but there are people who outgrow their diagnosis. You know, 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 it you know, 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. I'd like to take a quick break and thank our sponsor inside tracker. Inside tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals. I've long been a believer in getting regular blood work done. For the simple reason that many of the factors that impact your immediate and long-term health can only be analyzed from a quality blood test.

Now, a major problem with a lot of blood tests out there, however, is that you get information back about metabolic factors, lipids and hormones and so forth, but you don't know what to do with that

information. With inside tracker, they make it very easy because they have a personalized platform that allows you to see the levels of all those things, metabolic factors, lipids, hormones, etc. But it gives you specific directives that you can follow that relate to nutrition, behavioral modifications, supplements, etc. that can help you bring those numbers into the ranges that are optimal for you. If you'd like to try inside tracker, you can go to inside tracker.com slash

Huberman to get 20% off any of inside tracker's plans. Again, that's inside tracker.com slash Huberman. 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 oxytocin? Because it's one thing for an nasal spray to a oxytocin to improve social functioning. It's another to know that the effect is addressing an underlying biological deficit.

Yeah, that's such a great question. We should unpack that because there's been a lot of work in this area. The first question is where are we measuring the oxytocin? We mentioned oxytocin as all kinds of effects in the body as well as the brain. It's released into the blood, but it's also released directly into the brain. There's variable evidence about if you measure it in blood, is it a readout of the brain or not? 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 benefit, 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 Prada-Willy syndrome mouse, which is the module 2 gene that gets manipulated, and then there's a catnap 2 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 2 mouse, you can restore oxytocin neuron number 2 equivalent of control animals, suggesting that oxytocin is doing something in these oxytocin deficient animals, right? So 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 it's blood oxytocin levels that there are going to be a subset of individuals that just make less oxytocin 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 Antonio 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 the randomized meaning there was an equal chance you could get either drug or placebo, and they're then they're controlled, right? Okay, so we asked if we know what your pre-treatment, pre-treatment blood oxytocin level is, who's going to benefit from treatment? And we've had 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 two. One intervention, one nasal surgery. This was four weeks, sorry, I should have clarified. This is four weeks of treatment being administered oxytocin twice a day. Okay. And so we saw effectiveness there. Sorry to interrupt so much, but just male and female subjects?

We did, but again, because the autism is male, biased in prevalence, even if you make this heroic effort to over-recute, try to get more girls in the study, we usually try to aim for the prevalence, right? Because it's difficult to get girls just because there's fewer of them. Got it. Okay, but boys and girls were included. They're taking oxytocin over the period of several four 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? But you 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 studies 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 multi-site, 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. And were they looking to see who started off with low levels of oxytocin at pre-treatment? So what was interesting about that study, and there were a lot of issues with it, was that oxytocin is something where you have to, if you look at it, it degrades. It's like that's kind of what I joke about, right? So you need to take it. We take, when we go in, we have

like these really intense protocols, right? So you go in and we have vacutator tubes that are cold, and we put them on ice, and then the phlebotomist takes the blood from the child. So a lot of technical gymnastics, yeah. And then we make sure we spin it in a centrifuge cold, and then we piped it onto dry ice. So like, so we have very 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 the 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, you know, 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 and 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, 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 if there is

a subset of individuals that could benefit from oxytocin replacement therapy, right? And it's in until there's money to do that work, we may not ever know the answer. 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 of oxytocin administration.

In particular, in the children that did not benefit from oxytocin treatment, the rationales 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, you know, 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

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, 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? Right. That's a great question. And I know that, you know, 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 it's 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? But that work, you know, but I think the tricky part in 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 bats and having to choose

between these two, my money would be on vasopressin. 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, you know, time's ticking, and if oxytocin's safe, then, you know, I guess I'll put in my vote that, you know, parents should

at least talk to their physician, maybe even hand them the study to consider, but I can also understand the perspective of pediatrician who says, well, listen, it was a small number of kids that benefited, you're welcome to try it, but I don't, you know, doesn't seem like the results are that impressive, but, you know, this gets to a bunch of larger issues about, you know, medical care and randomized control 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, you know, if ultimately the goal of improving symptom profiles and 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 SSRIs 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, assessor eyes are atypical antidepressants like repriorone, well, butrin and things of that sort.

When they work, they probably work because of their ability to induce or assist neuroplasticity. Right. Also, the trials on psilocybin are not really about psilocybin, they're about neuroplasticity, at least the trials for depression, right? There may be other uses of psilocybin that relate more directly to the effects of psilocybin, but ultimately, you know, 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 and serotonin dramatically, as well as things like atypical 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.

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? But I think that that circles back to your point at the beginning, where 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 going to put into

it? And what is my primary outcome? Like one measure that I think is going to 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 Guest-Style, 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 I don't quote me

somewhere between two and, you know, two and five or three and six or so. We'll find the paper and put it in the show notes. Yeah. But, you know, so it could be to your point about neuroplasticity that oxytocin may be maximally beneficial in younger ages, right? And if you're, if these studies are these hodgepages across ages and across sort of different social phenotypes,

finding that signal is really important, right? And maybe age is a driver or, or maybe, you know, 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, you know, younger ages. Yeah, that's also a vote, in my opinion,

for early examination of kids, right? Like 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, but certainly if it's behavioral and drug intervention. 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 know, you're showing troublesome features and a parent wants to get their kid into a clinic and you could have a 12 month or 18 month wait time, right? And so there are a lot of people that are thinking about, are there are there a laboratory-based test 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 some, 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, 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 iGaze. And there's a lot of companies working on these things now to say this may not, you know, they're, and also obviously, again, autism is always controversial in this field, right? There's so many different stakeholders. A lot of clinicians will say, well, I don't, I don't want a 30 second

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. Well, you wouldn't want false positives, but I would think that a 30 second video clip provided is of something useful. It's going to be more valuable than nothing. Yeah. 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 and, you know, you know, for hearing challenges, we get vision tests. You get the Babinsky 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? 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? And so- Does it have to be a physician? Sorry to interrupt. Or could it, you know,

could a well-trained technician do this? Yeah, well, I mean, I think technically it's a DSM diagnosis, right? So it's usually somebody with a clinical degree. So it would be a clinical psychologist. It could be a behavioral pediatrician. It could be, you know, a child psychiatrist

or a child neurologist, but I mean, again, that requires years and years of training. And with, if we look in areas where people have fewer access to resource, I mean, particularly in poversed areas, the mean age of an autism diagnosis is years later than in wealthy areas where, you know, there's many different medical specialists with parents, you know, that aren't working three jobs and, you know, can sit waiting around, you know, and really lobby and really advocate

for their kids, right? Because, you know, 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, you know, 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, you know, it could be incredibly impactful. Are there human trials exploring MDMA, methyndyoxy, methamphetamine also referred to as ecstasy, um, and or psilocybin for treatment of autism? So I was aware that maps had an MDMA trial and autism. I don't know what's happened with that. Yeah, perhaps it's still ongoing. I'll check the

maps site. I mean, communication with them from time to time. I mean, the the reason for asking, of course, you know, but maybe in case, um, let some of the listeners don't, is the MDMA causes

these massive increases in serotonin. That seems to be the major source of the MDMA effect, so to speak, um, based on the work of our colleague, Rob Malenka, and at least one human study comparing MDMA to very high dose oxytocin treatment, kind of ruled out the oxytocin spike that's induced by MDMA is the as the source or the only source, but of course these chemicals can synergize. I mean, but based on its chemical profile, oxytocin release, massive serotonin release, dopamine

release, and propensity to enhance neuroplasticity. I mean, assuming all the safety protocols where, where they are, um, seems like not the perfect drug, but not a bad choice. Um, if of course, it's inducing the kind of plasticity that someone with autism would be seeking. Right. I mean, I think the tricky part, especially in children, right, is there's going to be a

reluctance to potentially give them psychedelics, right? And so, you know, is there a way to modify, you know, the chemical compound to, you know, be something that parents might be more willing to give to their children, right? Right. And I totally agree with that. I guess to play devil's advocate, not against you, but, um, uh, well, I'll just state it very directly and then I'll take the

heat as necessary. Um, I mean, I've done two episodes about the, uh, the drugs that, you know, millions, tens of millions, if not hundreds of millions of parents are already giving their kids for ADHD, which are, um, include amphetamines, including dioxine, methamphetamine is actually a prescription drug for a very small subset of kids with ADHD, but things like Adderall, Vive Ants, even methylphenidate riddle in, I mean, these are amphetamines. They induce dopamine

release and neuroponephrine release. And, uh, again, I'm not suggesting people, um, give their kids MDMA, um, 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, in my opinion. Well, time will tell, I'll reach out to the maps group and see, see what's happening. Let's talk about vasopressin. Yes. Because there's a lot to discuss there. So you told us this is a molecule that chemically is

very similar to oxytocin. Um, is it manufactured in the human brain and body? Yes. Okay. Do we know, uh, subset of the sites that it's known to be produced and where some of its actions are? I mean, you mentioned the kidney and the anti-diarreratic hormone, um, roles, but within the brain, like what brain areas have neurons that make vasopressin? Well, so we'll have the receptors for

the brain. Yeah. I mean, the receptors are all over, are all over the brain. And again, it varies depending on the species and, you know, the way the receptors are measured or in post-mortem tissue, right, which can be very difficult to get good samples, right? And so we need to have that caveat going in. Um, but yeah, I mean, it's, it's made in the hypothalamus, um, and it's released

all over the brain. And there is vasopressin receptors all over the brain, right? And, um, what's really interesting about vasopressin, I always sort of joke that oxytocin, you know, always saw it's a day in the sun, if you will. And the vasopressin was sort of the step child that was like left, you know, sort of behind. And the reason why I find this fascinating is again, like I think back to my, you know, my, my roots as a, you know, evolutionary biologist behavioral

neuroscientist. And what was interesting is that there were studies in the early to mid 1990s showing that vasopressin was critical for male social behavior. And so, um, there was work, you know, there was a variety of people. And I, I think Rob Malinko mentioned this on his, on, on the podcast he did about, you know, there's a group of people like Sue Carter, Larry Young, Tom Insoul,

some of these early people. And they gave vasopressin to male prairie voles. And very, vasopressin was what induced pair bonding with a female mate and also paternal care. And as I recall, those experiments were done in the context of looking at polygamy versus monogamy of these prairie voles. Prairie voles versus like a different species. So same genus, but a different species. So it might be a montainville or, you know, highly related, but these other

