Dr. Karen Parker: The Causes & Treatments for Autism

00:00:00.000 | Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools

00:00:04.780 | for everyday life.

00:00:09.200 | I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford

00:00:14.060 | School of Medicine.

00:00:15.520 | My guest today is Dr. Karen Parker.

00:00:17.680 | Dr. Karen Parker directs the social neurosciences research program at the Stanford University

00:00:22.860 | School of Medicine.

00:00:24.280 | The goal of her laboratory's research is to understand the biological basis of social

00:00:28.400 | functioning at every stage of the lifespan.

00:00:31.500 | So this includes the bonds that form between infant and parent or parents, as well as the

00:00:36.360 | bonds that occur between children as they grow up, which of course, form the template

00:00:40.680 | for social functioning when we become adults.

00:00:43.040 | Dr. Parker's research is heavily focused on autism, and indeed on all forms of autism

00:00:48.560 | spectrum disorders.

00:00:50.240 | Today we discuss autism, we talk about the prominent theories and current understanding

00:00:54.400 | of the biological basis for autism, as well as what still remains mysterious and unresolved

00:01:00.280 | about the causes of autism.

00:01:02.040 | You may have heard that the incidence or perhaps just the diagnosis of autism has dramatically

00:01:06.580 | increased in the last 10 to 15 years.

00:01:09.060 | And today we discuss why it is, in fact, that the incidence, not just the diagnosis, but

00:01:14.520 | the incidence of autism has so dramatically increased.

00:01:18.080 | And perhaps most excitingly, Dr. Parker shares with us brand new research findings from her

00:01:22.480 | laboratory that point to a new understanding of what causes autism, as well as a novel

00:01:28.220 | treatment for autism.

00:01:30.340 | Before we begin, I'd like to emphasize that this podcast is separate from my teaching

00:01:33.480 | and research roles at Stanford.

00:01:35.320 | It is, however, part of my desire and effort to bring zero cost to consumer information

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00:06:22.740 | And now for my discussion with Dr. Karen Parker.

00:06:26.020 | Welcome.

00:06:28.020 | Thank you.

00:06:29.020 | It's great to be here.

00:06:30.020 | This is going to be perhaps one of the longer conversations that we've been able to have

00:06:34.140 | over the years in part because whenever I see you on campus, we're heading in our respective

00:06:38.440 | directions, but I'm very excited because the topic of autism is one that is on a lot of

00:06:43.700 | people's minds.

00:06:44.700 | And I think the first question that always comes up, it seems, is whether or not the

00:06:50.520 | frequency of autism is indeed increasing or whether or not the field of medicine is getting

00:07:00.500 | better at detecting what was always there over time.

00:07:03.760 | Do we have any clear answers to that?

00:07:05.520 | Well, I think it's a multifactorial answer.

00:07:08.200 | So we're getting better at detecting autism, right?

00:07:11.280 | So in the past, we were diagnosing kids at nine or 10 years of age, right?

00:07:15.940 | And now clinicians are able to reliably diagnose kids at two to three years of age, right?

00:07:21.860 | So there's more people.

00:07:24.180 | There are pediatricians have autism screeners now.

00:07:27.900 | So when you bring in your baby and over the first couple of years of life, you're filling

00:07:32.020 | out screeners that are looking for autism symptoms, right?

00:07:36.580 | So there's just a lot more awareness around autism.

00:07:39.420 | But the rates have increased to now one in 36 US children have a diagnosis of autism,

00:07:45.420 | which is over two years ago.

00:07:47.860 | It was one in 44.

00:07:49.360 | So one in 36.

00:07:51.060 | Wow.

00:07:52.060 | I feel like it was just yesterday when it was one in 80.

00:07:55.180 | But is one in 36 the average across boys and girls?

00:08:00.940 | Does it skew differently if you look at just male births versus female births?

00:08:06.980 | Yeah, that's a great question.

00:08:07.980 | So autism is male biased and prevalence.

00:08:10.180 | So you have, and again, the studies vary.

00:08:12.900 | I mean, it's worth noting that autism is a highly clinically heterogeneous disorder,

00:08:18.140 | which means that if you've met one kid with autism, you've met one kid with autism, right?

00:08:23.020 | So we have to bear that in mind as we have this conversation.

00:08:25.780 | But different studies show that about for every one girl, there's three to four boys

00:08:31.780 | that are impacted by autism.

00:08:33.660 | So there's differences in the prevalence rate and also there's different monitoring sites.

00:08:39.220 | So the way in the US that these data are generated is the CDC has 11 monitoring sites across

00:08:46.260 | the country.

00:08:47.260 | And so they follow children and then that's where we, that's where the prevalence rates

00:08:53.020 | come from.

00:08:54.020 | And they release new prevalence rates every few years.

00:08:57.880 | So if physicians are able to detect autism early, say in a two year old or a three year

00:09:03.220 | old, to imagine that they're working off of tests that don't rely heavily on language

00:09:09.780 | because even though you can get some verbose two and three year olds, most two and three

00:09:15.220 | year olds don't have a very extensive vocabulary.

00:09:19.100 | And I'm guessing that they're also relying on things like visual gaze among other things.

00:09:27.620 | We've already made clear that this is not a discussion to allow people to diagnose themselves

00:09:33.200 | or others.

00:09:34.520 | But with that said, what are some of the diagnostic tools that people use?

00:09:40.160 | Is it language?

00:09:41.160 | Is it vision?

00:09:42.460 | Does it present as abnormal auditory processing?

00:09:48.120 | Maybe you could give us a sampling.

00:09:49.820 | So autism is a behavioral diagnosis, right?

00:09:52.920 | So unlike other areas of medicine where you might be able to take a blood test or there's

00:09:57.920 | other sort of tools, it's all a behavioral diagnosis by an expert.

00:10:03.440 | So usually a psychiatrist or a psychologist.

00:10:07.060 | And they look for two core features.

00:10:09.820 | So this is based on the DSM-5.

00:10:13.380 | And the two core features are pervasive social interaction challenges and the presence of

00:10:19.020 | restricted repetitive behavior.

00:10:21.420 | But there are a lot of people with autism who have anxiety.

00:10:24.620 | There are a lot of people with sensory challenges.

00:10:26.980 | There are a lot of people with seizure disorders, sleep disorders.

00:10:31.500 | So again, each person with autism has this sort of unique collection of traits.

00:10:38.940 | And that's how they get diagnosed.

00:10:41.500 | We're going to talk a lot today about interventions.

00:10:43.980 | But how early are some of the behavioral interventions-- and I should just say any interventions-- introduced

00:10:50.240 | nowadays?

00:10:51.240 | So if someone brings their child to the pediatrician and they take one of these tests and that

00:10:56.060 | child is deemed as having autism, will the one-year-old or the two-year-old immediately

00:11:04.220 | go into behavioral interventions?

00:11:06.620 | So usually you need to have the diagnosis of autism.

00:11:09.140 | And then there are behavioral interventions or a variety of different ones that are used.

00:11:14.060 | There are some studies where because autism is highly heritable, you can have one child

00:11:20.460 | with autism.

00:11:21.700 | And then if you have subsequent children, you're at an increased risk of having subsequent

00:11:26.180 | children with autism.

00:11:27.180 | And these are called baby sibling studies.

00:11:29.500 | So what you're doing is enriching the population of infants that you follow prospectively who

00:11:35.540 | are more likely to receive an autism diagnosis.

00:11:38.940 | And there are studies where some of those children are enrolled in behavioral studies

00:11:43.140 | even when they're quote unquote at risk.

00:11:46.300 | I've heard before that parents in which one or typically both parents are, say, of the

00:11:54.700 | engineering, math-y, physics quote unquote hard science type are more likely to have

00:12:02.440 | autistic children.

00:12:03.540 | Is that true?

00:12:04.540 | I mean, did that bear out in the data?

00:12:07.100 | If you look at profession or undergraduate major, does any of that correlate with the

00:12:14.420 | probability of having an autistic child?

00:12:16.740 | Yeah.

00:12:17.740 | Well, what I can say is that there's been some studies.

00:12:19.780 | So what we know is that autistic traits are continuously distributed across the general

00:12:24.620 | population.

00:12:25.880 | And there was a study and there's a couple different instruments that are used to be

00:12:30.300 | able to measure these autistic traits.

00:12:32.500 | So there's something called the social responsiveness scale, and then that's a US-based instrument.

00:12:37.320 | And there's an autism quotient that's a similar measure that was designed in England.

00:12:43.680 | And what we know from work with the AQ is that individuals that are in intense STEM fields

00:12:50.700 | like engineering, physics, and math have a greater burden of autistic traits, even if

00:12:55.200 | they don't have an autism diagnosis.

00:12:57.380 | Okay.

00:12:58.380 | So that leads me to wonder whether or not this whole business of a spectrum is actually

00:13:04.680 | multiple spectra, spectrums, is it spectrums or spectra?

00:13:10.400 | Someone will put it in the comments on YouTube.

00:13:12.300 | We know that for sure.

00:13:13.300 | Please let me know.

00:13:14.300 | I would like to know what is the plural of spectrum, spectrums, because when we hear

00:13:19.580 | the word spectrum, we think, okay, there's a spectrum of severity, right?

00:13:23.700 | And in fact, I have some experience with severe autism, not in my family, but where I went

00:13:29.220 | to undergraduate university, UC Santa Barbara, down the way from that school was the Devereaux

00:13:36.080 | school, which was a school which has been there for a long time that parents would send

00:13:40.900 | their kids if they were "severely autistic."

00:13:43.440 | It was actually where Dustin Hoffman went to study for his role in Rain Man.

00:13:50.420 | And the kids who were really delightful, they used to come into town every once in a while

00:13:54.060 | to the coffee shop where I'd study.

00:13:56.020 | And they would also continue on from there to Kmart, which is why the Dustin Hoffman

00:13:59.500 | character would say, "Got to go to Kmart.

00:14:01.900 | He would do that repetition."

00:14:02.900 | That's fascinating.

00:14:03.900 | That Kmart was down the road from our college housing and the Devereaux school.

00:14:09.180 | Those kids were literally in a away from home facility full time.

00:14:14.860 | And I spoke to some of the parents at one point, and they were at that facility, meaning

00:14:19.540 | the parents had sent their children away to live there full time.

00:14:22.860 | Of course, they'd get visits and they'd get visits home because they were, I suppose we

00:14:28.180 | could say, at the far end of some spectrum that made it, at least to the parents' idea,

00:14:34.180 | impossible for them to be at home.

00:14:36.140 | Okay, now at the other end of the spectrum, if one is just simply thinking in terms of

00:14:40.620 | severity, I know people who have self-identified as autistic, that's how they've referred to

00:14:46.820 | it.

00:14:47.820 | So I feel comfortable saying that they've said, "I am autistic."

00:14:52.300 | And they seem pretty high functioning, meaning they have driver's licenses, drive cars, are

00:14:57.500 | in healthy relationships, and manage life apparently well.

00:15:03.380 | They have some traits that, yes, I would agree, are a little bit different, so this is where

00:15:07.540 | we get into neurodivergence.

00:15:10.020 | But I guess the point is, should we think about autism as on a spectrum, or given the

00:15:14.920 | fact that there are these collections of different traits, could there be a spectrum of severity,

00:15:20.320 | also a spectrum of more stereotype behaviors, another spectrum that intersects with that

00:15:28.200 | that has to do with obsession with a particular topic?

00:15:31.380 | We could imagine that there are 50 or 60 different spectra or spectrums, I still don't know which

00:15:35.740 | one to say, and that when we talk about the spectrum, we're really talking about something

00:15:40.600 | that's in multiple dimensions, and not just one line that goes from severe to mild.

00:15:45.980 | Does that make sense?

00:15:47.300 | Yeah.

00:15:48.300 | I mean, I think this is where understanding the biological basis of behavior would then

00:15:54.020 | allow us to be able to say, "Here's these different dimensions," but not understanding

00:15:59.820 | the biology, you're left with, "Okay, are we lumpers or splitters?

00:16:03.880 | How do we think about this?"

00:16:05.940 | Because autism is highly heritable, so there's about 40 to 80% of autism is genetic, so these

00:16:15.220 | vary wildly, but the common thinking is that the majority, about 50% of autism is associated

00:16:22.460 | with common genetic variants.

00:16:24.820 | And so the way that we've always thought about this is that autism is largely an inherited

00:16:34.180 | polygenic condition, but what I mean by that is that you have a lot of common variants

00:16:39.820 | that are additive, and so if you think about this collection of common genetic variants

00:16:44.900 | that underlie the spectrum, so if you have less of a dosing of some of these common variants,

00:16:51.940 | you might see somebody who's higher functioning, like you said, and if you end up with one

00:16:57.140 | of these single gene, highly penetrant disorders, you might see severe intellectual disability

00:17:03.340 | and sort of lower functioning on the other end of the spectrum, but I think that there

00:17:06.940 | is a lot that we don't know, and what you're bringing up, I think, underlines an issue

00:17:13.500 | with autism, which is common for many brain disorders, which is if you don't understand

00:17:20.000 | the underlying biological basis, it also gets very difficult to diagnose and treat, right,

00:17:26.140 | and that's where we are with a lot of different psychiatric and neurodevelopmental disorders.

00:17:31.380 | To date, has there been any specific neural network that we can point to and say, "Ah,

00:17:37.020 | that's the neural network that seems to be different in people who are on the autism

00:17:41.460 | spectrum."

00:17:42.460 | I saw a study published recently that seemed to point to the idea that the genes that are

00:17:49.020 | altered in autism at least include a large number of genes that are altered, or the proteins

00:17:55.920 | that are the consequence of those genes are altered and exist at the synapse, at the connections

00:18:01.020 | between neurons, and I'm asking it that way because some years ago, I was at a talk on

00:18:06.220 | autism at Stanford, and someone raised their hand and says, "Do we even know that autism

00:18:11.080 | is a brain issue, right?

00:18:12.720 | Couldn't it be an issue of the immune system or the cardiovascular system?"

00:18:17.140 | Which at the time seemed like, "Okay, gosh, of course it's a brain."

00:18:19.720 | But wait, then you stop and you think, "That's a really good question.

00:18:22.860 | How do we know it's a challenge of the brain?"

00:18:25.460 | Right.

00:18:26.460 | I think that's a great question, right?

00:18:27.460 | And there may be people talk about autisms, right?

00:18:30.280 | And so when you think about where the major player is, we're at the infancy of thinking

00:18:37.700 | about this, right?

00:18:38.700 | And so maybe for some people, it's more of a brain-based disorder.

00:18:43.020 | Maybe for some people, it's the connection with the gut and the brain, right?

00:18:47.300 | I think what's also really tricky, right?

00:18:49.100 | So one thing that you have to ask is, what are the barriers to progress in understanding

00:18:54.100 | autism, right?

00:18:55.140 | And so the way I think about this is that, let's just take for a moment that this is

00:19:00.100 | a brain disorder.

00:19:01.840 | How do you study it in people, right?

00:19:03.860 | So it's very difficult to get access to either cerebral spinal fluid, which is a fluid that

00:19:10.100 | bathes the brain, brain tissue biopsies.

00:19:13.860 | It's very hard to get people, especially children, that are really impacted into a brain scanner,

00:19:19.900 | right?

00:19:20.900 | Because they can't sit still.

00:19:21.900 | They may have sensory issues.

00:19:22.900 | They don't want to go into a scanner, right?

00:19:24.580 | So a lot of the tools that neuroscientists or psychiatrists have to think about looking

00:19:30.780 | at the brain are limited, right?

00:19:35.440 | And then the other part is, how do you model?

00:19:37.180 | So the other way we might think about getting access or thinking about model systems, what

00:19:43.700 | we need to do is think about the control animals, and we need to make sure that the species

00:19:48.660 | that we're modeling them in has features of control humans, if you will.

00:19:54.580 | So we need to have complex cognitive abilities.

00:19:57.140 | We need to have complex social skills.

00:19:59.500 | We need to have an organism that has vision as its primary sensory modality, right?

00:20:04.780 | Potentially sleep consolidating.

00:20:06.540 | So we need to think about all of those.

00:20:08.540 | And the tricky part, I think, until fairly recently was that we were doing all of this

00:20:13.860 | work in mouse models and the control mice just fundamentally lack many of the characteristics

00:20:21.300 | that are needed to model autism with fidelity, right?

00:20:25.620 | And I think that's, when we look at drug development pipelines, about 50% of preclinical failures.

00:20:33.700 | So that would be something that's tested in an animal that works and then fails in a human

00:20:38.940 | clinical drug trial, 50% of those failures can be attributed to poorly selected animal

00:20:44.180 | models.

00:20:45.180 | And so I think part of where we will be getting traction is picking, developing sophisticated

00:20:51.340 | models as a sort of point of entry into being able to understand some of these things that

00:20:55.540 | are really difficult to study in people.

00:20:57.620 | Yeah, that's such a key point.

00:20:59.300 | And for those that have not heard of preclinical models, preclinical models are non-human models.

00:21:04.700 | So it could be mouse, could be non-human primate, could be flies or worms for that matter.

00:21:09.140 | But we're going to talk a lot about non-human primate preclinical models and the work that

00:21:14.660 | you've been doing.

00:21:15.820 | And of course, also the work that you've been doing in humans, the other animal.

00:21:21.080 | The other primate.

00:21:22.080 | The other primate.

00:21:23.080 | Right, exactly.

00:21:24.080 | I love to remind people that we're primates, old world primates.

00:21:28.140 | And thank you for doing that.

00:21:29.460 | So you've been talking about the genetic influences on autism and of course, genes in the environment

00:21:33.480 | interact, right?

00:21:34.740 | It's never nature or nurture.

00:21:36.080 | It's always an interaction and that isn't just about the epigenome.

00:21:39.780 | It's also just about the fact that nature impacts the genome and our genome impacts

00:21:43.460 | the way that we interact with the environment, et cetera.

00:21:46.280 | So what is the role of the environment in autism, both the frequency and the presentation

00:21:51.180 | of autism?

00:21:52.180 | Right.

00:21:53.180 | So, I mean, there are, again, lots of different epidemiological studies.

00:21:56.700 | So advanced parental age, prematurity, severe prematurity as a risk factor for autism, maternal

00:22:04.720 | illness during pregnancy.

00:22:07.240 | So there's a bunch of different things that have been associated with an increased risk

00:22:12.680 | for autism.

00:22:14.160 | In terms of environmental influences and how they can intersect with biology, one of the

00:22:18.860 | things that I was really struck by in the early 2000s that at least by my read of the

00:22:24.260 | literature hasn't really gone anywhere was this idea that was proposed by Pashko Rakesh

00:22:28.140 | who used to run the neurobiology department at Yale, expert in brain neuroanatomy and

00:22:34.500 | non-human primates and in humans, embryology, really a luminary of our field.

00:22:39.700 | And he had a series of papers exploring how the migration of neurons during early development,

00:22:45.920 | you know, as you and I both know, but most people out there probably don't know because

00:22:49.700 | we haven't covered this in the podcast.

00:22:51.860 | It's not typical dinner table conversation, you know, when you, when an embryo, when a

00:22:55.620 | human embryo is developing that the neurons are born at one location and they migrate

00:22:59.340 | out some distance to their final resting place where then they grow out their connections

00:23:04.320 | and connect with one another.

00:23:05.920 | And that process of neural, neuronal migration is oh so critical for the eventual wiring

00:23:10.840 | of the brain.

00:23:12.060 | And Rakesh had this idea that perhaps, and I really want to emphasize perhaps that the

00:23:17.820 | more frequent incidence of autism might be correlated with the increase in early prenatal

00:23:24.560 | ultrasound.

00:23:26.020 | And he had these papers published in a number of really high profile journals including

00:23:30.020 | Prosthenia National Academy and Science and elsewhere showing that in a mouse model, if

00:23:34.140 | you do ultrasound, with each successive ultrasound, you got more migration errors, right?

00:23:40.520 | So there's, to me it was a, you know, an interesting example of the environment, frequency of ultrasound

00:23:45.740 | and cell migration having some sort of interaction.

00:23:49.100 | But it seemed like it never went anywhere.

00:23:51.020 | It never got tacked to okay, you should keep in mind the number of ultrasounds that you're

00:23:55.660 | getting for your child.

00:23:56.660 | And of course, ultrasounds are critical for pregnant women to get because they can stave

00:24:02.440 | off a number of developmental issues and they're super important.