species, so peri voles are monogamous. The male's well, I mean, that was the more 50% divorce. Yeah, that was not, I don't think it's that bad, but they're doing better than we are as a species. True. We should look to them for pointers. And all the divorce folks are saying, wait, why do you say better? I have some divorce friends that have said divorce is like the greatest thing. So we always say like doing better, doing worse, right? Um, anyway, that's a whole other

podcast. Um, and certainly not the uberman lab podcast, but, or maybe it is, but, um, or will be, but yeah, my understanding is that you have certain voles that mate with almost exclusively with one other vol for their entire lifespan. And then you have other voles located elsewhere. That in those colonies, they mate with lots of different voles. So the males and females have lots of different partners, um, raise young with lots of different partners, mating with lots of

different partners. And that if you give vase a present, then you can make the, I was going to call them polyamorous, but I don't know if they love each other. I'm going to answer for more fives and assume they love each other. The polygamous moles, not polyamorous, but polygamous moles, then become monogamous. Well, I, yeah, I would say that is probably not the take home message. So the take home message would be they had, let's say that there was like the good voles, right,

which are the prairie voles. And they were the ones that formed these monogamous parabons. Dad participates in paternal care with mom. They co-raised babies together. And then dad chases off intruders, right? And then there's the more A social voles. And so these are like the montane voles. And it will stay, it's a complicated story. But there's these montane voles where males and females live separately. Females like maybe live on the males territory. The male

mates with a few different females absolutely doesn't provide any paternal care at all. Mom raises babies by herself, right? So that's these are really the two. Like 1950s versus 2020s. Yes. Yes. To be it just to broadly stereotype. To broadly stereotype. And if you give, okay, so for prairie voles, they're sort of primed to form bonds and to be the males to be good daddies, if you will. And all you have to do is give them a single injection of vasopressin.

And, you know, or you can give an antagonist. And usually the way they form the bond is through mating, right? So they, you put them with a female, they may, they cohabit for a bit. There's been all kinds of parametric studies. I can't remember how many hours it takes to form a parabond. But then you can do these things called partner preference tests. And then you can say, here's the guy that you made it with. Here's this guy you don't know. And you can do it for males.

You can do it for females. And they pick their partner. They choose to go hang out with their partner. The montane voles, you know, either after mating with somebody may either be equal, or maybe they'll even go spend time with the new individual. So the cleanest story was that prairie voles are monogamous, montane voles are not monogamous. But in the prairie voles, you could give vasopressin instead of made it cohabitation. And you could turn on a, like, you know, a bond with

somebody after only living with them for a very short period of time, right? Or you could induce paternal behavior. And I was working with the voles species in grad school. I think the most interesting scientific experience that I've ever had, right? And you and I both know this, right? When you're young, you're actually the person doing the work, right? As you become, you know, the head of your lab, you're mostly writing grants and giving talks, right? And then you get to

hear about the super cool things that everybody in your lab is doing, right? Eventually the members of your laboratory kick you out of the lab. They literally say, like, get out of here, you're leaving things in the wrong place. Whereas initially, you're telling them, hey, that's in the wrong place within a year or two. For me, I think it took about four or five years. But by about year six, right? I was, um, demoted to my office to just write grants and write. I was told that one time,

I was back there and I tried to weigh in. I was like, so excited what they were working on. And they basically just said, go write grants and bring in more money, right? Like that was kind of their attitude. Like we get to be the ones who get to do the cool stuff. So back when I got to actually do the science, um, I remember I had this species where, and I, and again, I told you I came at this from an evolutionary perspective. So these were called meadow voles. And I found

them very interesting. So when I showed up in my thesis advisor's lab, she said, I said, I really want to study oxytocin and vasopressin. And I really want to study voles. And I know you have a voles species. And she said, why don't have prairie voles? I have these meadow voles. And I'm studying them because they're so sensitive to light. And they change their behavior based on light. And as she said, well, you can do what you want, but our grants basically have to have a circadian

component. So she said, you got to work that in. But then we kind of struck this deal. So I was hanging out in the animal rooms. And I thought it was really fascinating. So she had animals that were either on short day lengths or long day lengths. So the mimicking some summer and winter. And I was noticing that on winter day lengths, the, the males were hanging out with the females. And when the female had a litter, he was like participating. And I was like, whoa, these are not

supposed to be monogamous animals. And so I went into the field research. And they were doing all these radio telemetry studies. And so like if you, I wish you probably explain what those are, putting a little transmitter under the skin. It's painless for the animal. But that allows the researcher to monitor the behavior of the animal remotely without having to, you know, put them in cages and stuff. And so this is like under field conditions. And voles are everybody's favorite

snacks. So they have like a very limited lifespan in the wild. I mean, like on the order of months. And, and so like if you have a short lifespan, like you should just keep reproducing, right? And so what was interesting is at the end of the summer days, as you're going into winter, territories, claps, and males are found with females. And they co-raise babies. It makes sense. If it's, you're going to have a litter and mom needs to get up to go eat. You need somebody to

sit there and warm those babies. They're going to die because they're going to freeze to death, right? So I started saying like, wow, I think these metapholes are good dads. Like I'm noticing this. And so I told my thesis advisor, I want to study how oxytocin and vasopressin can, maybe this is involved in tracking these evolutionary mating strategies. And so again, like the coolest experience I ever had was on these males that were housed under short day links. So they were like

winter males. I was able to put vasopressin directly into their brains. And it was like turning on a light switch. And they ran around the cage, picked up all these babies, put them in a nest, and huddled over them. And if you put a placebo into their brain, nothing happened. And so to me, I always filed that away in, you know, in the back of my mind of like, wow, vasopressin is this

really interesting hormone. And maybe someday I will, I did a postdoc and something else, but it was always, you know, back in the back of my mind of, I really want to return to this. It's so incredible that a eight amino acid long peptide could basically turn these relatively negligent fathers into very attentive fathers. Yes. Yeah, it was fascinating. All right. I mean, it just speaks to the power of the peptide vasopressin, also speaks to the

power of brain circuitry. It also speaks to the idea that brain circuitry is often sitting latent in the background, you know, ready to be activated. That it's not just about neuroplasticity and building up a new circuit that some forms of neuroplasticity are about unveiling what's, what's already there. Absolutely. And that peptides can act like switches. Yeah. Which, you know, it kind of makes sense on the one hand, but I've never heard of a result

as traumatic as that. So I'm presuming you're going to tell us that that then led you to go back to vasopressin and explore its ability to induce good parenting and negligent fathers. I haven't studied that yet. No. Well, so I think that, you know, my mom always says, chance favors the prepared mind. And so I was doing my postdoc at Stanford and I got recruited to stay on the faculty. And I, you know, had been doing work in stress,

vulnerability, and stress resilience. And I really, and I love doing that work. But I still felt this tug of, you know, I had spent all this time in a psychiatry department where I was surrounded by clinicians. And I realized that a lot of the stuff that I was doing had clinical relevance. Right. And so sometimes you sort of meet the moment, right. And so right as I was transitioning to,

to have my own lab in my department, there was a bunch of stuff going on. So there were a lot of very dedicated parents who were lobbying for funding for autism research because it was horrifically underfunded. Really? Horrifically underfunded. Wow. I mean, at rates of one in 36 kids. Well, not at the time, right. So it was, it was one in 150 or whatever it was back then. But there were all these parents and, and I mean, again, they're heroes in my eyes that they advocated so much for

their loved ones. And so there was, you know, they started forming parent grassroots organizations that have culminated. They all started joining together, which is now autism speaks. And then there was a man named Jim Simons, who runs one of the most successful hedge funds in the world. And he decided, wow, I'm in a, you know, there's let's put money into autism, right. And so they'll have

a personal link to autism. I, you'd have to ask him because oftentimes, not always, but oftentimes, when you hear about wealthy donors, yeah, I'm devoting a lot of money to one area of science. There's, there's a familial thing there. Yeah. You know, a member of their family or a close friend has this challenge and they, they really want to see that challenge. Absolutely. I mean, a lot of money I've gotten for my lab from philanthropists. And what I will say is the most impactful work I've

ever done is through philanthropy, right. They're crazy ideas that no funding agency ever touches, right. But yeah, so they put, they both put a lot, you know, there was a lot of emphasis. And so because the Simons Foundation started issuing requests for applications, there was a group at Stanford that formed and it was a clinician with a basic scientist. And my chair at the time said, well, you know, almost nothing is known about the biological basis of autism. Why don't you go,

I mean, to introduce you to the head of child psychiatry, you should go talk to this group. And so as I was preparing my slides and realizing that, you know, social interaction impairments were core feature of autism, I thought, wow, you know, these neuropeptides may really be, you know, a part of this puzzle. And so that's actually really how I got pulled into autism research was

through that. And it was, I was, you know, everybody at the time was very interested in oxytocin. And, you know, I remember thinking, so we actually did probably the most definitive blood oxytocin study because there was this idea, again, like this marketing campaign of like the oxytocin deficit hypothesis of autism. And, you know, given how clinically heterogeneous autism was, we got money actually from the Simon's foundation and we did the first study with maybe 200 kids. And what we

were able to show was that blood oxytocin was not a marker of autism, right? So it wasn't like there was a bimodal distribution, meaning to completely non-overlapping levels of oxytocin and people with autism, people without autism. So the lower your blood oxytocin levels, actually regardless of who you were, you could be a child with autism, you could be an unaffected sibling with autism, or you could be a unrelated control child. And it was the lower your blood oxytocin

levels, the greater your sort of social difficulties. And the slopes, you know, were different. They started at different points because the behaviors were obviously different. But that's what got us thinking about our clinical trial, which is that blood oxytocin level is not going to be this great differentiator between people with and without autism, right? But we might be able to find a subgroup who could benefit from treatment. But what I like so much about your approach,

the way you described it is that it sets aside. We don't want to say discards, but it sets aside this thing that we call autism, which is already hard to define and diagnose. And there's all these different spectrums and you're trying to and just says, okay, children with autism have challenges in social cognition, social behavior, social bonding. So do adults with autism for that matter. Let's just focus on that. And not worry so much about whether or not somebody is

diagnosed as autistic or not. And just focus on what are some of the potential neuropeptide deficits or overexpression of neuropeptides that may in some way relate to those social challenges. Right. And then one can circle back to the question about autism in collecting those data. But it also points to this idea that like when we go after a disease like Alzheimer's, we can often miss the possibility that Alzheimer's while it has deficits in cognition and memory,

could also be a bunch of other things like a metabolic disorder of the body. And so maybe you go after a particular symptomology and try and attack that and you might actually potentially treat or cure multiple diseases. And so very different approach. And I hope people are catching on to the subtlety, but also the potential impact of that.

Because if I heard correctly, you said there are people who are not autistic who have social functioning deficits and they too have less circulating oxytocin. Right. So I would say we haven't studied people where we brought them in and characterized it. Right. So these are typically developing kids. But what we did is in the abilities that are typical of a control child, we still saw that gradient, right. And so I think it just sort of begs the

question about, you know, what is oxytocin's role in human sociality, right? I mean, I think there's just so much that we don't understand about both of these molecules in terms of their disease liability if they're low or they're healing potential if we are, you know, able to use them as modulators of other therapies. So how did you move from oxytocin to vasopressin? You mentioned that everyone was all excited about oxytocin. Still the one that we hear the most

about. Yeah. Although after this podcast episode and when I start blabbing about vasopressin to everybody, you know, maybe that'll change, but I think it's going to take a lot more than that. But maybe it's because the name isn't as there's something about oxytocin that like kind of sounds like the love, it looks like the love hormone, but like vasopressin should be renamed. Right. Well, it should be called something else. Like not anti-diarrietic hormone, not vasopressin.

I mean, you're going to tell us how critically important it is. Perhaps even more important than oxytocin for autism and social functioning. So I don't know. By the end of this podcast, it will come up with a new name. It's needed, right? Well, I'll put it out there.

Okay. So how did you get to vasopressin? Okay. So it was interesting with oxytocin because we didn't, you know, and again, I was skeptical that we would see these big group differences, but, you know, it was a little bit of like, okay, you know, what everyone's saying, this is not going to be the big solution, right? And so I actually came at it from the work that we did in monkeys. And so I think I mentioned previously at the beginning of the podcast that there were a lot of limitations that

I saw. And then sometimes if you come into a field, you know, when you're, you're a little bit of an outsider, right? Like, I'm not a clinician. I don't see autism patients, but I also, I have this really strong interest in social behavior and the biology of it. And so I was thinking about what are, what are things that we need to do to better address the challenges and autism? So one of them was, why are we looking in blood? Right? Like if you look at neurological conditions, there has been

a lot of progress made by doing biomarker discovery in cerebral spinal fluid, right? So like the biological substrates or clues of markers of say various forms of dementia or, or MS were first found in spinal fluid, right? Because it's the, it's the fluid that bathes the brain in the spinal column. And so if you're looking for the biochemistry of an illness, that's the closest fluid that you can get to the brain, right? So a drug just won't do it. Maybe, right? So that was part of my thinking.

But then there was the issue of the animal models, right? So there was drug after drug after drug that was tested in mice and they failed in human clinical trials. And so it made me start thinking, could we develop a primate model of naturally occurring social impairments, right? So can we, because in autism, these social impairments are, if you will, naturally occurring, right? And so,

you know, this is the spontaneously occurring children. And so it made me wonder, could we identify monkeys in a large colony that have social impairments in, and after talking to clinicians who treat these children, can I spend a lot of time validating a monkey model where there will be monkeys that have features that look like they have direct relevance to core autism symptoms? And so what I did was there's a primate center, the California National Climate Research Center.

And so what we did is, so I think I mentioned earlier that there's these surveys that can be used to look at autistic traits in the general human population, right? And so we refined one of these, and we did what we call back translates. So basically, it's an instrument that's used for humans, and then what we did is modified it to be able to use this rating scale in recessed macaques,

which are an old world monkey, and I know you're familiar with them. And I was interested in looking at old world monkeys because there are some of the closest relatives to human that are used in biomedical research. And as I mentioned previously, these autistic traits are continuously distributed across the general human population, and that this genetic, let's call genetic liability, which is a fancy way of just saying that we think that there's a genetic risk that underlies

this continuum of behavioral traits, right? So if we think that that's true in humans and in one of our closest relatives, and we think that some of these genes create proteins that then are what sets up the developing brain to develop in the way that autistic brains develop. So let's just assume that that's the premise. That's what we went in with. Can we find recessed macaques that are just living in large outdoor colonies and identify animals that might be good models for autism?

And the answer is yes, we could do this all kinds of different ways. One is we could just take people and score monkey behaviors outside their cages while they're interacting with their peers. We can use rating scales. And again, the rating scale we use, it's called the social responsiveness scale. So this is called the macaque social responsiveness scale revise. It's a mouthful. But what it allows us to do is measure autistic like traits and monkeys. And we can also bring monkeys in for

experimental tests to see where their eyes look or how do they perform? How do they respond to videos of other monkeys? You know, if they're making affiliate of overtures, do they do like, you know, or macaque school, which is a positive response? Well, they do that, right? I'm going to apologize for interrupting again, but I just had to tell people this because I spent time up at the UC Davis primate center as a graduate student. And by the way, what we're referring to here are non-invasive

observational studies, at least less far. These are monkeys living in large exclosures, not enclosures, large exclosures, forming colonies and social relationships. And you know, I think anyone that sees monkeys at the zoo and we all learn that monkeys go, and they don't, if you want a monkey to like you, you learn this working with macaques. First of all, they don't, the affiliate of call is they do this really not in the little ones. You have very well. I spent a lot of time with these

monkeys and the little ones. They do this thing where they go, I stood, I stood, nurse the little ones every once in a while. They go, and they're just, you know, it's like makes your heart melt. I think there must have been an oxytocin dump at that moment. That's probably happening right now. But if you want the monkeys to like you, you have to give an affiliative facial gesture, which is not

a smile. That's actually an aggressive gesture. So as Karen, Dr. Parker, just showed you, it's lip smacking, which is, so if you see a monkey at the zoo and you want it to pay attention to you, you're going to have to lip smack. And if it doesn't, either you're not doing it right or it just doesn't like you. Exactly. Great. All right. Thanks. Now we'll go back to the study of, or the establishment of this really key experiment. Right. So then what we did is we identified these

animals and we spent a lot of time. So one, one of the things that I do as one of my areas of expertise is validating animal models. So a lot of, like I mentioned, like a lot of reason why experiments fail is people will take an animal off the shelf and say, oh, I'm going to do this, right? But if you're, you know, if you're studying a disorder that's characterized by visual issues, is it, is it the best thing to do in a nocturnal species that has all faction, is it's

primary sense remodality or is it, right? Or is it better? You know, and again, I will say all models have value. There's all, you know, there's reasons you just have to, you know, you basically have to stand by what you're modeling. And so I think one of my, the biggest issues I have with a sort of mouse phenotyping mafia is that, you know, there's this group of tests that they use and they use it in every single disorder, right? And then if there's a positive hit, it's like, oh, this is like,

you know, this test is really for Parkinson's today, but it's for depression tomorrow, right? And so, so my goal was to, to devise very specific tests that would allow us to evaluate, you know, core features of autism in this model. And the answers we found it, right? So if you look at monkeys that spend a lot of time alone, they have a much greater burden of autistic-like traits, measuring on this rating scale. They have diminished social motivations. So other monkeys will come up and

interact with them, but they don't engage in social overtures that much themselves. They do less grooming, less of a failure of behaviors. They, in some of the work that we're doing, they don't lip smack back. And we can talk a little bit about that. We did a pharmacological probe and we can talk a bit about what Bays or Presson does to that, which is kind of exciting. And so we spent a lot of time validating this behavioral phenotype, right? To say that we really feel like there were

our core aspects of it that are allowing us to model autism, right? And I have a paper which, if you want to put it in, it's all about creating this monkey model and the power of doing it and where it took us clinically. We'll provide a link to that in the show note captions. I also just want to throw up my vote for the fact that you did this work because again, I don't disparage mouse model work, but we've just seen over and over again that the incredibly small fraction of

mouse models that lead to valid therapeutics and humans. And there's just a lot of differences between primate brains and rodent brains. And we have a very elaborate frontal cortex, a bunch of other circuitry that mice, if they have that, they probably use it for other things. And it's just very hard to draw conclusions from those models. And they're great for probing

functions that are, let's just call them more autonomic type functions. And for doing some of the initial investigations, but I think while I don't want to see every research lab switch over to primates, I think one has to be really thoughtful about the kinds of experiments one does with primates at all. This sort of behavioral assessment and the identification of a primate model for autism seems like a very good use of human resources.

Right. Well, and the other thing I will say is that there were medications that were only tested in rodents that when they were when they were tested in people had really negative consequences. I can give you two examples. So one is the litamide, which was a morning sickness medication that was given to women that were pregnant. And the safety testing in talks with toxicity testing was done only in mice. I didn't know that. Yes. And that's why it went on the market. It went on the market

in Europe. And there were all these children born with profound limb abnormalities. When they went back and tested the drug in Marmosets, neither Reese's monkeys or cinemologist monkeys, an old world monkey, they had the limb abnormalities. And so all they had to do, and again, I as an animal lover treat the life of a single monkey or a single mouse for that matter, an individual monkey, excuse me, or an individual mouse for that matter as critical. I am a species.

I do think there's a difference between their life and our lives when it comes to what study one does. But just the idea that these severe developmental defects in humans could have been avoided by doing an experiment, perhaps even on one Marmoset. And again, I feel for the life of discomfort of that Marmoset. But the idea that that could have saved so many human lives, it's just striking. Well, and there was also that street drug MPTP. That was a synthetic heroin,

right? That caused like overnight Parkinsonianism, right? When like I think the dopamine cells were just ablated, right? But when you went and looked in mice, MPTP didn't have those effects. It was only in primates and other humans and other primates, right? So, and I agree with you, I am an animal lover. I think that we have to be very careful whenever we do any animal experiments, right? And so you really need to have a good justification. I think for any science that's done, I will say that

upfront. And you know, we have this, you know, new generation of stem cell and organoid work, which I think is going to, you know, allow us to make all kinds of disease progress, right? So without having to study a whole animal models. Or in complimentary, right? But I mean, I think,

again, I think we need to pick the model based on the question we're asking, right? And so if you want to have a medication that's safe and well tolerated, you know, in people, or effective, and you want to move the needle on complex social cognition, you want to be testing it in a species that also has complex social cognition. Look, the Netflix show Chimpympire. Yeah. People haven't seen it. They should watch it. When you watch it, you realize they're very much like us. Yeah.