00:24:05.960 | But you know, we've heard about ultrasound, you know, within the scientific literature

00:24:09.980 | and then occasionally we'll hear other theories about okay, it's having two parents who are

00:24:14.180 | both engineers and then we'll hear, oh, you know, it's, you know, toxicity in the food

00:24:18.700 | environment.

00:24:19.700 | We've heard, you know, hypotheses about vaccines or the adjuvants that the vaccines are contained

00:24:24.660 | in.

00:24:25.660 | You know, in that large cloud of theories, has anything really emerged from them?

00:24:32.180 | It's like okay, there really seems to be at least one major risk factor, environmental

00:24:37.180 | risk factor because I feel like all those theories come up, get some popular press,

00:24:42.340 | a bunch of papers are published, sometimes those papers are retracted like in the case

00:24:46.040 | of the vaccines, and then the theory kind of dies.

00:24:51.340 | So is there any specific environmental influence on autism that we can say yes, there really

00:24:57.780 | seems to be something there?

00:24:59.340 | Yeah.

00:25:00.340 | I mean, so it's a really spectacularly good question.

00:25:03.180 | I think the tricky part about it is that every single person that comes into a trial has

00:25:08.300 | a different genetic background, right?

00:25:10.020 | And so until we can have these a priori stratified trials where you could then, you know, as

00:25:16.460 | a good scientist, you would only manipulate maybe one, two variables at a time, right?

00:25:20.860 | But when you're doing these large epidemiological studies because you can't, it's very difficult

00:25:25.420 | to do experimental studies, right, especially with developing children.

00:25:30.460 | I think that's an incredibly difficult study to do, right?

00:25:33.580 | So there's been an interest in this field of there's these neurogenetic syndromes that

00:25:40.100 | have high penetrance for autism, which basically means that you could have a disorder or another

00:25:47.380 | genetic condition, let's say, it doesn't have to be a single gene, but that a lot of those

00:25:51.540 | kids tend to also get an autism diagnosis.

00:25:54.380 | And so there's been work in like, so for instance, Fragile X is a good example, where because

00:25:58.940 | autism is so diverse in terms of clinical presentation, that let's say you have a medication

00:26:05.200 | that could work for a handful of kids in the trial, you may not be statistically powered

00:26:09.780 | to see it, right?

00:26:10.820 | So you know, the way I think about the autism world is there's so little we don't know.

00:26:16.820 | So think about being in a dark room and you have a flashlight and you only see where you

00:26:22.340 | shine the light, right?

00:26:23.880 | And so if you think about a very heterogeneous, genetically heterogeneous study, it's going

00:26:30.460 | to be very difficult to tease out these pieces because an environmental risk factor might

00:26:35.740 | be a driver for one kid, but not another, right?

00:26:38.660 | And so I think what we need to do is to have these genetically defined subgroups of individuals

00:26:44.600 | and then be able to test the gene by environment interactions or in this genetically defined

00:26:51.560 | group of individuals, can we test this certain medication to see if it's beneficial for this

00:26:56.860 | subgroup of children?

00:26:58.660 | Got it.

00:26:59.660 | So you mentioned Fragile X, which we know presents with autism-like symptoms in some

00:27:06.180 | cases.

00:27:07.180 | And then I think of another disease like Timothy syndrome, a mutation in an L-type calcium

00:27:12.060 | channel, which for those of you that don't know what these L-type calcium channels are,

00:27:16.220 | they're not just important for the function of neurons in the brain, they're really important

00:27:19.340 | for the function of neurons and other tissues, including the heart tissue, right?

00:27:24.400 | So kids with Timothy syndrome have cardiac issues and they have autism.

00:27:30.760 | So I think it's important for us to kind of explore this a bit because in most people's

00:27:35.440 | minds kids with autism have autism and occasionally they'll have other issues, gut issues or heart

00:27:42.020 | issues or musculoskeletal issues, but we often think that that's the consequence of the autism,

00:27:47.860 | but oftentimes they have multiple things going on and the autism actually could be secondary

00:27:53.000 | or independent of the other thing that's going on.

00:27:56.160 | So this is what leads me back to this idea of a spectrum.

00:28:01.460 | Is it possible that what we call autism is actually 50 different disorders or 50 different

00:28:07.160 | conditions depending on what one wants to call them?

00:28:12.580 | What is autism really?

00:28:15.520 | How does it really center around, and I think here maybe it's useful to go, like do we go

00:28:19.920 | to the diagnostic criteria, like how do we decide if a child has autism if they also

00:28:24.980 | have a bunch of other things that are challenging them?

00:28:27.320 | I mean, I think that that's the $64,000 question, right, and again in other areas of medicine.

00:28:34.100 | So if you think about, let's think about cancer biology, right, like decades ago somebody

00:28:39.220 | would come in with cancer and you would hit them with radiation and chemotherapy and that

00:28:42.800 | was the best that we could do, right?

00:28:44.600 | But with the invention of a lot of molecular tools, you can remove a tumor and you can

00:28:49.700 | do molecular profiling and even have personalized medications made, right, to attack that tumor.

00:28:56.200 | And so what's really tricky when you have a behavioral diagnosis that's not biologically

00:29:03.700 | defined, you see a lot of heterogeneity.

00:29:08.660 | So it's incredibly difficult, I think, to answer this question because we don't know

00:29:13.220 | how many kinds of autisms there are, right?

00:29:16.420 | Like there will be people who say if you have a disorder like Fragile X or Prader-Willi

00:29:21.660 | Syndrome or Timothy's Syndrome or a variety of these other conditions, there will be people

00:29:28.020 | – I've heard clinicians say, well, that's not really autism, right?

00:29:31.140 | That's a piece of Fragile X, right?

00:29:33.380 | But if it's a behavioral diagnosis and they meet behavioral criteria, it becomes this

00:29:39.060 | weird circular argument, right?

00:29:40.800 | So like until we really understand what autism is, I think that it's going to be very tricky

00:29:49.320 | to start, you know, sub-defining different aspects of the condition.

00:29:55.720 | As we all know, quality nutrition influences, of course, our physical health but also our

00:29:59.860 | mental health and our cognitive functioning, our memory, our ability to learn new things

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00:30:05.120 | And we know that one of the most important features of high quality nutrition is making

00:30:08.900 | sure that we get enough vitamins and minerals from high quality unprocessed or minimally

00:30:13.320 | processed sources, as well as enough probiotics and prebiotics and fiber to support basically

00:30:19.080 | all the cellular functions in our body, including the gut microbiome.

00:30:22.600 | Now, I, like most everybody, try to get optimal nutrition from whole foods, ideally, mostly

00:30:29.180 | from minimally processed or non-processed foods.

00:30:32.200 | However, one of the challenges that I and so many other people face is getting enough

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00:31:26.200 | Well, this is probably a good time for us to think about the work that you've done in

00:31:31.540 | terms of trying to tack the biology of social communication and behavior, right?

00:31:40.740 | Those things interact, not just language, but also behavior, to autism in humans using

00:31:47.640 | non-human primate models.

00:31:49.560 | And then, of course, to also discuss some of the work that you've been doing in humans.

00:31:53.380 | And we can't have that discussion without first having a discussion about two neuropeptides

00:31:58.780 | that I think most people have heard of, at least one of them, and I think there's a lot

00:32:02.900 | of misunderstanding about, but you're going to clarify that for us, which are oxytocin

00:32:07.840 | and vasopressin.

00:32:09.220 | So before we dive into the important work that you've been doing on vasopressin in particular,

00:32:15.900 | but also oxytocin and autism, what are oxytocin and vasopressin really?

00:32:22.500 | Okay.

00:32:23.500 | So they're these small little peptide, they're nine amino acids long, so very tiny.

00:32:28.500 | They only differ by two amino acids, and they're these ancient peptides that are hundreds of

00:32:33.460 | millions of years old.

00:32:35.340 | And in almost any species studied, whether it's the current version, you might have vasotocin

00:32:41.460 | or other mesotocin, which are sort of precursor forms in other species, but they're highly

00:32:47.020 | evolutionarily conserved.

00:32:48.840 | And they're involved in social behavior in pretty much any, it could be egg laying, it

00:32:53.660 | could be, but reproduction and social behavior across the phylogenetic taxes.

00:32:59.460 | So house cats make vasopressin and oxytocin, humans obviously make vasopressin and oxytocin,

00:33:06.020 | and pretty much every other species that has to interact with and connect with other members

00:33:10.420 | of its species.

00:33:11.420 | Especially mammals, right?

00:33:12.420 | So oxytocin and vasopressin are pervasive in mammalian species.

00:33:16.520 | Do the different species tend to make oxytocin and vasopressin in similar brain areas and

00:33:24.800 | tissues?

00:33:25.800 | Yes, but not completely overlapping, but I think the thing that the beautiful mystery

00:33:31.640 | about these and the infuriating piece of them is that because they're so structurally similar,

00:33:38.400 | they can have similar effects.

00:33:40.960 | And there's four receptors that they bind to.

00:33:43.380 | So if you think about a hormone or a neurotransmitter, so oxytocin and vasopressin, if you think

00:33:47.680 | about them like a key and a receptor like a lock, and you have to put them together

00:33:51.980 | to open a door, open behavior, they can bind to these four receptors.

00:33:56.620 | So it can be very difficult to disentangle which one is acting and at which receptor

00:34:03.600 | and where in the brain.

00:34:04.900 | Oh, so oxytocin and vasopressin are chemically similar?

00:34:07.900 | Yes.

00:34:08.900 | Interesting.

00:34:09.900 | So where would you say lies their greatest output divergence, which is just nerd speak

00:34:15.720 | for, is there an example of something that oxytocin does that vasopressin doesn't and

00:34:20.020 | vice versa?

00:34:21.020 | Yeah.

00:34:22.020 | Okay.

00:34:23.020 | So what's really fascinating is these two neurotransmitters or hormones were discovered

00:34:27.080 | for their peripheral effects, which basically means not in their brain, but somewhere in

00:34:31.000 | their body.

00:34:32.000 | And so oxytocin is involved in uterine contractions and milk let down and so was during lactation.

00:34:39.180 | So people sort of always thought of it as the female hormone.

00:34:42.420 | And then vasopressin has, at least in the peripheral system, has been involved in urinary

00:34:50.980 | output regulation, blood pressure.

00:34:53.900 | And so we only knew about their physiological roles as sort of classic hormones for decades.

00:35:01.820 | And what was interesting is these naming conventions are fascinating in medicine, right?

00:35:08.600 | So you could name a virus after where it was first found, right?

00:35:13.340 | Or it could be named after somebody who discovered the disease, like Alzheimer's for instance

00:35:17.740 | is a good example.

00:35:19.000 | And what was interesting, oxytocin was only named once, vasopressin was named twice.

00:35:23.260 | So it's either called arginine vasopressin or antidiuretic hormone.

00:35:27.360 | And so it had two different names.

00:35:29.300 | And so as you can imagine, sometimes genes are named twice.

00:35:31.900 | And so somebody in cancer is studying one gene and somebody in autism is studying another

00:35:36.260 | and they're not even communicating because they don't even realize that they've, at least

00:35:39.760 | historically now we have all kinds of gene annotation sites, so it's less likely to happen

00:35:44.040 | now.

00:35:45.040 | But what was fascinating is these hormones were named, oxytocin is Greek for quick birth.

00:35:50.480 | So for decades, people only appreciated their physiological roles.

00:35:55.440 | But there are neuroanatomists saying, "Hey, so these are both made, they're made in a

00:35:59.160 | lot of different places, but the action sort of happens in the hypothalamus where they're

00:36:04.120 | made."

00:36:05.120 | And so there were anatomists that said, "Wait, these sort of project back into the brain.

00:36:08.360 | What are these doing in the brain?"

00:36:10.080 | And one of my favorite historical stories was I had a mentor, a colleague who I didn't

00:36:18.300 | train with, but he was a real source of wisdom to me for many years, and his name's Court

00:36:23.500 | Peterson.

00:36:24.500 | And he told me this wonderful story about this duke zoologist named Peter Klopfer.

00:36:29.500 | And Peter was studying ungulates, so sheep and goats.

00:36:33.180 | And he wrote a story, a paper, in 1971 called Mother Love What Turns It On.

00:36:38.800 | And one thing about science is I love going back and seeing where do the pearls of wisdom

00:36:43.560 | come from.

00:36:44.560 | And so he wrote this and said, "Oxytocin is orchestrating all these events of motherhood."

00:36:51.360 | And there are sheep and goats in particular that have offspring that are precocious, meaning

00:36:56.440 | they're basically born ready, within an hour they can run with the herd, unlike our species,

00:37:00.840 | which is altricial, meaning we have very helpless infants.

00:37:04.520 | And mom needs to bond really quickly with that baby if it's going to be running around

00:37:08.940 | and you only, from an evolutionary perspective, you want to be investing in the baby that

00:37:13.400 | you're is not somebody else's, right?

00:37:15.880 | And he hypothesized that it was oxytocin that was being co-released into the brain and during

00:37:22.360 | milk let down, that was what turned mother love on.

00:37:26.060 | And that was really the beginning of this whole field of thinking.

00:37:29.600 | And so that opened up thinking about oxytocin in rodent maternal care and a variety of other

00:37:36.700 | instances.

00:37:38.400 | Can I just briefly interrupt you because I find this so interesting and I know it's interesting

00:37:42.040 | to everyone listening as well because yes, and thank you for making it clear that oxytocin

00:37:49.540 | has many different roles, but this role of mother love and bonding to infant has me needing

00:37:55.440 | to ask whether or not the idea was that oxytocin is released in the mother when she interacts

00:38:00.800 | with her own baby.

00:38:03.640 | And that leads me to the question, is oxytocin also released in the baby in reaction to the

00:38:10.080 | mother?

00:38:11.080 | And how long is that effect lasting?

00:38:13.760 | Because in order to have a pervasive bond with that baby and not just some other baby,

00:38:17.940 | and of course we still have visual cues and, you know, we know our baby versus another

00:38:21.560 | baby, most instances, there are rare exceptions or perhaps not so rare exceptions, but leaving

00:38:26.720 | those aside, you know, the mechanism that would allow for mother infant bonding and

00:38:33.900 | infant mother bonding by way of oxytocin presumably is something that is literally changing their

00:38:39.820 | brains saying it's, you are the, are the center of my life, right?

00:38:45.100 | And the baby of course is saying, well, you are my life because you are the source of

00:38:48.720 | life, right?

00:38:49.720 | And certainly for the early part, early part of life in that nowadays it seems that that

00:38:54.040 | that can extend well into the teens and twenties for some people, but you know, how, how is

00:38:59.700 | oxytocin working?

00:39:00.700 | Is it, is it working over the course of minutes, hours?

00:39:03.320 | Is there some specificity of this baby and this mom that links them in some more pervasive

00:39:08.700 | way?

00:39:09.700 | I mean, how is oxytocin doing this magic of bonding?

00:39:13.160 | Yeah.

00:39:14.160 | I mean, it's, it's very species specific, right?

00:39:16.760 | So I think that, and you need to think about like the evolutionary history of the species,

00:39:21.840 | right?

00:39:22.840 | So if you think about sheep or goats, the early studies that were done are you, the

00:39:29.200 | passage through the vaginal canal was what, you know, so you had activated oxytocin receptors

00:39:33.480 | that way, but if you gave an oxytocin antagonist, meaning you would give into the brain something

00:39:40.360 | that blocked the oxytocin receptors.

00:39:42.880 | So if the oxytocin is being released into the brain, but you have a pharmacological

00:39:46.720 | agent blocking its ability to bind to its receptors, these sheep and goats wouldn't

00:39:52.180 | bond to their baby for instance.

00:39:53.720 | So literally the passage of the baby out of the vaginal canal triggers the oxytocin pathway,

00:40:00.120 | the release of oxytocin.

00:40:01.120 | Right.

00:40:02.120 | As in L-actation does too.

00:40:03.120 | Nature is so beautiful because if you had to pick one event to trigger the release of

00:40:06.900 | oxytocin, if oxytocin's role is to create bonding with offspring, that will be the event because

00:40:12.120 | that's a tough one to mistake.

00:40:13.920 | Right.

00:40:14.920 | Right.

00:40:15.920 | But what I will say, because I think you will, you know, to avoid you getting attacked on

00:40:19.440 | Twitter or wherever you might get attacked.

00:40:20.440 | I'm going to get attacked anyway.

00:40:22.260 | If not for this discussion, then another one, but I'm tougher than I am.

00:40:26.520 | So but it's really species specific, right?

00:40:29.260 | So if you think about our species and a lot of primate species, we live in these extended

00:40:34.780 | family groups and that's how we evolved.

00:40:36.840 | And so unlike a goat or a sheep that might live in a herd where there's a lot of non-relatives

00:40:42.080 | - we lived in a community of relatives, right?

00:40:45.520 | And so we, and we do all kinds of care of extended relatives.

00:40:49.920 | And so you wouldn't necessarily expect in a primate species where you have this long

00:40:55.320 | rearing history where help from the family and bi-parental care where, where sort of

00:41:01.160 | everybody's sort of like, it takes a village to raise the baby.

00:41:04.700 | We readily adopt in our, in primate societies, right?

00:41:08.600 | And so, you know, like I had a C- I mean, I'll tell you something personal.

00:41:12.800 | I had a C-section and had, I had a lot of postpartum complications.

00:41:18.800 | And so lactation didn't work out that well for me.

00:41:21.280 | One of my friends would say I had massive DVTs and pulmonary emboli.

00:41:26.560 | And so I almost died after my son was born the first time.

00:41:30.040 | And so I didn't have a vaginal delivery.

00:41:32.440 | I couldn't...

00:41:33.440 | DVTs, deep vein thrombosis.

00:41:35.000 | Yeah.

00:41:36.000 | I was sort of like welcome to motherhood and I was in the ICU and had to get a filter put

00:41:41.200 | in, an inferior vena cava filter to stop me from dying because I had scattershot clots

00:41:47.740 | all over my lungs.

00:41:49.440 | And so I didn't really, you know, I didn't, I didn't do a vaginal delivery.

00:41:52.760 | I had a C-section and I wasn't really able to lactate and man, I love that baby, right?

00:41:58.960 | So, you know, I can give, you know, what I will say is it's really different in primates

00:42:03.000 | and we don't really understand how bonding occurs.

00:42:05.880 | But what I will say is that bonding between a mother, you really need to think about the

00:42:10.400 | evolutionary selective pressure.

00:42:12.100 | So I was an evolutionary biologist before I found neuroscience, right?

00:42:16.280 | And so I really, everything I do, I think about from an evolutionary perspective.

00:42:22.400 | So but it is, many people go into the oxytocin, vasopressin field because they have a lot

00:42:28.860 | of questions about social interactions, right?

00:42:31.260 | Like I think if you think about us as being social is actually one of the, one of the

00:42:37.340 | core characteristics of our species, right?

00:42:40.380 | So social interactions are rewarding from infancy.

00:42:43.540 | They keep us alive as you mentioned, right?

00:42:46.020 | And so I think it's not an accident that the way we think about disorder in our species

00:42:52.140 | is many disorders are disorders because of lack of social connectedness, right?

00:42:57.240 | So it could be something like autism where, you know, there's these pervasive social interaction

00:43:02.540 | impairments.

00:43:03.860 | It could be something like drug abuse where, you know, you, a risk factor for drug abuse

00:43:10.360 | is feeling, you know, socially disconnected and alone, right?

00:43:15.740 | Social isolation or loss of a loved one is a very strong predictor of the onset of a

00:43:21.340 | stress-related depressive anxiety disorder.

00:43:24.360 | In terms of when and how oxytocin is released, you mentioned mother-infant bonding.

00:43:31.980 | I think you said yes, that the infant is also releasing oxytocin, we think.

00:43:38.740 | So it's, it's bi-directional.

00:43:40.860 | We think.

00:43:41.860 | I think most of the work has been done in mom would be, and again, this has not been

00:43:45.920 | really done well in primates, right?

00:43:48.140 | So we're extrapolating this information from species that have different evolutionary histories

00:43:54.680 | than us, right?

00:43:55.680 | So it's goats, sheeps, prairie voles, mice, rats.

00:44:01.160 | So what do we know about the role of oxytocin in humans?

00:44:03.960 | Do we, I mean, we know it's there.

00:44:06.600 | We presume based on the animal models that it's involved in mother-infant bonding and

00:44:12.160 | presumably romantic partner bonding, at least you hear that a lot.

00:44:17.360 | It was unfortunately nicknamed the love hormone.

00:44:21.100 | And the reason it's unfortunate it was is that while that might cue attention to oxytocin

00:44:26.000 | and I'm a big fan of people paying attention to biological phenomenon, it discards the

00:44:31.280 | other and many roles of oxytocin.

00:44:34.000 | But what can we say about oxytocin in humans if anything?

00:44:38.360 | Do we know that it does, I mean, we're just, so we're assuming based on the animal models

00:44:42.920 | that it does something.

00:44:43.920 | I mean, this is very different than like dopamine where there's tons of animal model data,

00:44:47.320 | but we know, but there are brain imaging where we know where dopamine is expressed and do

00:44:52.240 | we even know where oxytocin receptors are expressed in the human brain?

00:44:55.760 | Presumably that information is out there.

00:44:57.560 | Recently, but again, there's a lot of specificity and I think if you're thinking about disorders,

00:45:02.760 | you would then have to study those specific subpopulations, right?

00:45:06.780 | And you need, you know, a lot of this work has been done, so you have to think about

00:45:09.640 | how do we study it, right?

00:45:10.960 | So the best way to study it would be to have radio tracers where you could then, which

00:45:14.800 | we do have for dopamine and other compounds, where you would then go and see where after

00:45:20.520 | somebody's performed a task, do we see, you know, activation, right, or uptake.

00:45:26.320 | There are some imaging studies that are usually done giving intranasal oxytocin and then you

00:45:31.820 | basically ask questions about, okay, we give you oxytocin intranasally, which presumably

00:45:36.140 | enters the brain, we could talk about reasons why we think that, and then we have you perform

00:45:41.280 | on some task, right?

00:45:42.700 | And so, you know, there's evidence if you give oxytocin, it diminishes the amygdala's

00:45:47.360 | response to fearful stimuli, right?

00:45:50.380 | So that it might have this sort of pro-social effect and it was actually data like that

00:45:55.280 | that caused people to start thinking initially about oxytocin.

00:46:00.660 | And those are data in humans.

00:46:01.800 | That's right.

00:46:02.800 | It reminds me that there was this brief moment where oxytocin wasn't just being discussed

00:46:06.520 | as the love hormone, it was being discussed as the trust hormone, right?

00:46:11.300 | Also, far too simple a heuristic, but again, I think it's cool that the, you know, that

00:46:17.840 | the press picks up on these things and at least tells people about what's being discovered.

00:46:22.280 | And we just always have to be careful to not have it lead to the assumption that that's

00:46:26.840 | the only role of a given hormone.

00:46:29.560 | So it can reduce, apparently it can reduce the output of the amygdala in some way, this

00:46:36.040 | brain area associated with threat detection.

00:46:40.420 | And so you could imagine how that would bias the person toward being more pro-social.

00:46:46.760 | Have there been studies exploring the role of oxytocin in making autistic children more

00:46:52.120 | pro-social?

00:46:53.480 | And behind that question, I suppose, is the assumption you can verify or not that autistic

00:47:00.160 | children are less pro-social than other children.

00:47:03.160 | Is that true?

00:47:04.600 | Or is it that, you know, autistic kids are just maybe more pro-social with the one friend

00:47:08.920 | they really, really like?

00:47:10.920 | I happen to know some kids with autism or however you want to phrase it, and they have

00:47:16.680 | close friends and they seem to really like those specific friends a lot.

00:47:21.880 | They seem very happy when they show up at the door and like all the hallmarks of a healthy

00:47:26.640 | social mind, but it is true that they are uncomfortable in groups and where there's

00:47:31.660 | a lot of noise.

00:47:32.660 | A busy birthday party is overwhelming for them, but you see them playing with one or

00:47:36.020 | two friends and like you could see all that and assume, okay, it's just kind of an introverted

00:47:42.160 | kid.

00:47:43.160 | Actually, it kind of reminds me of me.

00:47:44.160 | You know?

00:47:45.160 | I mean, I don't have a problem with crowds, but I much prefer to be with a small group

00:47:47.760 | of friends or one close friend.

00:47:49.280 | Yeah.

00:47:50.280 | I hear you.

00:47:51.280 | I'm that way too.

00:47:52.280 | Right.

00:47:53.280 | So, you know, how do we think about this?

00:47:55.120 | Okay.

00:47:56.120 | Well, I would say the social features of autism are interesting, right?

00:48:00.360 | And so you might have, there were, there was an attempt a long time ago, like 1979, there's

00:48:05.960 | a woman named Lorna Wing who tried to subtype the social features of autism, right?

00:48:11.940 | And so there could be people that are socially avoidant and really just don't want to have

00:48:17.500 | social interactions.

00:48:19.100 | There could be kids that are active, but odd, which means that they have an interest in

00:48:24.100 | being social, but maybe they don't read social cues, right?

00:48:29.000 | And they interact in ways that other kids don't understand or make could cause bullying,

00:48:34.940 | right?

00:48:35.940 | Like in junior high school.

00:48:36.940 | Yeah, exactly.

00:48:37.940 | Yeah.

00:48:38.940 | And that's often why, you know, some autistic kids do better with adults, right?

00:48:42.940 | Because adults know how to sort of channel discussions with somebody who might be a little

00:48:48.260 | socially awkward, right?

00:48:49.900 | But there's different phenotypes.

00:48:50.900 | I mean, people having a disinterest in social interactions could be that they're highly

00:48:56.200 | socially anxious, right?

00:48:58.460 | That making eye contact makes them anxious.

00:49:00.940 | � Again, that's another caveat.

00:49:20.180 | There have been some studies administering oxytocin to individuals with autism.

00:49:24.740 | And again, these are these single dose studies.

00:49:27.020 | So the first studies that were done were looking at single dose oxytocin in males because some

00:49:34.900 | of the, and we can talk a little bit about why oxytocin versus vasopressin, which vasopressin

00:49:39.900 | actually would have been my choice based on the animal literature, and we can talk about

00:49:44.180 | that.

00:49:45.180 | But vaso oxytocin was given to males partly because it wouldn't, the idea would be that

00:49:50.660 | the off target effects in the peripheral nervous system, i.e. milk let down uterine contractions

00:49:55.740 | are not going to happen in males, right?

00:49:57.380 | And so it was deemed that they might be safer subjects.

00:49:59.760 | Males are often also the go-to for research studies, as you may have talked about on your

00:50:04.820 | podcast before too.

00:50:05.980 | Yeah, something that fortunately is changing, thanks to a mandate by the NIH.

00:50:10.540 | Correct.

00:50:11.540 | I had to just kind of smile/raise my eyebrows a little bit at the idea that the assumption

00:50:19.580 | that oxytocin administered to males, yes, one can see why it wouldn't cause milk let

00:50:23.940 | down or uterine contractions, but of course there could be other peripheral effects of

00:50:29.420 | oxytocin in males.

00:50:30.520 | But they had to pick one, so they went with males.

00:50:33.020 | Okay, so, and there is this higher incidence of autism in males, so it's not a terrible

00:50:37.420 | place to start.

00:50:38.420 | You just would hope that they would also do the experiment on females.

00:50:42.180 | So they're doing this by nasal spray?

00:50:43.740 | So intranasal.

00:50:44.900 | One dose.

00:50:45.980 | Correct.

00:50:46.980 | And for reasons that I don't understand, it's 24 international units, and I think maybe

00:50:51.100 | somebody did the first study using it, and this is how science happens, right?

00:50:54.820 | And it worked, and so then everyone uses that protocol.

00:50:57.540 | And so then there's been a lot of studies looking at, you know, there's one reading

00:51:02.340 | the mind and the eyes, so can you look at pictures of somebody's eyes and then ask what

00:51:06.660 | is the emotion that they're feeling, right?

00:51:08.940 | After receiving this intranasal.

00:51:10.620 | Oxytocin or placebo.

00:51:13.260 | Where is your eye gaze going in a picture, right?

00:51:15.740 | So one of the theories is that people with autism may, at least a subset of them, lack

00:51:20.980 | social motivation.

00:51:22.100 | So maybe they're not looking in the places like eyes where you receive a lot of social

00:51:26.940 | cues that are relevant to social communication.

00:51:29.540 | And so some of these early studies showed that a single dose of oxytocin in people that

00:51:36.380 | had high-functioning autism, so they were verbal, like you said, they could come in

00:51:39.580 | for studies, and that it looked like it had some potential effectiveness.

00:51:43.420 | And so there became a really strong interest in the field to think about oxytocin potentially

00:51:49.460 | as a therapy for autism.

00:51:51.260 | And is oxytocin available over the counter?

00:51:53.540 | Does it require a prescription?

00:51:54.940 | I mean, you see sites that are selling it, but that doesn't mean anything these days.

00:51:59.540 | Right, yeah.

00:52:00.540 | There's gray market, there's all sorts of stuff going on.

00:52:03.460 | But I know people that have used oxytocin, there's actually a market for, and by the

00:52:09.380 | way, folks, I'm not suggesting this, but someone the other day told me that they've been regularly

00:52:12.740 | taking oxytocin ketamine nasal inhalations as part of their work with their licensed

00:52:22.100 | therapist on PTSD-type stuff relating to, let's just call it relational trauma.

00:52:29.900 | So that's happening.

00:52:32.460 | But let's just think about oxytocin alone for the moment.

00:52:36.500 | Are parents of autistic kids able to buy oxytocin nasal spray?

00:52:41.220 | No.

00:52:42.220 | So it would need to be written, the prescription would need to be written by a physician.

00:52:50.340 | And it's not on the market.

00:52:51.820 | So there's one thing we should say is there's only two drugs that are approved by the FDA

00:52:56.300 | to treat autism, and they're both antipsychotics, which they treat associated features like

00:53:02.340 | irritability, and they have off-target effects like weight gain, and so we don't have any

00:53:08.540 | medications that are currently approved in the U.S., or anywhere else for that matter,

00:53:13.980 | to treat the core features of autism.

00:53:17.060 | Interesting and unfortunate, and hopefully that will change in the not-too-distant future.

00:53:23.640 | Do we know that children with autism, people with autism, because I'm going to just sort

00:53:27.860 | of assume that autism is stable over the lifespan, like if a child is diagnosed with autism,

00:53:34.660 | are they going to be an adolescent and adult with autism?

00:53:37.880 | So I would say that in a lot of cases autism has lifelong impact, but there are people

00:53:42.640 | who outgrow their diagnosis.

00:53:45.760 | There are people who respond well to behavioral therapy.

00:53:49.300 | I mean obviously it's not the cure-all for everybody, there's lots of people who go through

00:53:52.340 | intensive behavioral therapy and probably see minimal benefit, but I mean it's certainly

00:53:56.900 | something that occurs in childhood, the diagnosis occurs in childhood, and for most people will

00:54:06.180 | then be present across the lifespan.

00:54:08.140 | So we could say people with autism, because each study sometimes will have adults, sometimes

00:54:12.520 | you'll have teenagers, sometimes you'll have kids.

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00:55:17.480 | Is it known whether or not people with autism, assuming they meet the criteria for being

00:55:22.360 | autistic at that moment, have lower natural circulating or active levels of oxytocin?

00:55:30.380 | Because, you know, it's one thing for a nasal spray of oxytocin to improve social functioning.

00:55:36.440 | It's another to know that the effect is addressing an underlying biological deficit.

00:55:44.100 | - Yeah, it's such a great question.

00:55:45.980 | Okay, so we should unpack that 'cause there's been a lot of work in this area.

00:55:49.420 | So the first question is where are we measuring the oxytocin, right?

00:55:52.800 | So we mentioned oxytocin has all kinds of effects in the body as well as the brain,

00:55:57.100 | and it's released into the blood, but it's also released directly into the brain.

00:56:01.160 | And there's variable evidence about if you measure it in blood, is it a readout of the

00:56:05.340 | brain or not, right?

00:56:06.340 | Or should you be looking at something like spinal fluid that's maybe a better biochemical

00:56:11.120 | proxy of the brain?

00:56:13.620 | Most studies, so what I will say is there's been a handful of small studies where there

00:56:20.660 | has been some, you know, there's been some benefit, maybe no benefit, small effects.

00:56:27.040 | We did a study that was a small study at Stanford, and it was based on mouse genetic data.

00:56:33.220 | And I'll sort of walk you through what we did.

00:56:36.500 | So there's multiple mouse models of these neurogenetic syndromes where people have social

00:56:43.540 | impairment, right?

00:56:44.540 | We can quibble about whether that's autism or not, but that they have social impairment.

00:56:48.560 | And so that there are this fragile X mouse, there's a Prader-Willi syndrome mouse, which

00:56:53.640 | is the Magyl 2 gene that gets manipulated, and then there's a Catnap 2 mouse.

00:56:58.980 | And in all of those instances, when you genetically modify those mice, you see a reduction of

00:57:05.660 | oxytocin in the hypothalamus.

00:57:08.340 | And what's interesting is that in those instances where you see this genetic modification, you

00:57:13.820 | do see lower blood levels in these genetically defined models.

00:57:18.620 | What's really cool is you can give oxytocin across development in those models, and at

00:57:24.100 | least in the Catnap 2 mouse, you can restore oxytocin neuron number to equivalent of control

00:57:31.480 | animals, suggesting that oxytocin is doing something in these oxytocin deficient animals,

00:57:37.000 | right?

00:57:38.000 | So these are not an oxytocin gene manipulation, but these are these syndromes where you see

00:57:42.920 | as a consequence of manipulating genes for these syndromes that oxytocin gets knocked

00:57:47.300 | down, right?

00:57:48.420 | And so our thinking when we went into our clinical trial was what if it's blood oxytocin

00:57:54.220 | levels that there are going to be a subset of individuals that just make less oxytocin

00:57:59.340 | humans, and that maybe those are the individuals who stand to benefit the most from treatment.

00:58:06.360 | And so we were the first group to ask across this range of individuals who showed up, and

00:58:14.120 | we did in all the trials that we'll talk about today, these are done with my colleague, Antonio

00:58:19.000 | Hardin at Stanford, who's a child psychiatrist, and we always have double blind, meaning that

00:58:24.640 | the investigative team is blind and that they are unaware, I should say, they're unaware

00:58:29.360 | of treatment, and then the families and the children are unaware.

00:58:32.880 | And then the randomized, meaning there was an equal chance you could get either drug

00:58:36.080 | or placebo, and they're controlled, right?

00:58:39.720 | Okay.

00:58:40.720 | So we asked if we know what your pretreatment blood oxytocin level is, who's going to benefit

00:58:47.260 | from treatment?

00:58:48.260 | And we thought a couple of really interesting things.

00:58:49.860 | One was that the lower your baseline, so your pretreatment blood oxytocin level, you showed

00:58:55.800 | much greater benefit from the oxytocin intervention.

00:58:58.800 | These are shown-

00:58:59.800 | One intervention, one nasal spray?

00:59:01.500 | This was four weeks, sorry, I should have clarified.

00:59:03.620 | This is four weeks of treatment being administered to oxytocin twice a day.

00:59:09.280 | And so we saw effectiveness there.

00:59:12.660 | Sorry to interrupt so much, but just male and female subjects?

00:59:16.360 | We did, but again, because autism is male biased and prevalence, even if you make this

00:59:21.640 | heroic effort to over recruit, try to get more girls in, in the study, we usually try

00:59:27.240 | to aim for the prevalence rate because it's difficult to get girls just because there's

00:59:31.040 | fewer of them.

00:59:32.040 | Got it.

00:59:33.040 | Okay.

00:59:34.040 | But boys and girls were included.

00:59:35.040 | Correct.

00:59:36.040 | They're taking oxytocin over the period of-

00:59:37.040 | Four weeks.

00:59:38.040 | Four weeks.

00:59:39.040 | And if they started off with lower baseline levels of oxytocin, you observed a benefit

00:59:43.240 | of the oxytocin treatment in those individuals.

00:59:46.280 | What about the individuals who had normal to high levels?

00:59:49.360 | You didn't see much benefit, right?

00:59:51.180 | And so that was a cue to me to think that there may be a subset of individuals that

00:59:57.600 | for whatever reason, they have lower oxytocin and they may stand to benefit more from treatment.

01:00:03.160 | And none of the prior studies had looked at blood oxytocin levels.

01:00:06.880 | And so what we had thought was that, well, maybe if everybody had measured baseline blood

01:00:12.800 | oxytocin levels, maybe some of these, maybe there would have been more positive outcomes.

01:00:17.960 | So but there's a lot of controversy in this field about whether oxytocin is a treatment

01:00:23.440 | for autism, right?

01:00:24.480 | So after we completed that trial, there was a large multi-site what's called a phase three

01:00:31.240 | oxytocin treatment trial that was done at, I think, five sites and they gave oxytocin

01:00:37.320 | for an extended period of time and they showed no benefit.

01:00:44.120 | Were they looking to see who started off with low levels of oxytocin at pretreatment?

01:00:49.800 | So what was interesting about that study, and there were a lot of issues with it, was

01:00:55.240 | that oxytocin is something where you have to, if you look at it, it degrades.

01:01:02.520 | That's kind of what I joke about, right?

01:01:03.960 | So you need to take it.

01:01:05.400 | When we go in, we have these really intense protocols, right?

01:01:09.640 | So you go in and we have vacutainer tubes that are cold and we put them on ice and then

01:01:14.240 | the phlebotomist takes the blood from the child.

01:01:16.600 | So a lot of technical gymnastics.

01:01:19.360 | And then we make sure we spin it in a centrifuge cold and then we pipet it onto dry ice.

01:01:23.760 | So we have very minimal loss of the signal.

01:01:27.360 | And so if you don't adhere to those rigid protocols, which is very difficult to do across

01:01:32.660 | multiple sites, it can be very difficult to get an accurate read of oxytocin.

01:01:38.840 | And so I think for me, it's still an open question.

01:01:42.000 | They didn't see the blood oxytocin predicted response in that study.

01:01:48.480 | The data weren't provided in the paper.

01:01:50.200 | It was just said that they didn't.

01:01:52.340 | But it's still an open question.

01:01:56.220 | And so that, you know, maybe that is the way, so if you give it acutely, like in those early

01:02:17.760 | studies we talked about, that maybe oxytocin, you know, diminishes fear.

01:02:22.160 | We know that oxytocin decreases the stress axis, the hypothalamic-pituitary-adrenal axis,

01:02:28.720 | and then it can diminish anxiety in animal models.

01:02:31.220 | So that's well-established.

01:02:32.220 | And in a former life, I was a stress researcher, so I've spent a lot of time thinking about

01:02:37.100 | this.

01:02:38.100 | But it's sort of, the sad thing is, is that once you have a negative trial, there isn't

01:02:43.420 | a lot of interest in funding the work going forward, right?

01:02:47.460 | And so I think it's still really an open question about if there is a subset of individuals

01:02:53.100 | that could benefit from oxytocin replacement therapy, right?

01:02:56.980 | And it's, and until there's money to do that work, we may not ever know the answer.

01:03:03.100 | Well, it will be important for that work to be done eventually.

01:03:06.660 | Hopefully the field will return to it despite whatever trends might be happening now.

01:03:11.500 | I think it's important to know for the parents of autistic children, whether or not there

01:03:17.440 | were any negative effects of oxytocin administration, in particular in the children that did not

01:03:24.820 | benefit from oxytocin treatment.

01:03:26.860 | The rationale is the following, well, of course, these things require a prescription.

01:03:31.440 | If a parent has a child with autism, especially if they're young enough that the behavioral

01:03:34.940 | interventions could possibly stand a good chance of inducing neuroplasticity, rewiring

01:03:40.140 | of the neural circuits that underlie social connection, well, then there's this time-limited

01:03:45.780 | window in which, you know, those parents presumably are willing to try most anything provided

01:03:52.740 | it's safe.

01:03:54.120 | So let's assume, and I'm making up these numbers now because I haven't seen this study, but

01:03:58.040 | according to what you told me, that let's say a third of the autistic boys and girls

01:04:02.900 | that come in have low baseline levels of oxytocin.

01:04:06.460 | They're the ones that are going to benefit from this oxytocin intervention.

01:04:09.880 | The other two thirds don't.

01:04:11.480 | Well, given the difficulties of measuring baseline levels of oxytocin, most people don't

01:04:15.340 | have access to those kinds of resources.