And there I say we're very much like them. Oh, yeah. It's far and away different than watching a bunch of mice. Yes. And I'm not being disparaging of mice. I'm assuming they have, then mice also have complex social cognition. Voles also have complex social cognition. But it's of the mouse vol type. And we don't know really even what to look for, right? But with primates, there's, you know, affiliate of gaze, there's, you know, affiliate of grooming, there's

ostracization of individuals in a troop. I mean, there's a, you know, banding, taking care of other babies. There's all sorts of interesting dynamics that maps so clearly on the human behavior and vice versa. Yeah. Yeah. So you establish this colony up at Davis, at the Regional Primates Center, that where you identified some monkeys that we don't know if they have autism, but you could see that they were less socially affiliated. Right. And I would never say they have autism.

Like I will say that upfront, you know, they have features that resemble human autism and that allow us to model this, right? So, so we started studying those animals. And what we wanted to do was do some biomarker discovery. So what we wanted to ask was, are there any molecules that allow us to differentiate these, what we'll call them naturally low social or low social monkeys from socially

competent high social monkeys. And so we measured a bunch of different readouts of neuro transmitter systems that were either involved in mammalian social behavior had been implicated in idiopathic meaning autism that doesn't have a genetic cause or these neurogenetic syndromes that we've been

talking about where there's pathways that are really associated with them. And so if we measured a bunch of these systems with 93% accuracy without even knowing what the monkey, who the monkey was, if they were lower high social, we could just put them in the low social or high social bucket. And was this by blood draw or cerebral spinal fluid? So this was, it was everything. We did blood,

we did CSF and we put all these measures into the hopper. We did a discriminant statistical analysis, which was like a machine learning algorithm where we just said, here's all this information, help me classify if this individual is higher low social. For cerebral spinal fluid is collected by spinal tap. Correct. And my understanding, I've never had one, but that spinal tap is of course more invasive than a blood draw, but it still is done as an outpatient

thing in humans. Like you can go in and get a needle inserted into the lower spine by an expert. They're going to draw cerebral spinal fluid. I mean, not that much more invasive and time consuming than getting a needle into your vein for a blood draw. Right. I mean, it's, we think of it as, it's technically a little bit more challenging. But their CSF draws in humans all the time. So in theory, this could map to a human study. And it did, which we'll talk about.

Very cool. So we went out and we did this. I have a spectacular statistician who's, we spent a lot of time together. His name's Joe Garner. And he is a statistical genius. And so he developed this and we do all of our work together. Or you know, I was saying 95% of it. We just love working together. And he developed a statistical winning, winnowing strategy to identify what were the key drivers and what was fascinating is in this first monkey cohort, it was the cerebral

spinal fluid levels of vasopressin that were really what was driving this classification. Right. So if we just knew your levels of your of vasopressin in spinal fluid, but not in blood interestingly, we could pretty closely perfect to perfect classify you as higher low social. And so then we replicated that again in another monkey cohort because obviously as a scientist, you always want to replicate your work. And then if it was really a biomarker, meaning it's a molecule in the body

that gives us an indication of something. And in this case, it's an indication of your social functioning. We were able to look at monkeys and we saw that the vasopressin was consistent across measurement time. So there was a wide variety of vasopressin levels, but within an individual monkey, it was pretty much the same. Right. So that's what you want to see with a biomarker. And then we showed that the vasopressin levels were closely linked to a group spent grooming, time spent and

grooming. And as we mentioned, I think we mentioned earlier, grooming is in many monkey species, critical behavior that solidifies social bonds and maintains them. And so the individuals with the lowest CSF vasopressin levels had spent the less time, the least amount of time in grooming. And grooming other monkeys. Other monkeys. Yeah. The salopathic grooming is a very interesting

behavior from watching Chimp Empire. I can tell you that new relationships are established in any ways by monkeys, these chimpanzees, sort of offering their back for grooming and another chimped elects to yes groom that chimp, then it establishes a some form of trust. And it all seems to have to do with proximity. Like how close are you going to let me get to you vice versa? In humans, we talk about personal space. And there's a whole set of things related to consent in

this whole alopathic grooming thing. And then if a chim misbehaves on an outing, then they aren't groomed by others. And they can actually get parasitic infections. And it can be very costly. It's very interesting to just think of alopathic grooming as not a kind of a primitive of language, but a whole language into itself. Absolutely. Yeah. And also just critical for the species. So that was really interesting to me that we were seeing these hints that vasocrossin

could be really important. But of course, somebody will say, and I will say up front, monkeys don't have autism. So then the question becomes, does this have what's called translational values? So can I see this observation in an animal model? And will it provide fundamental insights into humans? Right? And so I wanted to get cerebral spinal fluid from people to test this hypothesis because we had in parallel done a study looking at blood vasopressin levels and people within

without autism. And we didn't see a group difference there. Unlike this really profound difference that we saw when we looked at spinal fluid in the monkeys. And again, I think I mentioned the blood vasopressin levels were indistinguishable if you were higher low social monkeys. So there was something about looking more proximate to the brain that was giving us more information than say the blood alone. And so I said I wanted to get spinal fluid. And like you said,

people do this all the time. How would we, but we're, you know, it's not going to be a first pass, especially when we don't really have any evidence in people to go in for what we would call a research lumbar puncture. Right? And so I had to get really creative about how do I get spinal fluid from children and what we did was we piggybacked on to a clinical indication for a spinal fluid draw. So and we did this. So I tried to get funding for this. This is like, you know, again, I

mean, I think this is important for people to know how science is done, right? And so I wrote all these grant applications. Nobody would fund it. They said that this is really interesting. It's too high risk. You won't be able to pull it off. And, you know, I don't usually back down from a challenge. Like if I think something's a good idea and I want to do it, I'm going to find a way to do it. If somebody, if it's impossible, that's one thing. But if it's hard to do, it doesn't

mean you shouldn't do it. You just have to figure out how to do it. And so I always try to see bridges where other people see barriers, right? And so it's like, well, how can I access spinal fluid? And so I went around talking to all my friends who were on, and Stanford's really wonderful because it's such a small school, right? And so you're on all these different committees with all these different people. And so a lot of committees. Lots of committees. Exactly. But it's really cool

because you're on them with people from all different departments. Oh, yeah. I know people in departments that I wouldn't otherwise know. Yeah. And you get very, you get to know these people well in these many committees. And where we live, it's a small community, right? So like, I'm a worthy experiment. Karen, maybe there's a, I always wonder whether or not there's a larger experiment, right? Not on monkeys, not on the, the patients or the cloned up, but like we're

maybe worthy experiments, right? And they're looking at how we interact on committees. Anyway, please continue. So I started going up to people that I knew and said, hey, if you're taking spinal fluid, can I get a little bit of extra, right? And of course, we got, you know, IRB approval, meeting me at ethics approval and all this. And or you could get the remnant sample. And obviously again, get consent from the families. So we could either get a little bit extra when it was being

drawn for research indication. So, so they were getting a spinal tap, no matter what. And then we were just either we're getting a little bit extra or we were going to get the remnant that they were going to throw out, right? So you usually take more than you need because you don't want to have to do another spinal tap, right? And so we were able to go around and I hustled around and got all

these people involved to help me. We put hot pink stickers on the lumbar puncture trays so that in the emergency room, so if somebody was doing a spinal tap, they would call us so we knew about it and we could get, you know, samples again under people's consent. So we got all these people involved and we finally got samples from children with autism and children without autism. And then

we also made sure that whatever they were being worked up for was negative, right? So we got the the sort of healthiest people we could given that everybody was coming in for a medical reason to have a lumbar puncture. And in this in this first study, we had seven children with autism, seven children without autism. And we could nearly perfectly classify 13 out of 14 individuals by just knowing their CSF, vasopressin level alone, which is pretty remarkable given that there isn't

a biological indicator that we robust biological indicator that we know. So basically in this relatively small cohort, yeah, having low vasopressin is a biomarker of autism. Correct. And again, and what I will say is in our monkey studies and in our human studies, CSF oxytocin level became our control, right? So in our monkeys, there were no difference in CSF oxytocin by group. And then in this first study, there were no differences in CSF oxytocin levels.

A sample size of 14 is intriguing, but given autism so clinically heterogeneous, we want to replicate it. And so I knew that there was a professor at the NIH named Sue Suito who was collecting cerebral spinal fluid as part of a research study because she was interested in immune parameters and relate deficiency. So she had children that were medically healthy and they were getting, you know, just like at NIH, get these huge workups, right? So they were very well characterized participants.

So we were able to look at, and again, we also, this is the first time we were able to look at girls. So we had a small sample of girls and we had boys and we basically just asked the question, can we replicate this? And I was very interested in, well, will oxytocin be what's different in the girls, right? So maybe there will be some sex specificity here and it will see low CSF

vasopressin in the males and low CSF oxytocin girls. That was not the case. What we found was that if in the individuals with autism, regardless of their biological sex, that they all had lower CSF vasopressin levels than the individuals without autism. And because they were so well characterized,

we were also able to show on a gold standard research diagnostic assessment of autism. So it's an assessment that's used to, in a research situation to validate an autism diagnosis by an expert clinical opinion, that the lower your vasopressin levels in spinal fluid, the greater your social symptom severity, your clinical symptom severity. And then we asked, it's like, well, vasopressins involved in social behavior, but it's not really that involved in restricted

repetitive behaviors. And that was actually the case. So it was the CSF vasopressin track, the social symptom severity, not the repetitive symptom severity, suggesting that there might be other biological measures that could be included as a way to, you know, have a more powerful way to differentiate people within without autism. And so then I was really, so that was really exciting to replicate that. And then I had a colleague named John Constantino, who is now at Emory, but he

used to be at Washoe. And I knew that John, I had been at a meeting in, I think it was 2010, and I found out that he had what I will call liquid gold. So he had this minus 80 C freezer that was, had a bunch of neonatal infant CSF samples that he had from human infants. And he had collected them. And again, this was under ethical approvals. And it was basically, these infants came in for something that needed to be worked up that was very rare. But if they had it,

they would, you know, they could die. So they needed to get a medical treatment for it. But the vast majority of these children ended up being healthy. So it was a pretty healthy sample, if you will, right? And so I knew he had all these samples. And I said to him, wouldn't it be really interesting if we teamed up and we look at this CSF, azerpress in finding in children before the period when behavioral symptoms first manifest, right? And so, sorry, again, to, I'm going to

apologize every time. No, no, I just, but I think it's important because this was a question that, I was thinking about earlier, and I imagine many other people were too, you know, you find these monkeys that have social interaction deficits. You find kids that have social interaction deficits. And you see that there's low vase oppressing in both groups. This extends to male and female children. But then, of course, the question becomes, well, maybe they have low vase oppressing