01:04:18.260 | If it's safe to give oxytocin no matter what, well, then if I were that parent, I'd be knocking

01:04:23.940 | on my physician's door saying, "Hey, give me an oxytocin spray because my kid might

01:04:27.420 | fall into that one third category."

01:04:29.460 | If and only if it turns out that oxytocin is safe to give, but if there's a risk profile

01:04:34.540 | that doesn't justify that kind of shotgun approach, well, then I wouldn't do that.

01:04:38.680 | So is oxytocin spray safe?

01:04:42.140 | And if so, why doesn't every physician who has a patient with autism give them oxytocin

01:04:48.260 | nasal spray?

01:04:49.260 | Right.

01:04:50.260 | It's a great question.

01:04:51.260 | And I know that, you know, I'm a parent of three children and I know this sense of like

01:04:54.920 | you would do anything to help your child, right?

01:04:57.000 | And so I think the tricky part is that it was the one thing I will say is that all of

01:05:01.700 | the studies and there's been many of them have shown that oxytocin is relatively safe

01:05:07.700 | in a pediatric population, right?

01:05:10.420 | The tricky part is I don't know, there's physicians that, you know, really pay attention to clinical

01:05:14.780 | trials and if they don't see a benefit, they may not be willing to write the prescription,

01:05:19.340 | right?

01:05:20.340 | So until we could identify a group of children that could benefit, you know, we need to create

01:05:27.500 | the opportunity for physicians to recognize that this could potentially still be a treatment,

01:05:32.940 | right?

01:05:33.940 | But that work, you know, but I think the tricky part and what I will say is, and we can maybe

01:05:37.300 | talk a bit about vasopressin, which, you know, my feeling is that if I was placing bets and

01:05:42.540 | having to choose between these two, my money would be on vasopressin.

01:05:46.620 | Well, we are definitely going to talk about vasopressin in detail.

01:05:50.180 | I mean, the reason I mentioned that hypothetical scenario is just the sense of urgency and

01:05:55.220 | in some cases desperation that parents feel and, you know, time's ticking and if oxytocin

01:06:00.620 | is safe, then, you know, I guess I'll put in my vote that, you know, parents should

01:06:04.300 | at least talk to their physician, maybe even hand them the study to consider.

01:06:09.040 | But I can also understand the perspective of a pediatrician who says, "Well, listen,

01:06:11.860 | it was a small number of kids that benefited.

01:06:14.700 | You're welcome to try it, but I don't, you know, it doesn't seem like the results are

01:06:18.440 | that impressive."

01:06:19.440 | But, you know, this gets to a bunch of larger issues about, you know, medical care and randomized

01:06:25.100 | controlled trials and the desperation of parents and kids to treat neurodevelopmental challenges.

01:06:30.780 | I just want to ask because it feels relevant in a real way, you know, if ultimately the

01:06:38.940 | goal of improving symptom profiles in autistic kids is about improving social cognition and

01:06:46.460 | social behavior and that process involves rewiring of brain circuits, neuroplasticity,

01:06:53.520 | is there any reason to think that other approaches to inducing neuroplasticity would be beneficial

01:06:59.660 | even if they're not in the biological pathways that are disrupted in autism?

01:07:04.620 | I think, for instance, about the now extensive use of SSRIs for the treatment of depression,

01:07:11.680 | some cases it works, in some cases it doesn't.

01:07:14.020 | Side effect profiles are a serious concern as discussed on this podcast before, but ultimately

01:07:19.900 | we know that depression is not a serotonin deficiency.

01:07:23.000 | In most cases, SSRIs are atypical antidepressants like buprenorphine, wellbutrin and things

01:07:28.620 | of that sort.

01:07:29.620 | When they work, they probably work because of their ability to induce or assist neuroplasticity,

01:07:36.060 | right?

01:07:37.060 | Also, the trials on psilocybin are not really about psilocybin, they're about neuroplasticity.

01:07:43.940 | At least the trials for depression, right?

01:07:46.020 | There may be other uses of psilocybin that relate more directly to the effects of psilocybin.

01:07:50.520 | But ultimately, you know, what we're talking about here is the attempt to rewire the brain

01:07:54.600 | in a specific way, whether or not it's assisted by oxytocin or some other mechanism.

01:07:59.840 | So the question is, are there trials happening where people are exploring, say, psilocybin,

01:08:07.520 | MDMA, which by the way, we know increases oxytocin and serotonin dramatically, as well

01:08:13.460 | as things like atypical antidepressants in kids that have autism, not because we think

01:08:20.040 | that those autistic kids are deficient in any of the neurochemicals that these drugs

01:08:24.580 | would target, but that these drugs can help rewire the brain, and ultimately that's what

01:08:28.700 | these kids need.

01:08:29.700 | Right.

01:08:30.700 | It's a really great point.

01:08:31.700 | And there might be subsets of kids, right?

01:08:34.020 | There might be kids where there would be a medication that would target other pathways,

01:08:38.940 | but that potently releases oxytocin, right?

01:08:42.220 | But there might be kids that have an oxytocin deficiency, right?

01:08:45.260 | But I think that that circles back to your point at the beginning, where our point is

01:08:49.980 | that autism is a very heterogeneous condition and being able to know before you begin a

01:08:56.860 | trial, right, like who am I going to put into it and what is my primary outcome, like one

01:09:02.080 | measure that I think is going to move the needle, right?

01:09:04.420 | Like it kind of requires a crystal ball.

01:09:06.560 | So there's a lot of guesswork that goes into this.

01:09:09.600 | But I would very much like to see, I will say one other thing that, I have a colleague

01:09:14.860 | named Adam Guistela, who's at the University of Sydney, and he published a paper a year

01:09:19.160 | or two ago now, suggesting that oxytocin may be most effective in kids at younger ages.

01:09:26.620 | And don't quote me, somewhere between two and five or three and six or something like

01:09:31.900 | that.

01:09:32.900 | We'll find the paper and put it in the show notes.

01:09:33.900 | Yeah.

01:09:34.900 | So it could be, to your point about neuroplasticity, that oxytocin may be maximally beneficial

01:09:42.100 | in younger ages, right?

01:09:43.720 | And if these studies or these hodgepodge is across ages and across sort of different social

01:09:50.340 | phenotypes, finding that signal is really important, right?

01:09:55.220 | And maybe age is a driver or maybe low blood oxytocin regardless of what age you are, or

01:10:03.660 | maybe in Adam's case, if you recruit really young children, you're likely to see a benefit

01:10:08.880 | just because the brain is wiring up and it's more plastic at younger ages.

01:10:13.980 | Yeah.

01:10:14.980 | That's also a vote, in my opinion, for early examination of kids, right?

01:10:21.880 | Like parents really need to get autism screening and perhaps maybe the most important thing

01:10:26.460 | is to make autism screening as available and as inexpensive as possible for everyone because

01:10:32.260 | of the importance of early intervention, even if it's purely behavioral intervention, but

01:10:36.020 | certainly if it's behavioral and drug interventions.

01:10:38.300 | The clinic wait times are really long, right?

01:10:40.780 | So you have to have a specialist who's capable to diagnose autism.

01:10:45.140 | And so you could have a clinic where you're showing troublesome features and a parent

01:10:50.360 | wants to get their kid into a clinic and you could have a 12-month or 18-month wait time,

01:10:55.000 | right?

01:10:56.000 | And so there are a lot of people that are thinking about, are there laboratory-based

01:11:01.260 | tests that we can develop maybe either for detection or clinical referral, right?

01:11:06.220 | So could we come up with a biomarker panel, for instance, where we might be able to say,

01:11:12.540 | wow, here's a panel where we think this child is at reasonable risk for developing autism.

01:11:20.180 | Can we make sure they're prioritized for getting a diagnosis, right?

01:11:23.900 | So we can get them an early intervention, but right now we don't have that, right?

01:11:29.160 | So having some sort of laboratory-based test, whether it could be biological or if we could

01:11:35.240 | do something with eye gaze, and there's a lot of companies working on these things now

01:11:39.600 | to say this may not, and also obviously again, autism is always controversial in this field,

01:11:46.600 | right?

01:11:47.600 | There's so many different stakeholders.

01:11:48.600 | A lot of clinicians will say, well, I don't want a 30-second video clip replacing expert

01:11:53.100 | clinical opinion.

01:11:54.100 | There's good reasons for them to feel that way, but I think if there was a way to prioritize

01:11:58.560 | people that are in this line, we could get diagnoses faster.

01:12:03.900 | Well, you wouldn't want false positives, but I would think that a 30-second video clip,

01:12:08.260 | provided it's of something useful, it's going to be more valuable than nothing given the

01:12:12.320 | time sensitivity.

01:12:14.340 | What are some of the barriers to getting this behavioral testing to be not just more prominent

01:12:19.820 | but pervasive?

01:12:21.460 | Like it seems to me that, well, I recall in school they gave us the hearing test.

01:12:26.300 | We all marched onto the bus.

01:12:27.460 | We get the beep test and for hearing challenges.

01:12:33.540 | You get vision tests.

01:12:34.540 | You get the Babinski reflex test, not the moment you come out of the womb, but pretty

01:12:39.060 | soon after.

01:12:40.060 | I mean, why isn't this stuff happening for autism for every kid?

01:12:47.680 | It's not scalable, right?

01:12:49.240 | So these interviews with parents and the tests that you do can take hours, right?

01:12:54.360 | And any given clinician, even if they're working really long hours, there just aren't that

01:12:59.180 | many people that have the extensive training needed to make these expert diagnoses, right?

01:13:04.360 | And so I think that there's clinicians that are doing the absolute best they can, but

01:13:08.820 | they can only see a certain number of people a week, right?

01:13:12.380 | Does it have to be a physician?

01:13:13.740 | Sorry to interrupt.

01:13:15.140 | Or could a well-trained technician do this?

01:13:19.460 | Yeah.

01:13:20.460 | Well, I mean, I think technically it's a DSM diagnosis, right?

01:13:24.100 | So it's usually somebody who has a clinical degree.

01:13:26.140 | So it would be a clinical psychologist.

01:13:27.860 | It could be a behavioral pediatrician.

01:13:30.180 | It could be a child psychiatrist or a child neurologist, but I mean, again, that requires

01:13:34.900 | years and years of training.

01:13:37.260 | And if we look in areas where people have fewer access to resource, I mean, particularly

01:13:44.220 | in impoverished areas, the mean age of an autism diagnosis is years later than in wealthy

01:13:50.560 | areas where there's many different medical specialists with parents that aren't working

01:13:55.660 | three jobs and can sit waiting around and really lobby and really advocate for their

01:14:02.440 | kids because if they don't show up for work that day, they're not going to get fired from

01:14:06.780 | their job, right?

01:14:07.780 | And so I think that if there's some sort of solution that allows there to be a more democratic

01:14:15.140 | approach to saying we need a really quick way, like you said, to be able to identify

01:14:21.460 | at-risk children, especially if it's a blood test or something like that, you know, it

01:14:26.820 | could be incredibly impactful.

01:14:29.980 | Are there human trials exploring MDMA, methylenedioxymethamphetamine, also referred to as ecstasy, and/or psilocybin

01:14:39.700 | for treatment of autism?

01:14:42.340 | So I was aware that MAPS had an MDMA trial in autism.

01:14:47.500 | I don't know what's happened with that.

01:14:50.420 | Yeah.

01:14:51.420 | Perhaps it's still ongoing.

01:14:52.420 | I'll check the MAPS site.

01:14:53.420 | I'm in communication with them from time to time.

01:14:55.060 | I mean, the reason for asking, and of course, you know, but maybe in case some of the listeners

01:15:00.560 | don't, is that MDMA causes these massive increases in serotonin.

01:15:05.300 | That seems to be the major source of the MDMA effect, so to speak, based on the work of

01:15:12.400 | our colleague, Rob Malanka, and at least one human study comparing MDMA to very high dose

01:15:19.160 | oxytocin treatment, kind of ruled out the oxytocin spike that's induced by MDMA as

01:15:25.100 | the source or the only source, but of course, these chemicals can synergize.

01:15:29.280 | But based on its chemical profile, oxytocin release, massive serotonin release, dopamine

01:15:34.260 | release, and a propensity to enhance neuroplasticity, I mean, assuming all the safety protocols

01:15:40.540 | were there, seems like not the perfect drug, but not a bad choice if, of course, it's inducing

01:15:48.780 | the kind of plasticity that someone with autism would be seeking.

01:15:52.220 | Right.

01:15:53.220 | I mean, I think the tricky part, especially in children, right, is there's going to be

01:15:56.100 | a reluctance to potentially give them psychedelics, right?

01:15:59.560 | And so, you know, is there a way to modify, you know, the chemical compound to, you know,

01:16:06.860 | be something that parents might be more willing to give to their children, right?

01:16:10.900 | Right.

01:16:11.900 | And I totally agree with that, I guess, to play devil's advocate, not against you, but

01:16:15.440 | well, I'll just state it very directly, and then I'll take the heat as necessary.

01:16:21.860 | I mean, I've done two episodes about the drugs that, you know, millions, tens of millions,

01:16:29.620 | if not hundreds of millions of parents are already giving their kids for ADHD, which

01:16:33.260 | are include amphetamines, including dioxin, methamphetamine is actually a prescription

01:16:38.260 | drug for a very small subset of kids with ADHD, but things like Adderall, Vyvanse, even

01:16:43.260 | methylphenidate Ritalin, I mean, these are amphetamines, they induce dopamine release

01:16:47.040 | and norepinephrine release.

01:16:48.540 | And again, I'm not suggesting people give their kids MDMA to try and ameliorate symptoms

01:16:54.140 | of autism, but something chemically similar to it ought to be developed, or at least explored

01:16:59.260 | in a human trial, in my opinion.

01:17:01.380 | Well, time will tell, I'll reach out to the MAPS group and see what's happening.

01:17:05.800 | Let's talk about vasopressin, because there's a lot to discuss there.

01:17:09.340 | So you told us this is a molecule that chemically is very similar to oxytocin.

01:17:14.540 | Is it manufactured in the human brain and body?

01:17:16.740 | Yes.

01:17:17.740 | Okay.

01:17:18.740 | Do we know a subset of the sites that it's known to be produced and where some of its

01:17:23.300 | actions are?

01:17:24.300 | And you mentioned the kidney and the antiderioratic hormone roles, but within the brain, like

01:17:29.980 | what brain areas have neurons that make vasopressin or have the receptors for vasopressin?

01:17:34.540 | Yeah.

01:17:35.540 | I mean, the receptors are all over the brain.

01:17:37.860 | And again, it varies depending on the species.

01:17:40.620 | And the way the receptors are measured are in post-mortem tissue, which can be very difficult

01:17:46.480 | to get good samples.

01:17:48.800 | And so we need to have that caveat going in.

01:17:52.380 | But yeah, I mean, it's made in the hypothalamus, and it's released all over the brain.

01:17:59.240 | And there is vasopressin receptors all over the brain.

01:18:02.460 | And what's really interesting about vasopressin, I always sort of joke that oxytocin always

01:18:09.020 | saw its day in the sun, if you will.

01:18:11.180 | And the vasopressin was sort of the stepchild that was left sort of behind.

01:18:16.820 | And the reason why I find this fascinating is, again, I think back to my roots as an

01:18:24.660 | evolutionary biologist, behavioral neuroscientist.

01:18:27.140 | And what was interesting is that there were studies in the early to mid 1990s showing

01:18:32.100 | that vasopressin was critical for male social behavior.

01:18:36.220 | And so there was work, there was a variety of people, and I think Rob Malenka mentioned

01:18:41.520 | this on the podcast he did, about there was a group of people like Sue Carter, Larry Young,

01:18:48.100 | Tom Insull, some of these early people.

01:18:50.540 | And they gave vasopressin to male prairie voles.

01:18:54.260 | And vasopressin was what induced pair bonding with a female mate and also paternal care.

01:19:03.460 | And as I recall, those experiments were done in the context of looking at polygamy versus

01:19:09.120 | monogamy of these prairie voles.

01:19:12.900 | Prairie voles versus like a different species, so same genus, but a different species.

01:19:18.640 | So it might be a montane vole or, you know, highly related, but these other species.

01:19:23.800 | So prairie voles are monogamous.

01:19:26.500 | The males-

01:19:27.500 | For life?

01:19:28.500 | Well, I mean, that was the mark.

01:19:29.500 | 50% divorce, right?

01:19:30.500 | Yeah.

01:19:31.500 | That was, I don't think it's that bad, but I think marketing-

01:19:32.500 | They're doing better than we are as a species.

01:19:33.960 | That's true.

01:19:34.960 | We should look to them for pointers.

01:19:35.960 | And all the divorce folks are saying, "Wait, why'd you say better?"

01:19:38.340 | I have some divorce friends that have said, "Divorce is like the greatest thing."

01:19:41.980 | So we always say like doing better, doing worse, right?

01:19:44.700 | Anyway, that's a whole other podcast and certainly not the Huberman Lab podcast, or maybe it is,

01:19:50.960 | or will be.

01:19:51.960 | Yeah, my understanding is that you have certain voles that mate with almost exclusively with

01:19:59.700 | one other vole for their entire lifespan.

01:20:02.400 | And then you have other voles located elsewhere that in those colonies, they mate with lots

01:20:08.860 | of different voles.

01:20:09.860 | So the males and females have lots of different partners, raise young with lots of different

01:20:13.780 | partners, mating with lots of different partners.

01:20:16.180 | And that if you give vasopressin, then you can make the, I always want to call them polyamorous,

01:20:21.660 | but I don't know if they love each other.

01:20:23.100 | I'm going to anthropomorphize and assume they love each other.

01:20:26.380 | The polygamous moles, not polyamorous, but polygamous moles then become monogamous.

01:20:31.820 | Well, yeah, I would say that is probably not the take-home message.

01:20:34.660 | So the take-home message would be they had, let's say that there was like the good voles,

01:20:38.980 | right?

01:20:39.980 | Which are the prairie voles.

01:20:40.980 | And they were the ones that formed these monogamous pair bonds.

01:20:43.540 | Dad participates in paternal care with mom.

01:20:46.520 | They co-raise babies together and then dad chases off intruders, right?

01:20:51.000 | And then there's the more asocial voles.

01:20:54.280 | And so these are like the montane voles.

01:20:57.860 | And we'll see, it's a complicated story, but there's these montane voles where males and

01:21:04.200 | females live separately.

01:21:06.060 | Females like maybe live on the male's territory.

01:21:08.360 | The male mates with a few different females absolutely doesn't provide any paternal care

01:21:12.020 | at all.

01:21:13.020 | Mom raises babies by herself, right?

01:21:14.360 | So these are really the two models.

01:21:15.840 | This is like 1950s versus 2020s.

01:21:18.160 | Yes.

01:21:19.160 | To be, just to broadly stereotype.

01:21:21.380 | To broadly stereotype.

01:21:23.100 | And if you give, okay, so for prairie voles, they're sort of primed to form bonds and to

01:21:29.500 | be the males to be good daddies, if you will.

01:21:32.180 | And all you have to do is give them a single injection of vasopressin and you know, or

01:21:37.540 | you can give an antagonist and usually the way they form the bond is through mating,

01:21:41.540 | right?

01:21:42.540 | So they, you put them with a female, they mate, they cohabit for a bit.

01:21:46.840 | There's been all kinds of parametric studies.

01:21:48.620 | I can't remember how many hours it takes to form a parabond, but then you can do these

01:21:52.960 | things called partner preference tests and then you can say, here's the guy that you

01:21:56.920 | mated with.

01:21:57.920 | Here's this guy you don't know and you can do it for males and you can do it for females

01:22:00.720 | and they pick their partner.

01:22:01.760 | They choose to go hang out with their partner.

01:22:03.500 | The montane voles, you know, either after mating with somebody may either be equal or

01:22:09.120 | maybe they'll even go spend time with a new individual.

01:22:11.440 | So the cleanest story was that prairie voles are monogamous, montane voles are not monogamous,

01:22:16.420 | but in the prairie voles, you could give vasopressin instead of mated cohabitation and you could

01:22:23.140 | turn on like, you know, a bond with somebody after only living with them for a very short

01:22:28.500 | period of time, right?

01:22:30.440 | Or you could induce paternal behavior.

01:22:33.180 | And I was working with the voles species in grad school.

01:22:35.460 | I think the most interesting scientific experience that I've ever had, right?

01:22:39.960 | And you and I both know this, right?

01:22:41.520 | When you're young, you're actually the person doing the work, right?