because of so many years or even months of social interaction deficits, right? That the direction of causality isn't clear. And so, when you said liquid gold, you know, referring to the CSF from these infants, taken prior to any opportunity for social interaction beyond just, you know, whatever interaction they had with their mother up until the point that the CSF draw was taken, this really gets at the issue of causality. Right. So, it's a quasi-perspective, you know,

because it was bain, and then a lot of time went by, right? And so, what we realized we could do was, and this was a heroic undertaking on John's part. So, these were, this was, these samples were collected back on paper medical records. So, he had to trace 2000 paper med... Paper, what's that? Yeah, exactly. So, he had to trace 2000, I think, paper medical records to an electronic medical record. And then, what we did is we, he looked to see who went on to develop

autism and who didn't, right? So, then, what we had was spinal fluid samples that have sort of been waiting in the freezer, if you will. And then, we could ask, you know, do individuals who later receive an autism diagnosis many months or even years later already have low vasopressin levels as infants? And the reason why this was a compelling question to ask is, there's evidence to suggest that behavioral therapies are more effective the younger the child is,

right? And if you think about it, if behavioral characteristics of autism emerge across development, you know, what if, and this was my, this is sort of my, we haven't, we haven't substantiated this yet, but this is like sort of my big question. What if all these autism susceptibility genes, some interact and converge upon a few common pathways in the brain, right? And so, for years,

people have talked about this excitatory inhibitory balance theory of autism. But what if vasopressin is one of those pathways because it's so critically involved in social functioning? And so, what I was interested in, and so, let's just say for a moment, you know, your genes are

set at birth, what if the vasopressin is already low in the brains of these infants? And so, it puts them on this very different trajectory where you have this cumulative effective, there may be a little bit less socially interested, and maybe they're not making the eye contact. And if there was a way to intervene really early, even potentially with a vasopressin replacement therapy, that you might be able to put them on a different developmental trajectory. So,

that was my big, what if question? And what was really remarkable was, so I had been asking John, hey, can I have your spinal fluid samples? And he finally agreed after he saw a couple of those papers, understandably, you wanted to make sure that we already had shown something in people and animals that were sort of, if you will, symptomatic with social impairment.

And what we found was, yes, this was the case. So, it was a small sample. It needs to be replicated, but individual is so infants that went on to have an autism diagnosis later in life already had low CSF vasopressin levels. Oxytocin levels did not differ between infants that received a subsequent autism diagnosis and those that didn't. So, suggesting that we have a biomarker that, you know, might really be a good readout for, you know, clinical referral or risk management

monitoring. Incredible. So, you're telling us that levels of vasopressin correlate with social cognition deficits, right? I think that warns a brief discussion about cerebral spinal fluid. I teach you an anatomy and a medical student. So, forgive me for having to ask this, but, you know, I think of cerebral spinal fluid as the stuff that exists in the ventricles and down the central canal, the spinal cord and provides essential nutrients and for neurons and other

cell types in the brain. But, it's also a reservoir for chemicals coming from the brain, which is why the spinal tap is useful. But, in the context of a cerebral spinal tap and you're measuring CSF and you're seeing, okay, lower levels of vasopressin in these individuals with these challenges with social deficits. Does that mean that they're making less vasopressin? Does it mean, I mean, it could have gone the other way too, like they're dumping too much vasopressin into the

CSF and it's not able to function in the brain. Like, you know, what do we know about CSF and what does it mean? Right. Well, I mean, it's a great question. So, I think this is just the tip of the iceberg, right? So, I think of the CSF as sort of like the kitchen sink of the brain, right? And what we need is real specificity. And so, I mean, my working hypothesis, and we'll talk a little bit about pharmacology, is that there's a deficiency in, in vasopressin production and individuals

with autism. But there's a lot of elegant experiments that need to be done to be able to answer this question. So, we have funding currently to look in post-mortem human brain tissue to look at in both blood, CSF, and hypothalamic tissue where vasopressin is made to look at inner relationships, right? Which is very difficult to do. But also to see if there's a fewer number of vasopressin producing cells and if vasopressin gene expression is diminished, right? Because that would help us

begin to answer, is this a production issue, right? So, if you think back to the prairie voles, they're sort of primed to be parental, right? Or in my case, the meta voles, right? But you can do this in any volespecies, or at least the two that I'm thinking of. And you put vasopressin into the

brain, and then all of a sudden it unlocks this behavior, right? So, is it possible that children with autism, or at least a subset of them, all you have to do is replace vasopressin and that there might be a subset of these kids minimally that could benefit from vasopressin replacement, if you will? Is there any evidence for excessive urination in kids with autism? Which, if anyone is going, what? Why is he asking that? If you recall, vasopressin is also anti-diuretic hormone.

I suppose the other question is, could you, has anyone looked at levels of vasopressin in the urine of autistic kids versus non-antistic kids? Because it's acting peripherally and you said blood draws, don't reveal any differences in circulating blood. We know that urine is filtered blood, right? Fair enough, but seems at least worth the look. So I have this awesome medical student in my lab named Lauren Clark, and we with three different physicians from different backgrounds. So

wrote a perspective piece that's currently under review, and it actually asks this question. So, you know, given all these weird medical naming conventions, it's possible that this information is existing in information silos and different disciplines, right? So it raises this idea of, if you have low vasopressin, so there's a, if you really don't have, you're not making vasopressin, you have a disorder called central diabetes insipidus, right? Which is characterized by

excessive thirst, lots of urination, and, and, and, you know, bedwetting potentially. And so, what we wanted to do was ask, has this been missed, right? So shouldn't there be a subset of kids with autism where we might be able to look at these other physiological features and say, yeah, this is the subset we want to be giving vasopressin to. And so she wrote this perspective where we did

a little bit of a review. And the answers, there's some intriguing studies that we reviewed in this paper where it looks like, and what's funny is when you read the discussion section, it'll be like, wow, there's all these kids with autism that are drinking lots of water. And we don't know why, or wow, there's a lot of bedwetting, but it's not tied to intellectual disability where you might see a lot of bedwetting or something. So all of these studies kind of raised this point of like, wow,

this is really interesting. And there's been no big epidemiological study done on this. And certainly not any study where people who come at it from brain science. And then the, the practitioners who were like an enterchoronologist, for instance, was, which is where some of these people could show up are, are really connecting the dots. So I think that remains to be determined, but we are actually about to launch a study to investigate this, right? I was meeting with Lauren yesterday about it.

So it's a really good question. And I hope to have information on it in the not too distant future. Is that recall alcohol is an antagonist of vasopressin? So there's a lot of different drugs that could interact with vasopressin. And so one thing I'm interested in is, are there any drugs that release vasopressin as a side effect? And could some of them be mobilized to treat autism? We also know that like acupuncture can release vasopressin. There's been some studies done in rats on that.

And so one question would just be, are there any alternative therapies where we can be releasing vasopressin naturally? Or do we need to, you know, do a replacement study where we give, you know, intranasal vasopressin to children with autism, right? And of course, I'm not, I want to say, I'm not advocating that people go out and do this on their own, right? Like I'm, I'm a big proponent of randomized clinical trials where you assess safety, right? And advocacy. Yes,

science and medicine. Right. But I appreciate you saying that. Yeah, some years ago, so this would be mid 90s. There was a small but very active subculture that I was not a part of, I swear, that were combining GHB, Gemahydroxybutyrate and vasopressin as combination, quote unquote, sex drugs. Really? Yes. Yeah. And I don't know what the rationale for including vasopressin was. Yeah. In any case, whether or not that's by way of enhancing social bonding or a direct

effect on sexual rousell itself is still unclear. But in any event, since we're talking about vasopressin, maybe you should tell us about the actual science of vasopressin. Sorry, maybe I should allow you to tell us about the actual scientific study of vasopressin. In other words, what happens if you give people vasopressin in a controlled environment? Right. Not the sort of environment I'm talking about, but a control. And the one thing I will say, because I have people contact us all the

time saying, where can I get vasopressin? And what I would say is, vasopressin means, you know, you're having effects on blood pressure, you're having effects on really important. Right. Vasod. Right. And people, and the dosing has to be appropriate. You know, you don't want people just going and trying this because there could be really severe adverse effects. Right. So that's why we've been studying this in a in a controlled clinical trial. Right. So I teamed

up with Antonio Hardin, who's the child psychiatrist that I've been working with for years. And we did the first sort of first in class, vasopressin treatment trial and children with autism. So again, this was everyone was unaware of who was on vasopressin, whether it was the family or the clinician who was doing the evaluation. And then it was randomized, placebo controlled. And then we basically gave

vasopressin again twice a day for four weeks to children. They were about six to 12 years of age. And then we had a primary outcome measure, which was the social responsiveness scale. We could get into discussions about what a primary outcome measure should be, you know, when to be great if there was a biological measure. But this is sort of what had been used in the past and something that the FDA approved us using. I was partly interested in using the SOS because we had used it in

monkeys, right. And we had shown at least in monkeys, we've never looked at this in people because of, you know, the lack of available samples. But that in monkeys in this general population that we've looked at, there's a continuous distribution of these SOS scores that relate to the CSF vasopressin levels. And so what was I wanted to know if we use the SOS as an outcome measure and we're administering vasopressin, can we change, you know, the scoring on this instrument based

on our animal data? So SOS is social responsiveness scale without going into a lot of detail because we can always refer people to the paper. And I think most people just want to understand the top contour. The SOS presumably has to do with how often the kid interacts with another kid, how often they initiate that interaction versus on the receiving end, things like affiliative play, how often they look at one another versus averting gaze, these kinds of things.

Yep. And then there's also a little bit about restructure repetitive behaviors. So even though it's called the social responsiveness scale, there's also an assessment of other features of autism in it. But you can sort of think about it as a quantitative way to assess features of interest in autism. And this was related to our biology and the monkeys. And so then we use this as this outcome measure in our trial. And, you know, as an experimentalist, I have this sort of trust

but verify, right? So you want to you want to see the same thing over and over and over again, right? Like scientists like repetition. And so we had parents fill out their impressions of what the child's behavior was, you know, before and after being on the medication. We also had a clinician make an evaluation, but we also had the kids perform laboratory based tests where they would see, like I mentioned, the reading the mind in the eyes test or we would show them a picture

of a face and say, what emotion is this? And so we were able to have what's called convergent validity, right? So it's a fancy scientific term to say, do all these measures that we think should be related are they related? And are we seeing the same thing? And the answer was yes, so that when we gave children with autism, vasopressin versus kids with autism, a placebo, the kids who were treated with vasopressin showed increases in social abilities on parent

report, clinician evaluation and child performance on laboratory based tests. Was that in was that immediate? Like they did the nasal spray and they immediately started receiving and initiating more social engagement, where was this a buildup over time? And what I'm getting at here is whether they're not this is the reflection of short or longer term neuroplasticity, like where there's structural changes in the brain or is this something that was more acute? We don't know the answer

to that. So we basically looked at dosing with the idea that we would, you know, and again, I think we've mentioned this about limitations on like there's so many things that a scientist would like to do, but you were always limited by a budget, right? And so when we started this work again, it was like philanthropic shoestring budgets, right? And so you had to really be laser focused on

what are the things that we can do on the budget at hand? So unfortunately, we didn't do like EEG or brain imaging or other things that would be, I think, potentially very interesting to do, because you might be able to see an early signature of response, right? So maybe after the first dose, let's say, wow, like there's some interesting changes that are predictive of somebody who would be a responder to the medication, and we don't know that yet. But we do know after this four-week period

that we saw, you know, these changes. And then in a subset of kids, we actually saw diminished anxiety and also diminished restricted repetitive behaviors. So suggesting that the laser press in effect may not only be on social behavior. Have you ever just wanted to try or try a

laser press in? You know, I haven't, but I think- You're in a psychiatry department after all. And I'm not suggesting that members of the psychiatry department are constantly testing the drugs that they use on their patients with themselves, but I've had several members of this department of

which I'm a courtesy member, member by courtesy, and even, we'll see if I'm still am after what I'm about to say, Dr. Carl Dice Roth, who's a clinician, our first guest on the human lab podcast, also a phenomenal neurobiology researcher, David Spiegel, Rob Malenka, and others that I've spoken to. You know, I think all of whom said, you know, that they felt as clinicians, Rob's not a clinician,

but anymore, right? But as a clinician, that they felt almost a responsibility to understand the effects and side effect profiles of the drugs that they were giving their patients, which I saw not as renegative or experimental, but rather as a very compassionate, like seeking empathy.

So I'm curious, have you ever just snuck a little role now? No, I never have, but there is a long history and medicine of people trying out, they believe so much in their solution that they go and vaccinate their family with the new vaccine that they've created or they try the medication

themselves, right? So- MDMA was developed by Sasha Kogan in a laboratory in the East Bay, first by a pharmaceutical company in the early 1900s, but then disappeared, it did disappear, and then it was resurrected independently in the 1970s and 80s, and then now it's one of the sort of hot topic items for the treatment of PTSD, still in late phase clinical trial, still illegal, but self-experimentation is one of the central themes of psychiatry, frankly.

Yeah, I mean, I guess I, you know, it's, I probably got in trouble in class for being too social, right? So, I guess I've never- I might send you over the other side. Yeah, yeah, exactly who knows, but no, I never know, and the thing is, is that these oxytocin and vasopressin, and again, these are done, and this is something that I think we've hit on over and over again in the podcast, is you need to

know who's, you're studying, right? What's the species? Who's the individual? You know, most of these have been done in, you know, neuro, I mean, a lot of the oxytocin and a little bit of the vasopressin work, the single dose work, was mostly done in what we'll call neurotypical people, right? Just asking, can we move around social behavior by just giving the single drug administration? Most people that are neurotypical didn't say that they could tell if they were on the drug or

the placebo, right? So- Interesting. So I think the question really becomes, you know, drugs have different,

you know, they work differently based on the individual who's taking them. So if you have a neurotypical individual and you give them vasopressin, you know, maybe they'll self-report that they don't see a difference, but if you had somebody who isn't producing enough vasopressin, maybe, you know, they would self-report after a period of time, or maybe even after the first dose, wow, I really see something different, right? Did any of the kids report how they felt? I just said like, wow,

I like playing with other kids more, were they self-aware in that way? And also feel free to mention if it feels right to you. Any, let's consider two outlier cases. One spectacular result of that, you know, a kid that went from very socially isolated to, you know, maybe very gregarious. Yeah. But let's also balance that with another outlier, the kid with low vasopressin who took vasopressin, for whom there was no significant shift. I'm presuming that within the data set,

you probably observe something like each of those. Yeah. So, I mean, what I'll say is that, so yeah, I mean, there were definitely kids who didn't respond to the medication. I mean, one thing I think it's important to say, and again, this was a small pilot trial, right? We're in the process of replicating this in a much larger sample. So, you know, as a scientist again,

you want to say, okay, this is really intriguing and interesting. And I've invested a lot in, you know, this monkey model and then doing all the CSF work in patients to suggest that there may be a there there here, but I want to see it replicate. We did have an article that Stanford medicine. I can send you the link. They were able to, I think, interview a family that had been in the trial. And so obviously, there's patient privacy and, you know, you have to, they have to say,

it's okay to talk about it, but this is a family that was contacted. I think they were anonymous, but this is in this report. And they basically said, the dad said that his son was walking around the, he was on the visa press and his son was walking around a grocery store and he like was looking for him. And he turned around and he said he was gobsmacked because his child was, you know, just talking to making chit chat with somebody like in an aisle. And he said

he had never seen that happen before. And so, you know, we do have anecdotal reports like that. And I think, you know, the tricky part is, are we, we didn't stratify anyone going into this trial, right? And so the concern always is, did we get really lucky in the first trial? And we somehow got the, the quote unquote, right people that entered the trial that were going to be the ones who would respond to the medication, or is this a medication that has sort of broad use in this

population? And we, you know, the second trial will be positive. You used nasal spray to deliver the visa press. And presumably that gets into the blood circulation of the brain and supplies neurons with the visa press. And but it's very non specific. And I'm not criticizing. But if you think about, you're just putting a bunch of visa press into the brain. And if people wonder why this is, it's because basically you have neurons of your central nervous system are part of your

olfactory system. And believe it out right behind your, where your nose meets your forehead, you know, the brain is right there. There's a little bit of bone and then the brain is, is, is right there. So, um, one of the reasons you can get in there, um, and it's easier than an ocular injection or something that wouldn't be a good approach. And it's easier than peripheral

and that should injection of the vein. But at the same time, I have to presume that this, I'm imagining this vase of press and just kind of like, permeate through the brain, binding to whatever receptors happen to be there. You said the receptors are everywhere. And then this significant improvement in social cognition. So that raises all sorts of interesting questions about like, what are, what relevant circuits are impacted? Or is it some global,

could it be some global increase in kind of awareness of surroundings? Although some autistic kids are overwhelmed by their awareness of surrounding. So, yeah, what are some thoughts about how vase of press and might be working to exert this, this really impressive and frankly, important effect? Right. So, I mean, could it increase social motivation? Does it, you know,

like, so let's talk about like how sort of complexity of social, um, sensory processing? Is it that we're directing attention to social cues where there wouldn't have necessarily been as much attentiveness, right? Um, are we increasing social motivation, which would suggest from some of the animal studies may actually be happening, right? Um, we don't know. And I think that's partly

when you have other models or if you're able, you know, to do imaging studies. I mean, one thing that's been a little bit of a holy grail in this field is that if we could get, um, tracers that are basically like, you know, a molecule that would allow us to inject it into somebody and then visualize the brain, like if I'm thinking about a pet tracer or a radio ligand where you could then ask

questions about, you know, what's happening in the brain? Can we, can we give vase of press in in the context of a, you know, functional brain imaging scan and ask like, where is the vase of press and binding? What kind of circuits are involved? Like that needs to be the next step of the work to know like where where our targets are. And you, you can do something like functional proteomics, right? Where if you know where vase of press and receptors are, you can overlay that

with studies of functional brain imaging, right? And that would allow you to say these areas are dense in vase of press and receptors. And do we see similar responses in what we call bold signal on a, on a brain scan? So let's, let's be more colloquial about this. Like do certain areas the brain light up, if you will, where we know vase of press and receptors are, are densely distributed, um, in ways that we know are tied to social motivation or social salience or other

things that we think could be moving the needle here, um, in the trial. How is this happening? And, and I think, you know, one thing, the reason why we did this work is, and I think it speaks to what you said earlier is there is an urgency on the part of parents to say, you know, my child's brain is developing, right? And, and there's a sense of that them, you know, by the sort of western model has failed a lot of people, you know, they look to doctors and say, what are, what are the

solutions? And doctors will say, well, we have a limited number of tools in the toolkit here. We just don't know, right? And so, you know, one of the reasons why they did that big oxytocin study was that people were trying to get the oxytocin anyway. So it was like, let's just make sure that this is safe. Let's see if it's effective. And so some of our thinking was, you know, as soon as some of this work hits, you know, like it gets, and some of the work has been covered by

the media. And so, you know, our feeling was, we can give this intranasally, and we can do it under safe monitoring ways. And so people are going to think about doing these things anyway. So let's just make sure that this is safe and let's test this in a rigorous way. So we don't know the mode of action. But then our feeling is, is that, you know, at least from the initial safety data, it looks

pretty safe. And, you know, and so the idea would be, and there's a long tradition and psychiatry, if we don't know the mechanism of action, but if we have a medication that can be impactful and improve the lives of people with autism, and we can diminish suffering and people can more readily reach their full potential, you know, to me, it actually seems unethical not to move forward in a way that's scientifically sound. Amen to that. This seems like a good time to raise

the topic of the microbiome, and not as an unrelated topic. And here's why I've seen a fair number of studies in mouse models arguing that in a mouse model of autism, which now, frankly, I have to, I don't wonder about the power of that model, but anyway, the models are out there in

the field. One can take the microbiome, basically, let's be direct, fecal transplants from a, and here I'm using air quotes, non-autistic mouse or a mouse that doesn't have social interaction deficits, and put that fecal transplant into a host that does have social deficits, and rescue some degree of social deficits. I don't know if this has actually been done in humans as well, and for those of you that are cringing, yes, they do fecal transplants in humans for treatment

of obesity and a bunch of other things. This isn't because scientists are obsessed with fecal matter, it's because fecal matter contains a lot of the microbiome elements, so the micro bacteria of the gut. And the reason I'm raising this now is, you know, one possibility, and it's not mutually exclusive with a brain mechanism, is that the administration of vasopressin somehow rescued of vasopressin deficiency in the gut. So the questions are as follows. Is there any evidence that

vasopressin is manufactured in or impacted by the gut microbiome of humans? We'll just start with humans, since I think most, and because that wouldn't be a smoking gun, but it'd be an interesting detective story. Well, okay, so the one piece of evidence that I will say that I find provocative and fascinating. And one thing I want to say is, I think there's really great work done in mice. I don't want to be a mouse basher, so I want to just like sort of go on the record that I'm

not bashing other models. If it's a conservative, I think about everything from an like an evolutionary perspective. If a mouse shares a brain structure with a human, and it's highly conserved, you know, mouse work can be incredibly important and very impactful, right? Yeah, my lab did years of mouse work. Some primate work were necessary. Now I only work on humans. But it absolutely has its uses. Yeah. But clearly the primate model for social deficits as it relates to autism,

you at least have me convinced that one has a lot of power. Right. Exactly. Okay, but I mean, I now say there is a really cool mouse study that was done that I found. And there's been, you know, lots of different studies. So there has been mice. So there's these, like I said, these genetically modified mice that have genetic syndromes that are, you know, where the individuals have social impairments. And some of these individuals, and again, here's a problem with the field.