01:22:44.420 | As you become, you know, the head of your lab, you're mostly writing grants and giving

01:22:49.460 | talks, right?

01:22:50.460 | And then you get to hear about the super cool things that everybody in your lab is doing,

01:22:53.980 | right?

01:22:54.980 | Eventually the members of your laboratory kick you out of the lab.

01:22:58.400 | They literally say like, get out of here.

01:22:59.980 | You're leaving things in the wrong place.

01:23:01.140 | Whereas initially you're telling them, Hey, that's in the wrong place within a year or

01:23:05.420 | two.

01:23:06.420 | For me, I think it took about four or five years, but by about year six, I was demoted

01:23:12.780 | to my office to just write grants and write papers.

01:23:14.820 | I was told that one time I was back there and I tried to wait and I was like, so excited

01:23:18.200 | what they were working on.

01:23:19.620 | And they basically just said, go write grants and bring in more money, right?

01:23:22.020 | Like that was kind of their attitude.

01:23:23.420 | Like we get to be the ones who get to do the cool stuff.

01:23:25.800 | So back when I got to actually do the science, I remember I had this species where, and I,

01:23:33.340 | and again, I told you, I came at this from an evolutionary perspective.

01:23:35.740 | So these were called meadow voles and I found them very interesting.

01:23:39.180 | So when I showed up in my thesis advisor's lab, she's, I said, I really want to study

01:23:43.620 | oxytocin and vasopressin and I really want to study voles and I know you have a voles

01:23:47.580 | species.

01:23:48.580 | And she said, well, I don't have prairie voles.

01:23:49.580 | I have these meadow voles and I'm studying them because they're so sensitive to light

01:23:54.000 | and they change their behavior based on light.

01:23:56.100 | And I, she said, well, you can do what you want, but our grants basically have to have

01:24:00.780 | a circadian component.

01:24:02.140 | And so she said, you got to work that in, but then we kind of struck this deal.

01:24:05.340 | So I was hanging out in the animal rooms and I thought it was really fascinating.

01:24:08.900 | So she had animals that were either on short day lengths or long day lengths.

01:24:13.220 | So the mimicking summer and winter.

01:24:16.220 | And I was noticing that on winter day lengths, the, the males were hanging out with the females

01:24:20.900 | and when the female had a litter, he was like participating and I was like, whoa, these

01:24:25.180 | are not supposed to be monogamous animals.

01:24:27.700 | And so I went into the field research and they were doing all these radio telemetry

01:24:32.740 | studies.

01:24:33.740 | And so like if you should probably explain what those are, putting a little transmitter

01:24:37.940 | under the skin, it's painless for the animal, but that allows the researcher to monitor

01:24:42.300 | the behavior of the animal in the field remotely without having to, you know, put them in cages

01:24:47.580 | and stuff.

01:24:48.580 | And so this is like under field conditions and voles are everybody's favorite snacks.

01:24:52.740 | So they have like a very limited lifespan in the wild.

01:24:55.100 | I mean like on the order of months and, and so like if you have a short lifespan, like

01:25:00.620 | you should just keep reproducing, right?

01:25:02.660 | And so what was interesting is at the end of the summer days, as you're going into winter,

01:25:07.100 | territories collapse and males are found with females and they co-raise babies.

01:25:11.460 | It makes sense.

01:25:12.460 | If it's, you're going to have a litter and mom needs to get up to go eat, you need somebody

01:25:16.920 | to sit there and warm those babies or they're going to die because they're going to freeze

01:25:20.000 | to death.

01:25:21.000 | Right?

01:25:22.000 | So I started saying like, wow, I think these metaphors are good dads.

01:25:24.940 | Like I'm noticing this.

01:25:26.240 | And so I told my thesis advisor, I want to study how oxytocin and vasopressin can, maybe

01:25:32.160 | this is involved in tracking these evolutionary mating strategies.

01:25:36.540 | And so again, like the coolest experience I ever had was on these males that were housed

01:25:41.420 | under short day length.

01:25:42.700 | So they were like winter males.

01:25:45.500 | I was able to put vasopressin directly into their brains and, and it was like turning

01:25:50.660 | on a light switch and they ran around the cage, picked up all these babies, put them

01:25:55.100 | in a nest and huddled over them.

01:25:57.540 | And if you put a placebo into their brain, nothing happened.

01:26:01.340 | And so to me, I always filed that away in, you know, in the back of my mind of like,

01:26:07.100 | wow, vasopressin is this really interesting hormone.

01:26:12.420 | And maybe someday I will, I did a postdoc on something else, but it was always, you

01:26:17.700 | know, back in the back of my mind of, I really want to return to this.

01:26:21.580 | It's so incredible that a eight amino acid long peptide could basically turn these relatively

01:26:28.820 | negligent fathers into very attentive fathers.

01:26:31.780 | Yes.

01:26:32.780 | Yeah.

01:26:33.780 | It was fascinating.

01:26:34.780 | I mean, it just speaks to the power of the peptide vasopressin also speaks to the power

01:26:39.000 | of brain circuitry.

01:26:40.000 | It also speaks to the idea that brain circuitry is often sitting latent in the background,

01:26:45.880 | you know, ready to be activated, that it's not just about neuroplasticity and building

01:26:50.440 | up a new circuit, that some forms of neuroplasticity are about unveiling what's, what's already

01:26:56.300 | there.

01:26:57.300 | So those peptides can act like switches, which, you know, kind of makes sense on the one hand,

01:27:02.080 | but I've never heard of a result as dramatic as that.

01:27:06.300 | So I'm presuming you're going to tell us that that then led you to go back to vasopressin

01:27:12.800 | and explore its ability to induce good parenting and negligent fathers.

01:27:17.260 | I haven't studied that yet.

01:27:19.500 | No.

01:27:20.500 | Well, so I think that, you know, my mom always says chance favors the prepared mind.

01:27:25.280 | And so I was doing my postdoc at Stanford and I got recruited to stay on the faculty

01:27:31.180 | and I, you know, had been doing work in stress vulnerability and stress resilience.

01:27:35.980 | And I really, and I love doing that work, but I still felt this tug of, you know, I

01:27:41.740 | had spent all this time in a psychiatry department where I was surrounded by clinicians.

01:27:46.380 | And I realized that a lot of the stuff that I was doing had clinical relevance, right?

01:27:50.780 | And so sometimes you sort of meet the moment, right?

01:27:54.140 | And so right as I was transitioning to have my own lab in my department, there was a bunch

01:28:00.200 | of stuff going on.

01:28:01.200 | So there were a lot of very dedicated parents who were lobbying for funding for autism research

01:28:06.800 | because it was horrifically underfunded.

01:28:08.840 | Really?

01:28:09.840 | Horrifically underfunded.

01:28:10.840 | Wow.

01:28:11.840 | I mean, at rates of one in 36 kids.

01:28:13.400 | Well, not at the time, right?

01:28:14.400 | So it was, it was one in 150 or whatever it was back then.

01:28:17.920 | But there were all these parents and I mean, again, they're heroes in my eyes that they

01:28:21.720 | advocated so much for their loved ones.

01:28:24.440 | And so there was, you know, they started forming parent grassroots organizations that have

01:28:28.600 | culminated.

01:28:29.600 | They all started joining together, which is now Autism Speaks.

01:28:32.820 | And then there was a man named Jim Simons who runs one of the most successful hedge

01:28:36.780 | funds in the world.

01:28:38.100 | And he decided, wow, I'm in a, you know, there's, let's put money into autism, right?

01:28:42.900 | And so-

01:28:43.900 | Does he have a personal link to autism?

01:28:44.900 | I, you'd have to ask him.

01:28:46.740 | Because oftentimes, not always, but oftentimes when you hear about wealthy donors devoting

01:28:53.700 | a lot of money to one area of science, there's, there's a familial thing there that, you know,

01:28:57.780 | a member of their family or a close friend has this challenge and they, they really want

01:29:02.180 | to see that challenge.

01:29:03.180 | Absolutely.

01:29:04.180 | I mean, a lot of money I've gotten for my lab from philanthropists and what I will say

01:29:07.980 | is the most impactful work I've ever done is through philanthropy, right?

01:29:11.700 | They're crazy ideas that no funding agency ever touches, right?

01:29:16.180 | But yeah, so they put, they both put a lot, you know, there was a lot of emphasis and

01:29:21.020 | so because the Simons Foundation started issuing requests for applications, there was a group

01:29:26.180 | at Stanford that formed and it was a clinician with a basic scientist.

01:29:31.380 | And my chair at the time said, well, you know, almost nothing is known about the biological

01:29:36.180 | basis of autism.

01:29:37.180 | Why don't you go, I'm going to introduce you to the head of child psychiatry.

01:29:41.940 | You should go talk to this group.

01:29:43.420 | And so as I was preparing my slides and realizing that, you know, social interaction impairments

01:29:49.200 | were a core feature of autism, I thought, wow, you know, these neuropeptides may really

01:29:53.980 | be, you know, a part of this puzzle.

01:29:58.060 | And so that's actually really how I got pulled into autism research was, was through that.

01:30:04.520 | And it was, I was, you know, everybody at the time was very interested in oxytocin and,

01:30:10.460 | you know, I remember thinking, so we actually did probably the most definitive blood oxytocin

01:30:16.540 | study because there was this idea, again, like this marketing campaign of like the oxytocin

01:30:20.860 | deficit hypothesis of autism.

01:30:22.780 | And, you know, given how clinically heterogeneous autism was, we got money actually from the

01:30:27.460 | Simons Foundation and we did the first study with maybe 200 kids.

01:30:33.440 | And what we were able to show was that blood oxytocin was not a marker of autism, right?

01:30:38.720 | So it wasn't like there was a bimodal distribution, meaning two completely non-overlapping levels

01:30:44.540 | of oxytocin in people with autism, people without autism.

01:30:48.100 | So the lower your blood oxytocin levels, actually, regardless of who you were, you could be a

01:30:53.580 | child with autism, you could be an unaffected sibling with autism, or you could be a unrelated

01:30:59.340 | control child.

01:31:00.500 | And it was the lower your blood oxytocin levels, the greater your sort of social difficulties.

01:31:06.500 | And the slopes, you know, were different.

01:31:08.020 | They started at different points because the behaviors were obviously different.

01:31:11.360 | But that's what got us thinking about our clinical trial, which is that blood oxytocin

01:31:15.840 | level is not going to be this great differentiator between people with and without autism, right?

01:31:21.840 | But we might be able to find a subgroup who could benefit from treatment.

01:31:25.560 | But what I like so much about your approach, the way you described it, is that it sets

01:31:32.560 | aside, we don't want to say discards, but it sets aside this thing that we call autism,

01:31:37.240 | which is already hard to define and diagnose.

01:31:39.740 | And there's all these different spectrums and you're trying to fit and just says, okay,

01:31:43.780 | children with autism have challenges in social cognition, social behavior, social bonding.

01:31:50.180 | So do adults with autism, for that matter.

01:31:52.860 | Let's just focus on that.

01:31:55.140 | And not worry so much about whether or not somebody is diagnosed as autistic or not.

01:32:00.040 | And just focus on what are some of the potential neuropeptide deficits or overexpression of

01:32:04.740 | neuropeptides that may in some way relate to those social challenges.

01:32:11.160 | And then one can circle back to the question about autism in collecting those data.

01:32:17.040 | But it also points to this idea that when we go after a disease like Alzheimer's, we

01:32:22.220 | can often miss the possibility that Alzheimer's, while it has deficits in cognition and memory,

01:32:28.220 | could also be a bunch of other things like a metabolic disorder of the body.

01:32:31.600 | And so maybe you go after a particular symptomology and try and attack that, and you might actually

01:32:38.200 | potentially treat or cure multiple diseases.

01:32:41.200 | It's a very different approach.

01:32:42.500 | And I hope people are catching on to the subtlety, but also the potential impact of that.

01:32:50.340 | Because if I heard correctly, you said there are people who are not autistic who have social

01:32:55.420 | functioning deficits.

01:32:57.620 | And they too have less circulating oxytocin.

01:33:02.420 | Right.

01:33:03.420 | So I would say we haven't studied people where we brought them in and characterized it, right?

01:33:07.180 | So these are typically developing kids.

01:33:10.520 | But what we did is in the abilities that are typical of a controlled child, we still saw

01:33:16.480 | that gradient, right?

01:33:18.260 | And so I think it just sort of begs the question about what is oxytocin's role in human sociality,

01:33:25.240 | right?

01:33:26.240 | I mean, I think there's just so much that we don't understand about both of these molecules

01:33:32.820 | in terms of their disease liability if they're low or their healing potential if we are able

01:33:39.940 | to use them as modulators of other therapies.

01:33:45.260 | So how did you move from oxytocin to vasopressin?

01:33:50.140 | You mentioned that everyone was all excited about oxytocin, still the one that we hear

01:33:54.620 | the most about, although after this podcast episode, and when I start blabbing about vasopressin

01:34:00.080 | to everybody, maybe that'll change, but I think it's going to take a lot more than that.

01:34:05.240 | But maybe it's because the name isn't as, there's something about oxytocin that kind

01:34:10.440 | of sounds like the love, it looks like the love hormone, but like vasopressin should

01:34:14.300 | be renamed.

01:34:15.300 | Right.

01:34:16.300 | It should be called something else, like not antiderioritic hormone, not vasopressin.

01:34:19.860 | I mean, you're going to tell us how critically important it is, perhaps even more important

01:34:23.740 | than oxytocin for autism and social functioning.

01:34:27.080 | So I don't know, by the end of this podcast, we'll come up with a new name.

01:34:31.760 | It's needed, right?

01:34:32.760 | Well, I'll put it out there.

01:34:35.260 | Okay.

01:34:36.260 | So how did you get to vasopressin?

01:34:38.620 | Okay.

01:34:39.620 | So it was interesting with oxytocin because we didn't, and again, I was skeptical that

01:34:43.420 | we would see these big group differences, but it was a little bit of like, okay, what everyone's

01:34:48.860 | saying, this is not going to be the big solution, right?

01:34:53.660 | And so I actually came at it from the work that we did in monkeys.

01:34:58.860 | And so I think I mentioned previously at the beginning of the podcast that there were a

01:35:03.220 | lot of limitations that I saw.

01:35:05.140 | And then sometimes if you come into a field, you know, when you're, you're a little bit

01:35:09.980 | of an outsider, right?

01:35:10.980 | Like I'm not a clinician, I don't see autism patients, but I also, I have this really strong

01:35:16.420 | interest in social behavior and the biology of it.

01:35:20.540 | And so I was thinking about what are things that we need to do to better address the challenges

01:35:30.300 | in autism?

01:35:31.300 | So one of them was why are we looking in blood, right?

01:35:33.420 | Like if you look at neurological conditions, there has been a lot of progress made by doing

01:35:37.980 | biomarker discovery in cerebral spinal fluid, right?

01:35:40.960 | So like the biological substrates or clues of markers of say various forms of dementia

01:35:48.700 | or MS were first found in spinal fluid, right?

01:35:54.140 | Because it's the fluid that bathes the brain and the spinal column.

01:35:57.620 | And so if you're looking for the biochemistry of an illness, that's the closest fluid that

01:36:01.820 | you can get to the brain, right?

01:36:03.220 | Blood draw just won't do it.

01:36:04.660 | Maybe, right?

01:36:05.660 | So that was part of my thinking.

01:36:06.660 | But then there was the issue of the animal models, right?

01:36:09.620 | So there was drug after drug after drug that was tested in mice and they failed in human

01:36:14.420 | clinical trials.

01:36:15.500 | And so it made me start thinking, could we develop a primate model of naturally occurring

01:36:23.560 | social impairments, right?

01:36:25.220 | So can we, because in autism, these social impairments are, if you will, naturally occurring,

01:36:30.420 | right?

01:36:31.420 | And so these spontaneously occur in children.

01:36:35.460 | And so it made me wonder, could we identify monkeys in a large colony that have social

01:36:42.500 | impairments and after talking to clinicians who treat these children, can I spend a lot

01:36:51.140 | of time validating a monkey model where there will be monkeys that have features that look

01:36:56.300 | like they have direct relevance to core autism symptoms?

01:37:00.600 | And so what I did was there's a primate center, the California National Primate Research Center.

01:37:06.260 | And so what we did is, so I think I mentioned earlier that there's these surveys that can

01:37:11.140 | be used to look at autistic traits in the general human population, right?

01:37:15.780 | And so we refined one of these and we did what we call back translate.

01:37:20.660 | So basically it's an instrument that's used for humans and then what we did is modified

01:37:26.120 | it to be able to use this rating scale in rhesus macaques, which are an old world monkey

01:37:31.620 | and I know you're familiar with them.

01:37:33.700 | And I was interested in looking at old world monkeys because there are some of the closest

01:37:38.240 | relatives to human that are used in biomedical research.

01:37:42.660 | And as I mentioned previously, these autistic traits are continuously distributed across

01:37:47.940 | the general human population and that this genetic, let's call it genetic liability,

01:37:55.340 | which is a fancy way of just saying that we think that there's a genetic risk that underlies

01:38:01.960 | this continuum of behavioral traits, right?

01:38:04.440 | So if we think that that's true in humans and in one of our closest relatives, and we

01:38:09.280 | think that some of these genes create proteins that then are what sets up the developing

01:38:15.360 | brain to develop in the way that autistic brains develop.

01:38:18.840 | So let's just assume that that's the premise, that's what we went in with.

01:38:22.020 | Can we find rhesus macaques that are just living in large outdoor colonies and identify

01:38:27.460 | animals that might be good models for autism?

01:38:30.740 | And the answer is yes, we could do this all kinds of different ways.

01:38:33.860 | One is we could just take people and score monkey behaviors outside their cages while

01:38:39.860 | they're interacting with their peers.

01:38:41.980 | We can use rating scales, and again, the rating scale we use, it's called the social responsiveness

01:38:47.120 | scale.

01:38:48.120 | So this is called the macaque social responsiveness scale, revised, it's a mouthful.

01:38:52.260 | But what it allows us to do is measure autistic-like traits in monkeys.

01:38:56.220 | And we can also bring monkeys in for experimental tests to see where their eyes look or how

01:39:01.900 | do they perform, how do they respond to videos of other monkeys, you know, if they're making

01:39:07.340 | affiliative overtures, do they do like, you know, macaques global, which is a positive

01:39:13.220 | response.

01:39:14.220 | Well, they do that, right?

01:39:16.820 | I'm going to apologize for interrupting again, but I just had to tell people this because

01:39:20.460 | I spent time up at the UC Davis primate center as a graduate student.

01:39:24.020 | And by the way, what we're referring to here are non-invasive observational studies, at

01:39:27.540 | least thus far.

01:39:28.540 | So these are monkeys living in large exclosures, not enclosures, large exclosures forming colonies

01:39:35.900 | and social relationships.

01:39:37.240 | And you know, I think anyone that sees monkeys at the zoo, and we all learned that monkeys

01:39:41.140 | go ee, ee, ee, and they don't ee, ee, ee.

01:39:44.140 | If you want a monkey to like you, you learn this working with macaques.

01:39:51.260 | First of all, they don't ee, ee, ee, the affiliative call is a hoo, hoo, they do this really nice.

01:39:57.040 | And the little ones, I spent a lot of time with these monkeys and the little ones, they

01:40:01.660 | do this thing where they go, I used to nurse the little ones every once in a while, they

01:40:04.960 | hoo, hoo, and they're just, you know, it just like makes your heart melt.

01:40:08.280 | I think there must have been an oxytocin dump at that moment that's probably happening right

01:40:11.380 | now.

01:40:12.380 | But if you want the monkeys to like you, you have to give an affiliative facial gesture,

01:40:16.220 | which is not a smile.

01:40:17.380 | That's actually an aggressive gesture.

01:40:19.140 | So as Karen, Dr. Parker just showed you, it's lip smacking, which is, yep.

01:40:24.240 | So if you see a monkey at the zoo and you want it to pay attention to you, you're going

01:40:27.720 | to have to lip smack.

01:40:28.780 | And if it doesn't, either you're not doing it right or it just doesn't like you.

01:40:32.580 | Exactly.

01:40:33.580 | Right.

01:40:34.580 | Great.

01:40:35.580 | All right.

01:40:36.580 | Thanks.

01:40:37.580 | Now we'll go back to the study of, or the establishment of this really key experiment.

01:40:39.980 | Right.