Often they will measure oxytocin but not vasopressin, right? So like they're not often both measured together, which I always do now. But there's been some really interesting evidence that in these mouse models that, and again, multiple studies, but like certainly low blood oxytocin levels in these mouse models. What, and with the sense that maybe they have some sort of abnormal gut microbiome. And then what they've done is they've given a probiotic to these mice, normalize their social

functioning. And that, there's an increase in oxytocin. And in a recent study, also, vasopressin at the level of the hypothalamus. So by giving a probiotic, you, I believe the oxytocin levels were increased in the blood. You saw more species typical social behavior. And this was all driven by this upregulation of oxytocin gene expression. And also, vasopressin in this very recent study. And what's interesting is there's this nerve called the

vagus nerve, which is, it's, I think, it means the wandering nerve. It's for vagabond. Yeah, exactly. Right. And even it's in the gut, but it actually has a direct projection to the nuclei in the hypothalamus where oxytocin and vasopressin are made. Oh, interesting. Yes. And so when you sever the vagus, you then in this one study, it's a neuron paper. I think it's like 2020. It's a super cool paper. And then what you do is you decrease the gene expression and you don't see the

rescue of the oxytocin levels or the social behavior in this model. So in other words, if I interpret this correctly, and I'll go look up the paper and provide a link to it, they're, they're by increasing the diversity of gut microbiota, because that's really what a probiotic does. So across the board, it increases the diversity of gut microbiota. No one specific illness, as I always say, because they all seem to end in illness. You know, multiple illnesses, illicit, illicit,

here we go again. You upregulate gene expression and thereby action of oxytocin and vasopressin in the hypothalamus. But that's a neural mediated thing. It's not as if the microbiota travels to the brain. Something changes in the gut, which activates the vagal pathway from gut to the specific nucleus in the brain. And we know that the vagal pathways involved, because it seems at least partially necessary. If you sever that, you give a vagotomy, then the, this effect is

blunted or eliminated. That's very interesting and ties the microbiome to oxytocin, vasopressin production in a neural and somewhat causal way and makes the data on fecal transplants make a lot of more sense. Because I was wondering, okay, so you take it, you know, taking the microbiota from one animal, put it into another animal, you're creating, you're transferring the milieu of the gut. But it doesn't say anything about mechanism. So this is a really cool paper.

It's fascinating. And there's also a study I've always wanted to do, is you can get a vagal nerve stimulator. They used to do them as implants, right? But you can also get one that you sort of clip onto the ear. And I've always wanted to ask if we use this in autistic individuals, and, you know, could we increase, like, can we alter social behavior, right? And would that be something that we could actually measure in the blood, especially if we're seeing this, this change in these blood levels,

right? Are you doing that experiment? No, but I've always, I've, I've always said we've got to get, we have to get you the funding to do that experiment. And I know a few times you raise the issue of funding. It's not something we spend a lot of time on this, discussing on this podcast, but I think what should be abundantly clear to the listeners throughout the course of this episode, as you mentioned earlier, you're very determined to get worked on. You'll figure out a way. But the way I

described finances and research is that it's absolutely necessary, but it's not sufficient. You got, of course, have to have the right people and the right lab head directing the work, but no money, no, no project. And it, and it is disappointing to see that despite the federal budget for research being still reasonable, it's not what we would like it to be. It's still very hard for amazing world-class labs like yours to say, you know, listen, there's this vagal thing and

clearly there's a rationale. It's not like you're pulling this out of, out of nowhere. And you want to go to this study, but what we're really talking about is three to five years of grant writing before you could even initiate that study. Meanwhile, autistic kids are going from age two to five to six. These are critical windows. So if ever there was a, there was a rationale for, you know, moving a lot of funding to, you know, I don't even call it high risk, but, you know, logically sound

hypothesis testing for the treatment of autism. It's now. So I'm going to get active on this front. So I won't get into how, but, you know, when I get something in my, in my neural circuits for talking, they tend to not shut down for a while. Well, there will be a community that is going to be immensely grateful. Well, it seems like the parents of these kids and the kids themselves could greatly benefit. So you mentioned that the first study on the suppressor administration that saw

these improvements in social functioning, you said a small cohort. How many, how many kids was it ultimately that you could use data from? Okay. So we had, I mean, you screen a lot. So I think are, you know, because we had very rigid criteria. So we ended up with 17 kids that were on active drug and 13 that were on placebo. And then not a tiny study. No. And the placebo show that we, we always have like a humanitarian open label extension arm, which allows for anybody who is in

placebo can get access to the drugs. So both Antonio and I feel very strongly about making sure that if we're doing a medication trial, everybody can benefit from it, right? So after words, if they say, okay, I was in the placebo group, but I really want the chance to try this thing. Yes. They can't, but then you also get more data. We get, right. So I think when the families are now aware that their child is on vasopressin and the clinicians are aware, you know, you really want,

there's a huge placebo response rate, right? And so, I mean, it's not a place to see a low response rate here, but, but we really would want to make sure that our evaluation of the social behavior is done unaware to the medication, but you can get good safety data, right? So, so you can have those, you know, 13 children who were on placebo. We can then also make sure that

their blood chemistry labs look good, that their electrocardiograms look good, right? And so, that also allows us to assess safety parameters in a greater number of children. In a fairly broad literature search, I was able to find, okay, microbiome, so fecal transplant is something that people are excited about as we're. And there are trials in people with autism ongoing. And using fecal transplant. Yes. Okay. Oxytocin nasal spray presumably still being

investigated by some groups, or it's been abandoned. Well, I think it's mostly been abandoned because there's no funding priorities for it, right? So, so I know that maybe in Australia, because of Adam's positive findings that I don't know what his plans are, but maybe he's doing work there. There might be a little bit of work with behavioral therapy and oxytocin, but this is the problem when there's one big trial that fails. The funding just completely dries up. So, even if there's

promise, I don't know a single funding agency that's going to touch it. Got it. And then there's the vasopressin administration work that you're doing. Right. I think it's worth contrasting that work with the fairly large trial that was done by a major pharmaceutical company exploring the role of vasopressin for the treatment of autism. You could tell us what they did because it's basically

the opposite of what you did. And you can tell us the outcome because I think that if anything, that study inadvertently provides support for the results that you observed, which is that administering, let's say, increasing vasopressin levels in the brain seems to ameliorate some of the social deficits of autism. Right. So, Roch had a compound called BalaVapton, which was a vasopressin V1A receptor antagonist, which basically means there's, I think I mentioned there's

these four neuropeptide receptors. And oxytocin, vasopressin bind to each other's receptors, but the V1A receptor is the one that is most implicated in social behavior. And so they had, and this is the tricky part about when medications are developed in pharma versus in academics. Right. In academics, there's definitely this transparency. We write grants. The abstracts are publicly available. We register our trials. They do too. But a lot of the, shall we say, early development is all put out

in publications. Right. And then it's also peer reviewed. And there's, you know, an open trail of why we're doing what we're doing. But in a pharmaceutical company, you know, they have the ability, because also they have all the funding to be able to do all kinds of development that may never see the light of day because of the proprietary basis of it. Right. And so, you know, when you go back to, so it's not, it still is not clear to me why they took the approach of using an antagonist

to the main vasopressin receptor in the brain. What's interesting is if you go back and you look at the animal literature, there are hamsters that if you give them vasopressin, they become aggressive. Right. And if you give male prairie voles, vasopressin, they can become aggressive. But let's think about the context that they're doing this in. These hamsters that show aggression are a social,

they live by themselves. If you give them vasopressin and the only social repertoire they have is to, you know, have sex with a female or to fight a male that they see, they have a very limited social repertoire. Right. And when the prairie volumail is being given vasopressin, it's often in the context of, like, protecting his mate and his offspring. And so then it's actually species appropriate for him to attack a moratering male on his territory who's going to, you know, kill his

babies, right. And so, so my thinking in reading the preclinical literature, the animal literature was that, all right, that makes a lot of sense in the context of those species. But we've never seen any evidence in our trial. Aggression didn't change. We also have an aggression measure in this current, in the current trial as well. But, you know, for me, the vast majority of evidence from

the animal literature suggested that vasopressin was pro-social. And that, you know, especially given our CSF findings, like over and over across species, across studies, across ages, that we should be giving vasopressin, especially given the correlations between vasopressin in CSF and symptom severity and autistic traits, you know, the former and people and the latter and the monkeys. And so they had some preliminary studies that I believe were maybe single dose, one that they

published. But then they had a trial where the primary outcome measure, the social responsiveness scale was negative. And then they had some secondary measures that maybe showed some promise. And then they were conducting another trial. And then they did a futility analysis. And I know they stopped the trial. And I don't think it was for safety reasons. But again, you know, a lot of this isn't made public, right, because it's a pharmaceutical company. So, you know, we, we will see

because we are going to be completing our larger trial, you know, this year. And, you know, as they say, the proof is in the pudding. So we will see if, you know, we can replicate our initial pilot findings. Well, sounds like they got it backwards that blocking vasopressin pathways would just make things worse. And that augmenting vasopressin makes things better. Although that last statement needs to be supported by this more extensive. Right. Well, I think, you know, there's been a lot of

speculation. And maybe there are people closer to the trial than me who might be able to speak to mechanism. But, you know, I would meet the Roche people at conferences and they would come to my talks. And I would always ask him, like, what's the mechanism of action? Why are you antagonizing the system when we're giving, you know, a vasopressin agonist, if you will. And, you know, some people had said, well, maybe by blocking the vasopressin receptor, you know, there's a way to have oxytocin