01:40:40.980 | So then what we did is we identified these animals and we spent a lot of time.

01:40:44.960 | So one of the things that I do as one of my areas of expertise is validating animal models.

01:40:51.240 | So a lot of, like I mentioned, like a lot of reason why experiments fail is people will

01:40:56.920 | take an animal off the shelf and say, "Oh, I'm going to do this."

01:41:00.340 | Right.

01:41:01.340 | But if you're, you know, if you're studying a disorder that's characterized by visual

01:41:05.280 | issues, is it the best thing to do in a nocturnal species that has olfaction as its primary

01:41:11.700 | sensory modality?

01:41:12.700 | Or is it-

01:41:13.700 | You're referring to mice.

01:41:14.700 | Right.

01:41:15.700 | Or is it better, you know, and again, I will say all models have value.

01:41:17.780 | There's all, you know, there's reasons you just have to, you know, you basically have

01:41:21.500 | to stand by what you're modeling.

01:41:23.420 | And so I think one of my, the biggest issues I have with this sort of mouse phenotyping

01:41:28.340 | mafia is that, you know, there's this group of tests that they use and they use it in

01:41:32.260 | every single disorder.

01:41:33.260 | Right.

01:41:34.260 | And then if there was a positive hit, it's like, "Oh, this is like, you know, this test

01:41:36.700 | is really for Parkinson's today, but it's for depression tomorrow."

01:41:39.940 | Right.

01:41:40.940 | And so, so my goal was to, to devise very specific tests that would allow us to evaluate,

01:41:46.860 | you know, core features of autism in this model.

01:41:49.100 | And the answer is we found it, right?

01:41:50.660 | So if you look at monkeys that spend a lot of time alone, they have a much greater burden

01:41:54.980 | of autistic-like traits measuring on this rating scale.

01:41:58.460 | They have diminished social motivations.

01:42:00.760 | So other monkeys will come up and interact with them, but they don't engage in social

01:42:06.140 | overtures that much themselves.

01:42:08.460 | They do less grooming, less affiliative behaviors.

01:42:12.940 | They, in some of the work that we're doing, they don't lip smack back and we can talk

01:42:16.820 | a little bit about that.

01:42:17.820 | We did a pharmacological probe and we can talk a bit about what vasopressin does to

01:42:21.260 | that, which is kind of exciting.

01:42:23.260 | And so we spent a lot of time validating this behavioral phenotype, right?

01:42:27.460 | To say that we really feel like there are core aspects of it that are allowing us to

01:42:34.380 | model autism.

01:42:35.380 | Right.

01:42:36.380 | And I have a paper, which if you want to put it in, it's all about creating this monkey

01:42:39.580 | model and the power of doing it and where it took us clinically.

01:42:44.500 | We'll provide a link to that in the show note captions.

01:42:46.580 | I also just want to throw up my vote for the fact that you did this work, because again,

01:42:53.000 | I don't disparage mouse model work, but we've just seen over and over again that the incredibly

01:42:57.420 | small fraction of mouse models that lead to valid therapeutics in humans, and that there's

01:43:02.420 | just a lot of differences between primate brains and rodent brains, and we have a very

01:43:08.120 | elaborate frontal cortex, a bunch of other circuitry that mice, if they have that, they

01:43:13.120 | probably use it for other things.

01:43:15.740 | And it's just very hard to draw conclusions from those models.

01:43:19.720 | And they're great for probing functions that are, let's just call them more autonomic type

01:43:26.180 | functions and for doing some of the initial investigations.

01:43:30.140 | But I think while I don't want to see every research lab switch over to primates, I think

01:43:37.100 | one has to be really thoughtful about the kinds of experiments one does with primates

01:43:41.220 | at all, this sort of behavioral assessment and the identification of a primate model

01:43:49.020 | for autism seems like a very good use of human resources.

01:43:53.720 | Right.

01:43:54.720 | Well, and the other thing I will say is that there were medications that were only tested

01:43:58.380 | in rodents that when they were tested in people had really negative consequences.

01:44:04.580 | I can give you two examples.

01:44:05.580 | So one is thalidomide, which was a morning sickness medication that was given to women

01:44:11.400 | that were pregnant.

01:44:13.060 | And the safety testing and toxicity testing was done only in mice.

01:44:16.620 | I didn't know that.

01:44:17.620 | Yes.

01:44:18.620 | And that's why it went on the market.

01:44:19.620 | It went on the market in Europe.

01:44:21.140 | And there were all these children born with profound limb abnormalities.

01:44:25.600 | When they went back and tested the drug in marmosets, neither rhesus monkeys or cinnamologous

01:44:32.560 | monkeys, an old world monkey, they had the limb abnormalities.

01:44:36.420 | And so all they had to do, and again, I as an animal lover treat the life of a single

01:44:41.660 | monkey or a single mouse for that matter, an individual monkey, excuse me, or individual

01:44:46.740 | mouse for that matter as critical.

01:44:49.900 | I am a speciesist.

01:44:50.900 | I do think there's a difference between their life and our lives when it comes to what study

01:44:56.620 | one does, but just the idea that these severe developmental defects in humans could have

01:45:03.360 | been avoided by doing an experiment, perhaps even on one marmoset.

01:45:08.740 | And again, I feel for the life of discomfort of that marmoset, but the idea that that could

01:45:14.340 | have saved so many human lives is just striking.

01:45:17.660 | Well, and there was also that street drug MPTP that was a synthetic heroin that causes

01:45:23.640 | like overnight Parkinsonianism, when I think the dopamine cells were just ablated, right?

01:45:29.460 | But when you went and looked in mice, MPTP didn't have those effects.

01:45:33.220 | It was only in primates and other humans and other primates, right?

01:45:36.580 | So, and I agree with you, I am an animal lover.

01:45:39.300 | I think that we have to be very careful whenever we do any animal experiments, right?

01:45:44.380 | And so you really need to have a good justification, I think, for any science that's done.

01:45:48.540 | I will say that upfront.

01:45:51.380 | And we have this new generation of stem cell and organoid work, which I think is going

01:45:55.920 | to allow us to make all kinds of disease progress, right?

01:46:00.340 | Without having to study whole animal models.

01:46:02.760 | Or in complementary, right?

01:46:04.640 | But I mean, I think, again, I think we need to pick the model based on the question we're

01:46:09.960 | asking, right?

01:46:11.060 | And so if you want to have a medication that's safe and well tolerated in people or effective,

01:46:19.120 | and you want to move the needle on complex social cognition, you want to be testing it

01:46:23.120 | in a species that also has complex social cognition.

01:46:25.820 | Look, the Netflix show, Chimp Empire, if people haven't seen it, they should watch it.

01:46:30.280 | When you watch it, you realize they're very much like us, and dare I say, we're very much

01:46:35.420 | like them.

01:46:36.420 | Oh, yeah.

01:46:37.420 | It's far and away different than watching a bunch of mice.

01:46:39.820 | Yes.

01:46:40.820 | And I'm not being disparaging of mice.

01:46:41.820 | I'm assuming they have, that mice also have complex social cognition, voles also have

01:46:45.200 | complex social cognition, but it's of the mouse vole type.

01:46:49.100 | And we don't know really even what to look for, right?

01:46:52.520 | But with primates, there's, you know, affiliative gaze, there's, you know, affiliative grooming,

01:46:56.880 | there's ostracization of individuals in the troop.

01:47:00.760 | I mean, there's a, you know, banding, taking care of other babies.

01:47:04.200 | There's all sorts of interesting dynamics that map so clearly onto human behavior and

01:47:09.200 | vice versa.

01:47:10.200 | Yeah.

01:47:11.200 | Yeah.

01:47:12.200 | So you establish this colony up at Davis at the regional primate center that, where you

01:47:18.280 | identified some monkeys that we don't know if they have autism, but you could see that

01:47:23.580 | they were less socially affiliative.

01:47:25.120 | Right.

01:47:26.120 | And I would never say they have autism.

01:47:27.120 | Like I will say that upfront, you know, they have features that resemble human autism and

01:47:33.180 | that allow us to model this, right?

01:47:35.360 | So we started studying those animals and what we wanted to do was do some biomarker discovery.

01:47:41.420 | So what we wanted to ask was, are there any molecules that allow us to differentiate these,

01:47:46.640 | but we'll call them naturally low social or low social monkeys, from socially competent

01:47:51.300 | high social monkeys?

01:47:53.040 | And so we measured a bunch of different readouts of neurotransmitter systems that were either

01:47:58.760 | involved in mammalian social behavior, had been implicated in idiopathic, meaning autism

01:48:04.660 | that doesn't have a genetic cause or these neurogenetic syndromes that we've been talking

01:48:09.420 | about where there's pathways that are really associated with them.

01:48:13.120 | And so if we measured a bunch of these systems with 93% accuracy without even knowing what

01:48:18.820 | the monkey, who the monkey was, if they were low or high social, we could just put them

01:48:22.440 | in the low social or high social bucket.

01:48:24.480 | And was this by blood draw or cerebral spinal fluid?

01:48:26.560 | So this was, it was everything.

01:48:27.800 | We did blood, we did CSF, and we put all these measures into the hopper.

01:48:31.140 | We did a discriminant statistical analysis, which was like a machine learning algorithm

01:48:35.380 | where we just said, here's all this information.

01:48:38.160 | Help me classify if this individual is high or low social.

01:48:42.840 | Cerebral spinal fluid is collected by spinal tap, correct?

01:48:45.440 | And my understanding, I've never had one, but that spinal tap is of course more invasive

01:48:50.400 | than a blood draw, but it still is done as an outpatient thing in humans.

01:48:56.160 | Like you can go in and get a needle inserted into the lower spine by an expert.

01:49:01.240 | They're going to draw cerebral spinal fluid.

01:49:03.300 | I mean not that much more invasive and time consuming than getting a needle into your

01:49:09.840 | vein for a blood draw, right?

01:49:12.080 | I mean it's, we think of it as, it's technically a little bit more challenging, but there's

01:49:19.680 | CSF draws in humans all the time.

01:49:22.080 | So in theory this could map to a human study.

01:49:24.700 | And it did, which we'll talk about.

01:49:26.760 | So we went out and we did this, I have a spectacular statistician who's, we spent a lot of time

01:49:32.000 | together.

01:49:33.000 | His name's Joe Garner and he is a statistical genius.

01:49:36.160 | And so he developed this and we do all of our work together, or I would say 95% of it.

01:49:41.400 | We just love working together.

01:49:43.200 | And he developed a statistical winnowing strategy to identify what were the key drivers.

01:49:48.640 | And what was fascinating is in this first monkey cohort, it was the cerebral spinal

01:49:53.060 | fluid levels of vasopressin that were really what was driving this classification, right?

01:49:58.400 | So if we just knew your levels of your, of vasopressin in spinal fluid, but not in blood

01:50:03.160 | interestingly, we could pretty closely perfect to perfect classify you as high or low social.

01:50:10.080 | And so then we replicated that again in another monkey cohort, because obviously as a scientist

01:50:14.340 | you always want to replicate your work.

01:50:16.560 | And then if it was really a biomarker, meaning it's a molecule in the body that gives us

01:50:21.640 | an indication of something, and in this case it's an indication of your social functioning,

01:50:26.520 | we were able to look at monkeys and we saw that the vasopressin was consistent across

01:50:31.720 | measurement time.

01:50:32.820 | So there was a wide variety of vasopressin levels, but within an individual monkey it

01:50:38.200 | was pretty much the same, right?

01:50:39.540 | So that's what you want to see with the biomarker.

01:50:41.740 | And then we showed that the vasopressin levels were closely linked to time spent in grooming.

01:50:49.920 | And as we mentioned, I think we mentioned earlier, grooming is in many monkey species,

01:50:54.600 | a critical behavior that solidifies social bonds and maintains them.

01:50:59.020 | And so the individuals with the lowest CSF vasopressin levels had spent the least amount

01:51:05.000 | of time in grooming.

01:51:07.000 | Grooming other monkeys.

01:51:08.000 | Other monkeys, yes.

01:51:09.000 | And that's another-

01:51:10.000 | Allopathic grooming is a very interesting behavior from watching Chimp Empire, I can

01:51:13.620 | tell you that.

01:51:15.280 | New relationships are established in many ways by monkeys, these chimps, chimpanzees,

01:51:21.540 | sort of offering their back for grooming.

01:51:23.420 | And if another chimp elects to, yes, groom that chimp, then it establishes some form

01:51:29.880 | of trust.

01:51:31.240 | And it all seems to have to do with proximity, like how close are you going to let me get

01:51:34.680 | to you, vice versa.

01:51:35.680 | In humans, we talk about personal space and there's a whole set of things related to consent

01:51:40.360 | in this whole allopathic grooming thing.

01:51:42.140 | And then if a chimp misbehaves on an outing, then they aren't groomed by others and they

01:51:49.780 | can actually get parasitic infections and it can be very costly.

01:51:54.120 | It's very interesting to just think of allopathic grooming as not a kind of a primitive of language,

01:52:02.680 | but a whole language into itself.

01:52:04.440 | Absolutely.

01:52:05.440 | Yeah.

01:52:06.440 | And also just critical for the species.

01:52:07.440 | So that was really interesting to me that we were seeing these hints that vasopressin

01:52:12.440 | could be really important.

01:52:14.640 | But of course, somebody will say, and I will say upfront, monkeys don't have autism, right?

01:52:19.280 | So then the question becomes, does this have what's called translational value?

01:52:23.380 | So can I see this observation in animal model and will it provide fundamental insights into

01:52:30.520 | humans, right?

01:52:31.520 | So I wanted to get cerebral spinal fluid from people to test this hypothesis because we

01:52:37.480 | had in parallel done a study looking at blood vasopressin levels in people without autism.

01:52:43.740 | And we didn't see a group difference there, unlike this really profound difference that

01:52:47.880 | we saw when we looked at spinal fluid in the monkeys.

01:52:50.000 | And again, I think I mentioned the blood vasopressin levels were indistinguishable if you were

01:52:54.280 | high or low social monkeys.

01:52:55.800 | So there was something about looking more proximate to the brain that was giving us

01:52:59.680 | more information than say the blood alone.

01:53:02.800 | And so I said I wanted to get spinal fluid.

01:53:05.160 | And like you said, people do this all the time.

01:53:07.020 | How would we, but we're, you know, it's not going to be a first pass, especially when

01:53:11.640 | we don't really have any evidence in people to go in for what we would call a research

01:53:16.300 | lumbar puncture, right?

01:53:17.760 | And so I had to get really creative about how do I get spinal fluid from children?

01:53:23.880 | And what we did was we piggybacked onto a clinical indication for spinal fluid draws.

01:53:32.120 | And we did this.

01:53:33.120 | So I tried to get funding for this.

01:53:34.120 | This is like, you know, again, I mean, I think this is important for people to know how science

01:53:37.760 | is done, right?

01:53:38.760 | And so I wrote all these grant applications, nobody would fund it.

01:53:41.480 | They said that this is really interesting, it's too high risk, you won't be able to pull

01:53:45.760 | it off.

01:53:46.760 | And, you know, I don't usually back down from a challenge.

01:53:49.440 | Like if I think something's a good idea and I want to do it, I'm going to find a way to

01:53:52.440 | do it.

01:53:53.440 | And if it's possible, that's one thing.

01:53:54.660 | But if it's hard to do, it doesn't mean you shouldn't do it.

01:53:57.160 | You just have to figure out how to do it.

01:53:59.080 | And so I always try to see bridges where other people see barriers, right?

01:54:03.720 | And so it's like, well, how can I access spinal fluid?

01:54:05.800 | And so I went around talking to all my friends who were on, and Stanford's really wonderful

01:54:10.400 | because it's such a small school, right?

01:54:12.600 | And so you're on all these different committees with all these different people.

01:54:15.880 | And so...

01:54:16.880 | A lot of committees.

01:54:17.880 | Lots of committees.

01:54:18.880 | I can attest.

01:54:19.880 | A lot of committees.

01:54:20.880 | Exactly.

01:54:21.880 | But it's really cool because you're on them with people from all different departments.

01:54:22.880 | Yeah.

01:54:23.880 | You're on departments that I wouldn't otherwise know.

01:54:24.880 | Yeah.

01:54:25.880 | And you get to know these people well in these many committees.

01:54:30.400 | And where we live, it's a small community, right?

01:54:32.400 | So like...

01:54:33.400 | Maybe we're the experiment, Karen.

01:54:34.480 | Maybe there's a...

01:54:35.480 | I always wonder whether or not there's a larger experiment, right?

01:54:37.520 | Not on monkeys, not on the patients or the clinical, but like maybe we're the experiment,

01:54:41.840 | right?

01:54:42.840 | Yeah.

01:54:43.840 | I mean, yeah.

01:54:44.840 | And they're looking at how we interact on committees.

01:54:45.840 | Anyway, please continue.

01:54:46.840 | So I started going up to people that I knew and said, "Hey, if you're taking spinal fluid,

01:54:51.120 | can I get a little bit of extra?"

01:54:52.240 | And of course, we got IRB approval, meaning we had ethics approval and all this.

01:54:57.880 | Or you could get the remnant sample and obviously, again, get consent from the families.

01:55:02.680 | So we could either get a little bit extra when it was being drawn for a research indication.

01:55:07.420 | So they were getting a spinal tap no matter what.

01:55:09.720 | And then we were just either...

01:55:10.720 | We're getting a little bit extra or we were going to getting the remnant that they were

01:55:14.400 | going to throw out, right?

01:55:15.400 | So you usually take more than you need because you don't want to have to do another spinal

01:55:19.340 | tap, right?

01:55:20.400 | And so we were able to go around and I hustled around and got all these people involved to

01:55:25.240 | help me.

01:55:26.240 | We put hot pink stickers on the lumbar puncture trays so that in the emergency room, so if

01:55:31.880 | somebody was doing a spinal tap, they would call us so we knew about it and we could get

01:55:36.240 | samples, again, under people's consent.

01:55:40.560 | So we got all these people involved and we finally got samples from children with autism

01:55:45.740 | and children without autism.

01:55:48.380 | And then we also made sure that whatever they were being worked up for was negative, right?

01:55:52.740 | So we got the sort of healthiest people we could, given that everybody was coming in

01:55:57.040 | for a medical reason to have a lumbar puncture.

01:55:59.560 | And in this first study, we had seven children with autism, seven children without autism,

01:56:06.180 | and we could nearly perfectly classify 13 out of 14 individuals by just knowing their

01:56:11.560 | CSF vasopressin level alone, which is pretty remarkable given that there isn't a biological

01:56:17.380 | indicator that we, a robust biological indicator that we know.

01:56:20.780 | So basically in this relatively small cohort, having low vasopressin is a biomarker of autism.

01:56:27.960 | Correct.

01:56:28.960 | And again, and what I will say is in our monkey studies and in our human studies, CSF oxytocin

01:56:34.240 | level became our control, right?

01:56:36.580 | So in our monkeys, there were no difference in CSF oxytocin by group.

01:56:41.400 | And then in this first study, there were no differences in CSF oxytocin levels.

01:56:47.600 | A sample size of 14 is intriguing, but given autism so clinically heterogeneous, we want

01:56:54.200 | to replicate it.

01:56:55.200 | And so I knew that there was a professor at the NIH named Sue Sweeto who was collecting

01:57:02.520 | cerebral spinal fluid as part of a research study because she was interested in immune

01:57:07.640 | parameters and folate deficiency.

01:57:09.920 | So she had children that were medically healthy and they were getting, just like at NIH, get

01:57:15.120 | these huge workups, right?

01:57:16.280 | So they were very well characterized participants.

01:57:19.000 | So we were able to look at, and again, we also, this is the first time we were able

01:57:22.600 | to look at girls.

01:57:23.600 | So we had a small sample of girls and we had boys and we basically just asked the question,

01:57:28.440 | can we replicate this?

01:57:30.080 | And I was very interested in will oxytocin be what's different in the girls, right?

01:57:35.420 | So maybe there will be some sex specificity here and it will see low CSF vasopressin in

01:57:40.580 | the males and low CSF oxytocin in girls.

01:57:43.880 | That was not the case.

01:57:44.880 | What we found was that if in the individuals with autism, regardless of their biological

01:57:50.460 | sex, that they all had lower CSF vasopressin levels than the individuals without autism.

01:57:56.880 | And because they were so well characterized, we were also able to show on a gold standard

01:58:02.140 | research diagnostic assessment of autism.