me be more bioavailable. Sounds like some gymnastics. Yeah, I totally agree. And so I've never had a, I've never received a compelling response from anybody about why they did their trial. And then, you know, the differences. I mean, when this was ongoing and, you know, there was potentially room for both, right? You know, maybe I thought that maybe there's some optimal band of vasopressin signaling in the brain, right? And so maybe there's some people where they have too much vasopressin

and some who have too little, right? And so this was a lot of babies, but it doesn't, to me, seem like that's the case, especially if our current trial has a positive readout. I'd be remiss if I didn't ask for your stance and read of the landscape on the data about vaccines and autism. I'm not talking about COVID vaccines here. I want to be really clear about that, but there was a theory running about not just in the press, but in scientific literature,

for a while, that vaccines could cause autism. Yeah. That was proposed. My understanding is that was debunked. That idea still lives on the internet. But what is the evidence? Or let's say, let's go through this sequentially. What was the idea? What was the evidence for that idea? And then what caused the demise of the, at least the scientific support for that idea? Leaving open, of course,

that new data may come. Right. But let's talk about what is known now. Right. And I think what I will say is being evidence-based is sort of like something that all scientists should strive for, right? And so the backstory on this is there was a guy named Andrew Wakefield who published a paper and he basically said the preservatives and vaccines are causing autism. So not the specific vaccine, but the adjuvant, the stuff that's preserving. The mercury was one of those. The stuff that's

keeping the vaccines bio-effective. Right. At least that was my understanding. Yeah, that's mine as well. And so, and then it turned out- Right. I want to be clear because the internet is a cruel and diabolical place. My stance is that that was the hypothesis. I don't agree with that stance. Right. Right. Right. And so, or if we want to just back up a little bit broader, there was this idea that something about vaccines were causing autism. But the study was debunked. He lost his

medical license and the paper was retracted, right? Well, he lost his medical license on the basis of the fact that the study was wrong or was there- I think he figured the data. That's why we're called as well. But there was evidence of him literally making up the data. Right. Right. So, it was in a case of like sloppy technique. It was a case of- Right. of intentional fraud. Right. That's my understanding. Again. What was the- does anyone ever

like look into what his motivation for what what it was? Like why someone would- I mean, through a way this whole career. Right. Yeah. I don't- I don't know. But I think the hard part about that is understandably people got very frightened, right? That we're doing something to our children that could have, you know, un- anticipate a consequences. And, you know, when something like that

happens, then we dump- you know, we spend a lot of money investigating it. And so, the good news is at this point, there have been multiple, multiple studies that haven't shown a correlation between, you know, vaccines and autism. I do believe the preservatives have been changed as a result. So, that's something we should check that, you know, that might be something where, you know, there's been a public health change on preservatives that are in vaccines. That's interesting in its own

right. I mean, we don't want to cause alarm if- but that's- that's interesting, you know, that- that in this data fraud case, it might have queued people to the idea that certain things might have been needing change, even though it wasn't the specific issue that this- this fraudulent researcher was focused on. Or- The change was made to make sure people would vaccinate their children, right? Like, so this is something that I think we should have lots of caveats here, like, you know, post- the

post- the studies, like, make sure that what we're saying is accurate, right? But I think that my concern is that we've spent- you know, so the good news is that, you know, the major- like every single study that I'm aware of does not show a relationship between vaccination and autism, right? And so, I think that most scientists and medical doctors that I know that are part of like the,

you know, standard biomedical research community do not believe the vaccines cause autism. They vaccinate their own children, you know, they recommend vaccinations to other people's children. And so I think that's where we are. You know- Could I just ask a question?

Yeah. And I feel more than obligated to do this because I don't- you know, I think I have a pretty good finger on the pulse of the listenership of this podcast, but I think there's a range of of stances on this where some people have a lot of trust in the standard medical establishment. Others have less trust in the standard medical establishment. And I wouldn't be doing my job if I

didn't try and represent all those sides. And, you know, one thing that I've heard is that over the last 20 or 30 years, there's been a dramatic increase in the number of vaccinations that kids get. And I don't know if that's true. But when we save vaccinations, we could be talking about, you know, measles, mumps, favela, polio. We could also be talking about measles, mumps, favela, polio, flu shots every year, rabies, vaccine, tetanus vaccine, you know, HPV, HPV, right?

With one that wasn't even available when I was in college, you know, as everyone in college, who was well aware, there wasn't an HPV vaccine. Didn't change people's behavior a whole lot, but, you know, there's a vaccine, there's multiple vaccines, and then there's, you know, all the vaccines. Right? And I think that one of the concerns that I hear about is that the idea that, okay, there's some critical vaccines, but then which ones are perhaps less critical if any. And these are

the kinds of discussions that are starting to surface. And that, you know, have parents and potential parents, you know, rightfully thinking about this stuff. And no one really knows where to get the information. But like I've tried, and I can't find a pediatrician that says, hey, listen, these, but not those. Or you can certainly find board certified physicians that say, many and certain board certified physicians that say, none, you actually can find those.

The noncategory tend to hide themselves a little bit more than others for obvious reasons. But it's hard to get a sense of like which vaccines are critical and which ones aren't. If you're a parent and you're not versed in this stuff. And so you could imagine that like people are, you know, kids are taking many more vaccines and only some of those are critical. Or maybe all of them are critical. I think, I mean, guess the way I would maybe turn it on its head is that,

you know, because of this study that did in some way so much harm, right? We spent, we spent, I don't even want to hazard a guess about how much money worldwide went into studying, you know, the vaccines and autism based on a fraudulent data, right? Like that's to me a real tragedy. But at the time they didn't know it was fraudulent. No, right. Exactly. So they went

after this thinking it was true. But I think, I think the thing, the consequence of all this, that I think is also extremely sad is that everybody, because everyone got so riled up and so fearful, there has been historically until recently many researchers who are like, oh man, I don't want to touch immunology and autism with a 10-foot pole, right? And yeah. You know, I wouldn't concern myself fearless, but like my lab never had any reason to work on those, on those important problems.

But I'll tell you, like, that seems like it's not a kettle of fish. It's a ball of barbed wire with a bunch of, you know, napalm burning around it. You know, I mean, you say one thing, your career's ending. You say the opposite thing, your career is also ending. You know, it's a mess. But I think this highlights that there are so many parents, you know, again, and I think we need to listen to parents' stakeholders, right? Like, you know, there needs to be a dialogue,

whenever anybody's studying any illness, to talk to the people who are involved, right? And and I think that there are parents who will report, wow, like, there are, there is immune system dysregulation in my child. And but because of this historical issue with vaccines, it's only been very recently that I think people, scientists, medical doctors have said, okay, we're hearing a lot about this from parents. And are there a group of individuals who have,

you know, immune issues that could be driving their autism, right? We don't know, and everything should be evidence-based. But I think that, like you said, with this cancel culture and all this fear, scientists sometimes will pick topics very judiciously based on, you know, like, hey, I just want to be left in peace. And I'm trying to help this community. And if there is areas of the enterprise that you think are going to cause all kinds of grief, then people are going to be

less reluctant to study them, even if it's critically needed. Well, that's a perfect place to say thank you. I realize you're not addressing the vaccine autism issue directly, but you're so clearly going after the target, trying to figure out what are the biological mechanisms that are disrupted in autism and by extension, other deficits of social function in kids and adults. You've identified this incredible relationship between vasopressin, which should have more

prominence in my opinion than oxytocin. It's lesser cousin. Just kidding. Oxytocin lovers. But also have shown, you know, yes, in a small study, but you're now extending this to larger cohort, as you mentioned, a causal relationship when vasopressin is administered to these low vasopressin

and slash low social function in kids. They're symptoms improve. So I know I speak for many people when I say that I truly appreciate your dog goodness in going after this problem, especially on the complicated landscape of lack of funding for doing novel and truly high risk work, especially on the backdrop of the sociopolitical landscape around autism. It's a complicated thing even to discuss. As I mentioned in the introduction, we had to have some fluency around autism, so we

sometimes said autistic. Sometimes we said people with autism, you know, it's a tough one, but in order to make progress, real progress in this area, we need people like you, we need you, and you're doing it to get in there and just go, okay, let's get at the biological functions, let's get at the novel treatments, and you're making amazing progress. So I'm so grateful that you're doing it and that you'll continue to do it and that you came here today to teach us what you've

been up to. I'm also grateful and I just want to say thank you for that and that we absolutely have to get you back here to give us an update on your progress really soon and again and again and again. Thank you so much. I love being here. All right, well, I've loved this conversation and I'll sign off by saying folks, this is how diseases are cured. Thank you for joining me for today's discussion with Dr. Karen Parker about the biological basis of social functioning and autism.

To learn more about Dr. Parker's research, please see the links in our show note captions. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero-cost way to support us. In addition, please subscribe to the podcast on both Spotify and Apple and on both Spotify and Apple, you can leave us up to a five-star review. If you have questions for me or comments about the podcast or guests you'd like me to consider on

the Huberman Lab podcast, please put those in the comment section on YouTube. I do read all the comments. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. Not so much on today's episode, but on many previous episodes of the Huberman Lab podcast, we discuss supplements. While supplements aren't necessary for everybody, many people derive tremendous benefit from them for things like improving

sleep, for hormone support, and for improving focus. To learn more about the supplements discussed on the Huberman Lab podcast, go to livemomentus.com.us. If you're not already following me on social media, I am Huberman Lab on Instagram, X, formerly called Twitter, LinkedIn, Facebook, and Threads. And at all of those places, I discuss science and science-related tools, some of which overlaps with the content of the Huberman Lab podcast, but much of which is distinct from the content covered

on the Huberman Lab podcast. So again, it's Huberman Lab on all social media channels. If you haven't already subscribed to our neural network newsletter, our neural network newsletter is a zero-cost

newsletter that comes out every month. It includes podcast summaries, as well as protocols in the form of short PDFs of maybe just one to three pages, where I list out the specific protocols, for instance, for improving dopamine functioning, or for improving your sleep, or for deliberate cold exposure, deliberate heat exposure, or fitness protocols, and on and on, all of which are presented in brief fashion, very direct, just the protocols listed out again, completely zero cost.

To sign up, you simply go to HubermanLab.com, go to the menu function, scroll down to newsletter, and enter your email. And I should point out that we do not share your email with anybody. Thank you once again for joining me for today's discussion with Dr. Karen Parker. And last but certainly not least, thank you for your interest in science.