01:58:04.700 | So it's an assessment that's used in a research situation to validate an autism diagnosis

01:58:12.480 | by an expert clinical opinion that the lower your vasopressin levels in spinal fluid, the

01:58:17.880 | greater your social symptom severity, your clinical symptom severity.

01:58:23.500 | And then we asked, it's like, well, vasopressin's involved in social behavior, but it's not

01:58:28.040 | really that involved in restricted repetitive behaviors.

01:58:30.720 | And that was actually the case.

01:58:31.760 | So it was the CSF vasopressin track the social symptom severity, not the repetitive symptom

01:58:37.160 | severity, suggesting that there might be other biological measures that could be included

01:58:43.060 | as a way to have a more powerful way to differentiate people with and without autism.

01:58:49.240 | And so then I was really, so that was really exciting to replicate that.

01:58:54.180 | And then I had a colleague named John Constantino, who is now at Emory, but he used to be at

01:58:58.860 | Wash U.

01:58:59.860 | And I knew that, John, I had been at a meeting in, I think it was 2010, and I found out that

01:59:04.040 | he had what I will call liquid gold.

01:59:06.840 | So he had this minus 80 C freezer that was, had a bunch of neonatal infant CSF samples

01:59:15.720 | that he had from human infants.

01:59:18.680 | And he had collected them, and again, this was under ethical approvals, and it was basically

01:59:24.640 | these infants came in for something that needed to be worked up that was very rare.

01:59:29.480 | But if they had it, they would, they could die, so they needed to get a medical treatment

01:59:33.280 | for it.

01:59:34.280 | But the vast majority of these children ended up being healthy.

01:59:37.800 | So it was a pretty healthy sample, if you will, right?

01:59:41.300 | And so I knew he had all these samples, and I said to him, wouldn't it be really interesting

01:59:45.280 | if we teamed up and we look at this CSF vasopressin finding in children before the period when

01:59:53.580 | behavioral symptoms first manifest, right?

01:59:56.040 | And so-

01:59:57.040 | Yeah, so, sorry again to-

01:59:58.040 | Sorry, am I getting too jargony?

01:59:59.040 | No, no, I just, but I think it's important because this was a question that I was thinking

02:00:03.520 | about earlier, and I imagine many other people were too.

02:00:06.120 | You find these monkeys that have social interaction deficits.

02:00:10.120 | You find kids that have social interaction deficits, and you see that there's low vasopressin

02:00:15.620 | in both groups.

02:00:16.780 | This extends to male and female children.

02:00:19.360 | But then of course, the question becomes, well, maybe they have low vasopressin because

02:00:22.920 | of so many years or even months of social interaction deficits, right?

02:00:27.280 | The direction of causality isn't clear.

02:00:29.360 | And so when you said liquid gold, referring to the CSF from these infants taken prior

02:00:37.160 | to any opportunity for social interaction beyond just whatever interaction they had

02:00:41.980 | with their mother up until the point the CSF draw was taken, this really gets at the issue

02:00:47.000 | of causality.

02:00:48.000 | Right.

02:00:49.000 | So it's a quasi perspective because it was banked and then a lot of time went by, right?

02:00:53.380 | And so what we realized we could do was, and this was a heroic undertaking on John's part.

02:00:58.460 | So these samples were collected back on paper medical records.

02:01:03.120 | So he had to trace 2,000 paper-- Paper?

02:01:05.900 | What's that?

02:01:06.900 | Yeah, exactly.

02:01:07.900 | So he had to trace 2,000, I think, paper medical records to an electronic medical record.

02:01:13.000 | And then what we did is he looked to see who went on to develop autism and who didn't,

02:01:18.620 | right?

02:01:19.620 | And he had with spinal fluid samples that have sort of been waiting in the freezer,

02:01:23.680 | if you will.

02:01:24.680 | And then we could ask, do individuals who later receive an autism diagnosis many months

02:01:30.480 | or even years later already have low vasopressin levels as infants?

02:01:35.200 | And the reason why this was a compelling question to ask is there's evidence to suggest that

02:01:39.900 | behavioral therapies are more effective the younger the child is, right?

02:01:44.460 | And if you think about it, if behavioral characteristics of autism emerge across development, what

02:01:51.480 | if-- and this is sort of my-- we haven't substantiated this yet, but this is sort of my big question.

02:01:58.400 | What if all these autism susceptibility genes summon, interact, and converge upon a few

02:02:03.600 | common pathways in the brain, right?

02:02:05.440 | And so for years, people have talked about this excitatory inhibitory balance theory

02:02:09.700 | of autism.

02:02:10.960 | But what if vasopressin is one of those pathways because it's so critically involved in social

02:02:15.760 | functioning?

02:02:16.860 | And so what I was interested in-- and so let's just say for a moment, your genes are set

02:02:21.380 | at birth.

02:02:22.380 | What if the vasopressin is already low in the brains of these infants?

02:02:26.140 | And so it puts them on this very different trajectory where you have this cumulative

02:02:31.300 | effect of there may be a little bit less socially interested, and maybe they're not making the

02:02:35.980 | eye contact.

02:02:36.980 | And if there was a way to intervene really early, even potentially with a vasopressin

02:02:41.240 | replacement therapy, that you might be able to put them on a different developmental trajectory.

02:02:46.760 | So that was my big what if question.

02:02:49.720 | And what was really remarkable was-- so I had been asking John, hey, can I have your

02:02:54.240 | spinal fluid samples?

02:02:55.680 | And he finally agreed after he saw a couple of those papers, understandably he wanted

02:02:59.120 | to make sure that we already had shown something in people and animals that were sort of, if

02:03:03.460 | you will, symptomatic with social impairment.

02:03:05.960 | And what we found was, yes, this was the case.

02:03:07.880 | So it was a small sample.

02:03:09.140 | It needs to be replicated.

02:03:10.740 | But individual-- so infants that went on to have an autism diagnosis later in life already

02:03:16.800 | had low CSF vasopressin levels.

02:03:19.980 | Oxytocin levels did not differ between infants that received a subsequent autism diagnosis

02:03:25.280 | and those that didn't.

02:03:26.640 | So suggesting that we have a biomarker that might really be a good readout for clinical

02:03:34.140 | referral or risk management monitoring.

02:03:36.320 | Incredible.

02:03:37.320 | So you're telling us that levels of vasopressin correlate with social cognition deficits.

02:03:45.600 | Is that right?

02:03:47.640 | I think that warrants a brief discussion about cerebral spinal fluid.

02:03:51.960 | I teach neuroanatomy to medical students, so forgive me for having to ask this.

02:03:57.080 | But I think of cerebral spinal fluid as the stuff that exists in the ventricles and down

02:04:01.460 | the central canal of the spinal cord and provides essential nutrients for neurons and other

02:04:07.420 | cell types in the brain.

02:04:09.800 | But it's also a reservoir for chemicals coming from the brain, which is why the spinal tap

02:04:16.120 | is useful.

02:04:18.620 | But in the context of a cerebral spinal tap and you're measuring CSF and you're seeing,

02:04:26.040 | you know, lower levels of vasopressin in these individuals with these challenges with social

02:04:31.940 | deficits, does that mean that they're making less vasopressin?

02:04:36.440 | Does it mean, I mean, it could have gone the other way too.

02:04:38.540 | Like they're dumping too much vasopressin into the CSF and it's not able to function

02:04:42.100 | in the brain.

02:04:45.100 | What do we know about CSF and what does it mean?

02:04:47.240 | Right.

02:04:48.240 | Well, I mean, it's a great question.

02:04:49.240 | So I think this is just the tip of the iceberg, right?

02:04:52.780 | So I think of the CSF is as sort of like the kitchen sink of the brain, right?

02:04:57.880 | And what we need is real specificity.

02:05:00.200 | And so, I mean, my working hypothesis, and we'll talk a little bit about pharmacology,

02:05:05.700 | is that there's a deficiency in vasopressin production in individuals with autism, but

02:05:12.640 | there's a lot of elegant experiments that need to be done to be able to answer this

02:05:17.320 | question.

02:05:18.320 | So I'm standing currently to look in post-mortem human brain tissue, to look at in both blood

02:05:26.720 | CSF and hypothalamic tissue where vasopressin is made, to look at interrelationships, right,

02:05:33.680 | which is very difficult to do, but also to see if there's a fewer number of vasopressin-producing

02:05:39.600 | cells and if vasopressin gene expression is diminished, right?

02:05:42.800 | Because that would help us begin to answer, is this a production issue, right?

02:05:46.920 | So if you think back to the prairie voles, they're sort of primed to be parental, right?

02:05:52.480 | Or in my case, the meadow voles, right?

02:05:54.940 | But you can do this in any vole species, or at least the two that I'm thinking of.

02:05:59.040 | And you put vasopressin into the brain, and then all of a sudden it unlocks this behavior,

02:06:03.640 | right?

02:06:04.640 | So is it possible that children with autism, or at least a subset of them, all you have

02:06:09.680 | to do is replace vasopressin and that there might be a subset of these kids minimally

02:06:15.360 | that could benefit from vasopressin replacement, if you will.

02:06:20.380 | - Is there any evidence for excessive urination in kids with autism?

02:06:24.460 | Which if anyone's going, what, why is he asking that?

02:06:27.980 | If you recall, vasopressin is also anti-diuretic hormone.

02:06:31.840 | I suppose the other question is, could you, has anyone looked at levels of vasopressin

02:06:37.440 | in the urine of autistic kids versus non-autistic kids?

02:06:41.200 | Because it's acting peripherally, and you said blood draws don't reveal any differences

02:06:46.360 | in circulating blood.

02:06:48.040 | We know that urine is filtered blood, fair enough, but seems at least worth the look-see.

02:06:55.240 | - So I had this awesome medical student in my lab named Lauren Clark, and we, with three

02:07:00.120 | different physicians from different backgrounds, so wrote a perspective piece that's currently

02:07:05.140 | under review, and it actually asked this question.

02:07:07.820 | So given all these weird medical naming conventions, it's possible that this information is existing

02:07:15.380 | in information silos in different disciplines, right?

02:07:18.740 | So it raises this idea of if you have low vasopressin, so if you really don't have,

02:07:26.500 | you're not making vasopressin, you have a disorder called central diabetes insipidus,

02:07:30.740 | right, which is characterized by excessive thirst, lots of urination, and bedwetting

02:07:39.960 | potentially.

02:07:41.720 | And so what we wanted to do was ask, has this been missed, right?

02:07:45.380 | So shouldn't there be a subset of kids with autism where we might be able to look at these

02:07:49.440 | other physiological features and say, yeah, this is the subset we want to be giving vasopressin

02:07:55.080 | to?

02:07:56.080 | And so she wrote this perspective where we did a little bit of a review, and the answer

02:07:59.400 | is there's some intriguing studies that we reviewed in this paper where it looks like,

02:08:05.660 | and what's funny is when you read the discussion section, it'll be like, wow, there's all these

02:08:09.300 | kids with autism that are drinking lots of water, and we don't know why, or wow, there's

02:08:15.040 | a lot of bedwetting, but it's not tied to intellectual disability where you might see

02:08:19.200 | a lot of bedwetting or something.

02:08:20.860 | So all of these studies kind of raise this point of like, wow, this is really interesting,

02:08:25.780 | and there's been no big epidemiological study done on this, and certainly not any study

02:08:30.020 | where people who come at it from brain science and then the practitioners who are like an

02:08:35.880 | endocrinologist for instance, which is where some of these people could show up, are really

02:08:41.900 | connecting the dots.

02:08:43.180 | So I think that remains to be determined, but we are actually about to launch a study

02:08:48.280 | to investigate this, right?

02:08:49.780 | I was meeting with Lauren yesterday about it, so it's a really good question, and I

02:08:53.860 | hope to have information on it in the not too distant future.

02:08:57.420 | As I recall, alcohol is an antagonist of vasopressin.

02:09:01.880 | So there's a lot of different drugs that could interact with vasopressin, and so one thing

02:09:06.300 | I'm interested in is, are there any drugs that release vasopressin as a side effect,

02:09:11.740 | and could some of them be mobilized to treat autism?

02:09:14.460 | We also know that acupuncture can release vasopressin.

02:09:18.780 | There's been some studies done in rats on that.

02:09:21.860 | And so one question would just be, are there any alternative therapies where we can be

02:09:27.220 | releasing vasopressin naturally, or do we need to do a replacement study where we give

02:09:33.140 | intranasal vasopressin to children with autism, right?

02:09:36.180 | And of course, I want to say I'm not advocating that people go out and do this on their own,

02:09:40.260 | right?

02:09:41.260 | Like I'm a big proponent of randomized clinical trials where you assess safety and advocacy.

02:09:46.700 | Science.

02:09:47.700 | Yes, science.

02:09:48.700 | Science and medicine, right.

02:09:49.700 | But I appreciate you saying that.

02:09:50.700 | So some years ago, so this would be mid-90s, there was a small but very active subculture

02:09:59.860 | that I was not a part of, I swear, that were combining GHB, gamma-hydroxybutyrate, and

02:10:10.060 | vasopressin as combination, quote unquote, sex drugs.

02:10:15.020 | Really?

02:10:16.020 | Yes.

02:10:17.020 | And I don't know what the rationale for including vasopressin was.

02:10:21.820 | In any case, whether or not that's by way of enhancing social bonding or a direct effect

02:10:26.700 | on sexual arousal itself is still unclear.

02:10:29.500 | But in any event, since we're talking about vasopressin, maybe you should tell us about

02:10:32.980 | the actual science of vasopressin.

02:10:35.180 | Sorry.

02:10:36.180 | Maybe I should allow you to tell us about the actual scientific study of vasopressin.

02:10:41.140 | In other words, what happens if you give people vasopressin in a controlled environment?

02:10:46.260 | That's the sort of environment I'm talking about, but a controlled environment.

02:10:48.300 | And the one thing I will say, because I have people contact us all the time saying, where

02:10:51.580 | can I get vasopressin?

02:10:52.580 | And what I would say is, vasopressin means you're having effects on blood pressure, you're

02:10:58.640 | having effects on really important-- Right, vasode, vasculature.

02:11:03.060 | Right.

02:11:04.060 | And the dosing has to be appropriate.

02:11:06.820 | You don't want people just going and trying this, because there could be really severe

02:11:10.140 | adverse effects, right?

02:11:11.420 | So that's why we've been studying this in a controlled clinical trial, right?

02:11:16.220 | So I teamed up with Antonio Harden, who's the child psychiatrist that I've been working

02:11:20.920 | with for years.

02:11:22.160 | And we did the first, sort of first in class, vasopressin treatment trial in children with

02:11:27.160 | autism.

02:11:28.160 | So again, this was-- everyone was unaware of who was on vasopressin, whether it was

02:11:32.980 | the family or the clinician who was doing the evaluation.

02:11:36.820 | And then it was randomized, placebo controlled.

02:11:40.140 | And then we basically gave vasopressin, again, twice a day for four weeks to children.

02:11:45.620 | They were about six to 12 years of age.

02:11:48.140 | And then we had a primary outcome measure, which was the social responsiveness scale.

02:11:52.620 | We could get into discussions about what a primary outcome measure should be, wouldn't

02:11:57.260 | it be great if there was a biological measure?

02:12:00.220 | But this is sort of what had been used in the past and something that the FDA approved

02:12:04.460 | us using.

02:12:05.780 | I was partly interested in using the SRS because we had used it in monkeys, right?

02:12:10.680 | And we had shown, at least in monkeys, we've never looked at this in people because of

02:12:15.580 | the lack of available samples.

02:12:17.820 | But in monkeys, in this general population that we've looked at, there is a continuous

02:12:22.940 | distribution of these SRS scores that relate to the CSF vasopressin levels.

02:12:29.160 | And so what was-- I wanted to know if we use the SRS as an outcome measure and we're administering

02:12:35.240 | vasopressin, can we change the scoring on this instrument based on our animal data?

02:12:40.660 | So SRS is social responsiveness scale without going into a lot of detail because we can

02:12:46.700 | always refer people to the paper.

02:12:48.420 | And I think most people just want to understand the top contour.

02:12:51.340 | The SRS presumably has to do with how often the kid interacts with another kid, how often

02:12:58.620 | they initiate that interaction versus on the receiving end, things like affiliative play,

02:13:04.260 | how often they look at one another versus averting gaze, these kinds of things.

02:13:09.180 | And then there's also a little bit about restrictive repetitive behaviors.

02:13:13.140 | So even though it's called the social responsiveness scale, there is also an assessment of other

02:13:18.240 | features of autism in it.

02:13:19.820 | But you can sort of think about it as a quantitative way to assess features of interest in autism.

02:13:26.280 | And this was related to our biology in the monkeys.

02:13:29.840 | And so then we use this as this outcome measure in our trial.

02:13:34.020 | And as an experimentalist, I have this sort of trust but verify, right?

02:13:39.500 | So you want to see the same thing over and over and over again, right, like scientists

02:13:43.380 | like repetition.

02:13:44.400 | And so we had parents fill out their impressions of what the child's behavior was before and

02:13:53.700 | after being on the medication.

02:13:55.700 | We also had a clinician make an evaluation, but we also had the kids perform laboratory

02:14:01.980 | based tests where they would see, like I mentioned, the reading the mind and the eyes test, or

02:14:07.860 | we would show them a picture of a face and say, "What emotion is this?"

02:14:11.900 | And so we were able to have what's called convergent validity, right?

02:14:16.020 | So it's a fancy scientific term to say, "Do all these measures that we think should

02:14:20.100 | be related, are they related and are we seeing the same thing?"

02:14:23.620 | And the answer was yes, so that when we gave children with autism vasopressin versus kids

02:14:30.300 | with autism of placebo, the kids who were treated with vasopressin showed increases

02:14:35.900 | in social abilities on parent report, clinician evaluation, and child performance on laboratory

02:14:41.660 | based tests.

02:14:44.820 | Was that immediate?

02:14:45.900 | Like they did the nasal spray and they immediately started receiving and initiating more social

02:14:52.340 | engagement or was this a buildup over time?

02:14:54.660 | And what I'm getting at here is whether or not this is the reflection of short or longer

02:14:59.860 | term neuroplasticity, like were there structural changes in the brain or is this something

02:15:04.560 | that was more acute?

02:15:06.200 | We don't know the answer to that.

02:15:07.540 | So we basically looked at dosing with the idea that we would, and again, I think we've

02:15:11.820 | mentioned this about limitations on, like there's so many things that a scientist would

02:15:17.000 | like to do, but you were always limited by a budget, right?

02:15:19.980 | And so when we started this work, again, it was like philanthropic shoestring budgets,

02:15:24.540 | right?

02:15:25.540 | And so you had to really be laser focused on what are the things that we can do on the

02:15:29.320 | budget at hand.

02:15:30.320 | So unfortunately we didn't do like EEG or brain imaging or other things that would be,

02:15:35.860 | I think, potentially very interesting to do because you might be able to see an early

02:15:39.940 | signature of response, right?

02:15:41.640 | So maybe after the first dose, let's say, wow, like there's some interesting changes

02:15:45.580 | that are predictive of somebody who would be a responder to the medication.

02:15:49.460 | And we don't know that yet, but we do know after this four week period that we saw these

02:15:56.340 | changes.

02:15:57.340 | In the last set of kids, we actually saw diminished anxiety and also diminished restricted repetitive

02:16:02.600 | behaviors.

02:16:03.600 | So suggesting that the vasopressin effect may not only be on social behavior.

02:16:10.180 | Have you ever just wanted to try or tried vasopressin?

02:16:15.280 | You know, I haven't, but I-

02:16:16.280 | You're in a psychiatry department after all, and I'm not suggesting that members of the

02:16:20.040 | psychiatry department are constantly testing the drugs that they use on their patients

02:16:23.180 | with themselves, but I've had several members of this department, of which I'm a courtesy

02:16:28.880 | member, member by courtesy, in any event, and we'll see if I still am after what I'm

02:16:33.140 | about to say, Dr. Carl Deisseroth, who's a clinician, our first guest on the Huberman

02:16:38.680 | Lab podcast, also a phenomenal neurobiology researcher, David Spiegel, Rob Malenka, and

02:16:48.640 | others that I've spoken to.

02:16:51.220 | You know, I think all of whom said, you know, that they felt as clinicians, Rob's not a

02:16:56.240 | clinician anymore, right?

02:16:57.760 | But as a clinician, that they felt almost a responsibility to understand the effects

02:17:02.280 | and side effect profiles of the drugs that they were giving their patients, which I saw

02:17:05.420 | not as renegade or experimental, but rather as very compassionate, like seeking empathy.

02:17:12.080 | So I'm curious, have you ever just snuck a little roll?

02:17:14.440 | No?

02:17:15.440 | No, I never have.

02:17:16.440 | There is a long history in medicine of people trying out, they believe so much in their

02:17:22.240 | solution that they go and vaccinate their family with the new vaccine that they've created

02:17:27.320 | or they try the medication themselves, right?

02:17:29.620 | So I don't-

02:17:30.620 | Well, MDMA was developed by Sasha Colgan in a laboratory in the East Bay, first by a pharmaceutical

02:17:35.160 | company in the early 1900s, but then kind of disappeared, it did disappear, and then

02:17:39.060 | it was resurrected independently in the, in the 19, I think '70s and '80s, and then now

02:17:43.880 | it's one of the sort of hot topic items for the treatment of PTSD.

02:17:49.640 | Still in late phase clinical trial, still illegal, but self-experimentation is one of

02:17:55.480 | the central themes of psychiatry, frankly.

02:17:57.480 | Right.

02:17:58.480 | Yeah.

02:17:59.480 | I mean, I guess I got in trouble in class for being too social, right?

02:18:04.360 | So I guess I've never-

02:18:05.360 | They might send you over the other side.

02:18:06.920 | Yeah, yeah, exactly.

02:18:07.920 | Who knows?

02:18:08.920 | But I never know, and the thing is, is that these oxytocin and vasopressin, and again,

02:18:14.400 | these are done, and this is something that I think we've hit on over and over again in

02:18:17.680 | the podcast, is you need to know who's you're studying, right?

02:18:21.360 | What's the species?

02:18:22.440 | Who's the individual?

02:18:23.840 | You know, most of these have been done in neuro, I mean, a lot of the oxytocin and a

02:18:29.180 | little bit of the vasopressin work, the single dose work, was mostly done in what we'll call

02:18:33.560 | neuro-typical people, right?

02:18:35.240 | Just asking, "Can we move around social behavior by just giving the single drug administration?"

02:18:41.360 | Most people that are neuro-typical didn't say that they could tell if they were on the

02:18:45.600 | drug or the placebo, right?

02:18:47.080 | Interesting.

02:18:48.080 | So I think the question really becomes, you know, drugs have different, you know, they

02:18:53.240 | work differently based on the individual who's taking them.

02:18:56.400 | So if you have a neuro-typical individual and you give them vasopressin, you know, maybe

02:19:00.920 | they'll self-report that they don't see a difference.

02:19:03.840 | But if you had somebody who isn't producing enough vasopressin, maybe, you know, they

02:19:09.040 | would self-report after a period of time or maybe even after the first dose, "Wow, I really

02:19:13.920 | see something different," right?

02:19:15.780 | Did any of the kids report how they felt?

02:19:18.280 | They just said like, "Wow, I like playing with other kids more."

02:19:22.800 | Were they self-aware in that way?

02:19:24.840 | And also feel free to mention, if it feels right to you, any, let's consider two outlier

02:19:31.360 | cases.

02:19:32.360 | One spectacular result of that, you know, a kid that went from very socially isolated

02:19:37.000 | to, you know, maybe very gregarious.

02:19:39.860 | But let's also balance that with another outlier, the kid with low vasopressin who took vasopressin

02:19:45.940 | for whom there was no significant shift.

02:19:47.520 | I'm presuming that within the data set, you probably observe something like each of those.

02:19:52.040 | Yeah.

02:19:53.040 | So, I mean, what I'll say is that, so yeah, I mean, there were definitely kids who didn't

02:19:57.640 | respond to the medication.

02:19:58.640 | I mean, one thing I think it's important to say, and again, this was a small pilot trial,

02:20:03.080 | right?

02:20:04.080 | We're in the process of replicating this in a much larger sample.

02:20:07.680 | So, you know, as a scientist, again, you want to say, "Okay, this is really intriguing and

02:20:11.160 | interesting and I've invested a lot in, you know, this monkey model and then doing all

02:20:15.680 | the CSF work in patients to suggest that there may be a there there here, but I want to see

02:20:20.680 | it replicate."

02:20:22.240 | We did have an article that Stanford Medicine, I can send you the link, they were able to,

02:20:29.760 | I think, interview a family that had been in the trial.

02:20:32.620 | And so obviously there's patient privacy and, you know, you have to, they have to say it's

02:20:37.320 | okay to talk about it, but this is a family that was contacted.

02:20:40.360 | I think they were anonymous, but this is in this report.

02:20:44.240 | And they basically said, the dad said that his son was walking around the, he was on

02:20:48.680 | vasopressin and his son was walking around a grocery store and he, like, was looking

02:20:53.640 | for him.

02:20:54.860 | And he turned around and he said he was gobsmacked because his child was, you know, just talking

02:20:59.480 | to making chitchat with somebody like in an aisle.

02:21:02.880 | And he said he had never seen that happen before.

02:21:05.840 | And so, you know, we do have anecdotal reports like that.

02:21:09.400 | And I think, you know, the tricky part is, are we, we didn't stratify anyone going into

02:21:14.960 | this trial, right?

02:21:16.120 | And so the concern always is, did we get really lucky in the first trial and we somehow got

02:21:21.280 | the, the quote unquote right people that entered the trial that were going to be the ones who

02:21:25.980 | would respond to the medication?

02:21:27.960 | Or is this a medication that has sort of broad use in this population and we, you know, the

02:21:34.200 | second trial will be positive?

02:21:37.900 | You used nasal spray to deliver the vasopressin and presumably that gets into the blood circulation

02:21:44.880 | of the brain and supplies neurons with vasopressin.

02:21:48.920 | But it's very nonspecific and I'm not criticizing it, but if you think about it, you're just

02:21:53.100 | putting a bunch of vasopressin into the brain.

02:21:54.920 | And if people wonder why this is that it's because basically you have neurons of your

02:21:59.200 | central nervous system are part of your olfactory system.

02:22:02.380 | And believe it or not, right behind your, where your nose meets your forehead, the brain

02:22:06.880 | is right there.

02:22:07.880 | There's a little bit of bone and then the brain is, is right there.

02:22:10.280 | So one of the reasons you can get in there and it's easier than an ocular injection or

02:22:15.860 | something that wouldn't be a good approach.

02:22:17.760 | And it's easier than peripheral injection into the vein.

02:22:22.160 | But at the same time, I have to presume that this, I'm imagining this vasopressin just

02:22:26.120 | kind of like permeating through the brain, binding to whatever receptors happen to be

02:22:29.760 | there.

02:22:30.760 | You said the receptors are everywhere.

02:22:32.440 | And then this significant improvement in social cognition.

02:22:36.680 | So that raises all sorts of interesting questions about like what are, what relevant circuits

02:22:42.300 | are impacted.

02:22:44.180 | Or is it some global, could it be some global increase in kind of awareness of surroundings?

02:22:51.000 | Although some autistic kids are overwhelmed by their awareness of surroundings.

02:22:54.200 | So yeah.

02:22:55.440 | What are some thoughts about how vasopressin might be working to exert this, this really

02:23:00.320 | impressive and frankly important effect?

02:23:02.280 | Right.

02:23:03.280 | So, I mean, could it increase social motivation?

02:23:04.860 | Is it, you know, like, so let's talk about like how sort of complexity of social sensory

02:23:09.960 | processing.

02:23:10.960 | Is it that we're directing attention to social cues where there wouldn't have necessarily

02:23:16.340 | been as much attentiveness, right?

02:23:18.960 | Are we increasing social motivation, which would suggest from some of the animal studies

02:23:23.420 | may actually be happening, right?

02:23:25.640 | We don't know.

02:23:26.640 | And I think that's partly when you have other models or if you're able, you know, to do

02:23:31.440 | imaging studies.

02:23:32.440 | I mean, one thing that's been a little bit of a holy grail in this field is that if we

02:23:37.240 | could get tracers that are basically like a, you know, a molecule that would allow us

02:23:44.120 | to inject it into somebody and then visualize the brain, like if I'm thinking about a pet

02:23:48.140 | trace or a radio ligand, where you could then ask questions about, you know, what's happening

02:23:53.740 | in the brain.

02:23:54.740 | Can we, can we give vasopressin in the context of a, you know, functional brain imaging scan

02:24:01.300 | and ask like, where is the vasopressin binding?

02:24:03.740 | What kind of circuits are involved?

02:24:05.340 | Like that needs to be the next step of the work to know like where, where our targets

02:24:10.560 | are.

02:24:11.560 | And you, you can do something like functional proteomics, right?

02:24:13.900 | Where if you know where vasopressin receptors are, you can overlay that with studies of

02:24:19.300 | functional brain imaging, right?

02:24:20.920 | And that would allow you to say these areas are dense in vasopressin receptors and do

02:24:26.080 | we see similar responses in what we call bold signal on a, on a brain scan?

02:24:32.040 | So let's, let's be more colloquial about this.

02:24:34.020 | Like do certain areas of the brain light up, if you will, where we know vasopressin receptors

02:24:39.240 | are, are densely distributed in ways that we know are tied to social motivation or social

02:24:47.500 | salience or other things that we think could be moving the needle here in the trial?

02:24:52.880 | How is this happening?

02:24:54.520 | And I think, you know, one thing, the reason why we did this work is, and I think it speaks

02:24:58.460 | to what you said earlier is there is an urgency on the part of parents to say, you know, my

02:25:05.080 | child's brain is developing, right?

02:25:07.840 | And there's a sense of that, you know, by the sort of Western model has failed a lot

02:25:12.760 | of people.

02:25:13.760 | You know, they look to doctors and say, what are, what are the solutions?

02:25:16.280 | And doctors will say, well, we have a limited number of tools in the toolkit here.

02:25:20.140 | We just don't know, right?

02:25:22.040 | And so, you know, one of the reasons why they did that big oxytocin study was that people

02:25:26.960 | were trying to get the oxytocin anyway.

02:25:29.200 | So it was like, let's just make sure that this is safe.

02:25:32.120 | Let's see if it's effective.

02:25:33.740 | And so some of our thinking was, you know, as soon as some of this work hits, you know,

02:25:39.920 | like it gets in, some of the work has been covered by the media.

02:25:42.960 | And so, you know, our feeling was we can give this intranasally and we can do it under safe

02:25:50.400 | monitoring ways.

02:25:52.880 | And so people are going to think about doing these things anyway.

02:25:55.280 | So let's just make sure that this is safe and let's test this in a rigorous way.

02:25:59.460 | So we don't know the mode of action, but then our feeling is, is that, you know, at least

02:26:04.180 | from the initial safety data, it looks pretty safe.

02:26:08.440 | And you know, and so the idea would be, and there's a long tradition in psychiatry of

02:26:12.440 | we don't know the mechanism of action, but if we have a medication that can be impactful

02:26:18.520 | and improve the lives of people with autism and we can diminish suffering and people can

02:26:23.840 | more readily reach their full potential, you know, to me, it actually seems unethical not

02:26:29.520 | to move forward in a way that's scientifically sound.

02:26:33.080 | Amen to that.

02:26:36.200 | This seems like a good time to raise the topic of the microbiome and not as an unrelated

02:26:43.560 | topic.

02:26:44.560 | But I've seen a fair number of studies in mouse models arguing that in a mouse model

02:26:51.080 | of autism, which now, frankly, I have to kind of wonder about the power of that model.

02:26:57.920 | But anyway, the models are out there in the field.

02:27:01.160 | all right.

02:27:17.640 | That fecal transplant into a host that does have social deficits and rescue some degree

02:27:24.340 | of social deficits.

02:27:25.820 | I don't know if this has actually been done in humans as well.

02:27:28.680 | For those of you that are cringing, yes, they do fecal transplants in humans for treatment

02:27:32.560 | of obesity and a bunch of other things.

02:27:35.800 | This isn't because scientists are obsessed with fecal matter.

02:27:38.680 | It's because fecal matter contains a lot of the microbiome elements.

02:27:44.520 | So the microbacteria of the gut.

02:27:49.520 | And the reason I'm raising this now is, you know, one possibility, and it's not mutually

02:27:54.200 | exclusive with a brain mechanism, is that the administration of vasopressin somehow

02:27:59.520 | rescued a vasopressin deficiency in the gut.

02:28:02.940 | So the questions are as follows.

02:28:04.820 | Is there any evidence that vasopressin is manufactured in or impacted by the gut microbiome

02:28:12.060 | of humans?

02:28:13.200 | We'll just start with humans, since I think most, and because that wouldn't be a smoking

02:28:17.920 | gun, but it'd be an interesting detective story.

02:28:20.520 | Well, okay, so the one piece of evidence that I will say that I find provocative and fascinating,

02:28:25.540 | and one thing I want to say is I think there's really great work done in mice.

02:28:30.240 | I don't want to be a mouse basher.

02:28:31.640 | So I want to just like sort of go on the record that I'm not bashing other models.

02:28:36.600 | If it's a conserved, so I think about everything from like an evolutionary perspective.

02:28:40.520 | If a mouse shares a brain structure with a human and it's highly conserved, you know,

02:28:46.140 | mouse work can be incredibly important and very impactful, right?

02:28:50.000 | Yeah.

02:28:51.000 | My lab did years of mouse work, some primate work where necessary.

02:28:54.620 | Now I only work on humans, but absolutely it has its uses, but clearly the primate model

02:29:02.880 | for social deficits as it relates to autism, you at least have me convinced that that one

02:29:09.000 | has a lot of power.

02:29:10.000 | Let's just say that.

02:29:11.000 | Exactly.

02:29:12.000 | Okay.

02:29:13.000 | But I'm going to now say there is a really cool mouse study that was done that I found,

02:29:16.620 | and there's been, you know, lots of different studies.

02:29:18.980 | So there has been mice, so there's these, like I said, these genetically modified mice

02:29:23.600 | that have genetic syndromes that are, you know, where the individuals have social impairments.

02:29:30.080 | And some of these individuals, and again, here's a problem with the field.

02:29:34.700 | Often they will measure oxytocin, but not vasopressin, right?

02:29:37.140 | So like they're not often both measured together, which I always do now.

02:29:41.560 | But there's been some really interesting evidence that in these mouse models that, and again,

02:29:48.920 | multiple studies, but like certainly low blood oxytocin levels in these mouse models, and

02:29:55.300 | with the sense that maybe they have some sort of abnormal gut microbiome.

02:30:01.400 | And then what they've done is they've given a probiotic to these mice, normalized their

02:30:06.620 | social functioning, and there's an increase in oxytocin, and in a recent study also vasopressin,

02:30:14.440 | at the level of the hypothalamus.

02:30:16.620 | So by giving a probiotic, you, I believe the oxytocin levels were increased in the blood.

02:30:23.320 | You saw more species typical social behavior, and this was all driven by this upregulation

02:30:30.200 | of oxytocin gene expression, and also vasopressin in this very recent study.

02:30:35.280 | And what's interesting is there's this nerve called the vagus nerve, which is, it's I think,

02:30:41.760 | it means the wandering nerve.

02:30:43.960 | It's for vagabond.

02:30:44.960 | - Yeah, exactly, right.

02:30:47.160 | And even it's in the gut, but it actually has a direct projection to the nuclei in the

02:30:52.740 | hypothalamus where oxytocin and vasopressin are made.

02:30:56.020 | - How interesting.

02:30:57.020 | - Yes.

02:30:58.020 | And so when you sever the vagus, you then in this one study, it's a neuron paper, I

02:31:03.480 | think it's like 2020, it's a super cool paper.

02:31:06.820 | And then what you do is you decrease the gene expression and you don't see the rescue of

02:31:12.240 | the oxytocin levels or the social behavior in this model.

02:31:16.080 | - So in other words, if I interpret this correctly, and I'll go look up the paper and provide

02:31:19.440 | a link to it, there, by increasing the diversity of gut microbiota, 'cause that's really what

02:31:28.680 | a probiotic does, sort of across the board increases the diversity of gut microbiota.

02:31:33.540 | No one specific illness, as I always say, 'cause they all seem to end in illness, multiple

02:31:37.920 | illnesses, illnesses, illnesses.

02:31:39.920 | - Here we go again, you upregulate gene expression and thereby action of oxytocin and vasopressin

02:31:48.520 | in the hypothalamus.

02:31:50.120 | But that's a neural mediated thing.

02:31:52.560 | It's not as if the microbiota travel to the brain.

02:31:55.240 | Something changes in the gut, which activates the vagal pathway from gut to the specific

02:32:00.000 | nucleus in the brain.

02:32:01.000 | And we know that the vagal pathway is involved because it seems at least partially necessary.

02:32:05.480 | If you sever that, you give a vagotomy, then this effect is blunted or eliminated.

02:32:12.120 | That's very interesting and ties the microbiome to oxytocin and vasopressin production in

02:32:18.680 | a neural and somewhat causal way and makes the data on fecal transplants make a lot of

02:32:27.680 | more sense.

02:32:28.680 | 'Cause I was wondering, okay, so you take the microbiota from one animal, put him into

02:32:32.600 | another animal, you're transferring the milieu of the gut.

02:32:38.520 | But it doesn't say anything about mechanism.

02:32:41.280 | So this is a really cool paper.

02:32:43.200 | - It's fascinating.

02:32:44.200 | And there's also a study I've always wanted to do, is you can get a vagal nerve stimulator.

02:32:48.600 | They used to do them as implants, but you can also get one that you sort of clip onto

02:32:52.820 | the ear.

02:32:54.120 | And I've always wanted to ask if we use this in autistic individuals, could we increase,

02:33:01.520 | like can we alter social behavior, right?

02:33:04.320 | And would that be something that we could actually measure in the blood, especially

02:33:07.120 | if we're seeing this change in these blood levels, right?

02:33:10.200 | - Are you doing that experiment?

02:33:11.480 | - No, but I've always said it would be so cool.

02:33:15.560 | - We have to get you the funding to do that experiment.

02:33:17.800 | And I know a few times you've raised the issue of funding.

02:33:20.000 | It's not something we spend a lot of time discussing on this podcast, but I think what

02:33:24.400 | should be abundantly clear to the listeners throughout the course of this episode is,

02:33:28.480 | as you mentioned earlier, you're very determined to get work done.

02:33:30.880 | You'll figure out a way.

02:33:32.480 | But the way I describe finances and research is that it's absolutely necessary, but it's

02:33:38.240 | not sufficient.

02:33:39.240 | You of course have to have the right people and the right lab head directing the work,

02:33:42.680 | but no money, no project.

02:33:44.880 | And it is disappointing to see that despite the federal budget for research being still

02:33:50.920 | reasonable, it's not what we would like it to be, it's still very hard for amazing world-class

02:34:00.120 | labs like yours to say, "Hey, you know, listen, there's this vagal thing and clearly there's

02:34:03.880 | a rationale.

02:34:04.880 | It's not like you're pulling this out of nowhere and you want to go to this study."

02:34:09.020 | But what we're really talking about is three to five years of grant writing before you

02:34:12.240 | could even initiate that study.

02:34:14.080 | Meanwhile, autistic kids are going from age two to five to six.

02:34:17.960 | These are critical windows.

02:34:19.080 | So if ever there was a rationale for moving a lot of funding to, I don't even call it

02:34:28.120 | high risk, but logically sound hypothesis testing for the treatment of autism, it's

02:34:33.520 | now.

02:34:34.520 | So I'm going to get active on this front.

02:34:36.440 | So I won't get into how, but when I get something in my neural circuits for talking, they tend

02:34:43.280 | to not shut down for a while.

02:34:44.600 | Well, there will be a community that is going to be immensely grateful.

02:34:47.740 | Well, it seems like the parents of these kids and the kids themselves could greatly benefit.

02:34:52.540 | So you mentioned that the first study on vasopressin administration that saw these improvements

02:34:57.860 | in social functioning, you said a small cohort, how many kids was it ultimately that you could

02:35:02.440 | use data from?

02:35:03.440 | Okay.

02:35:04.440 | So we had, I mean, you screen a lot.

02:35:06.060 | So I think our, you know, cause we had very rigid criteria.

02:35:08.980 | So we ended up with 17 kids that were on active drug and 13 that were on placebo.

02:35:15.440 | And then-

02:35:16.440 | So not a tiny study.

02:35:17.440 | No, and the placebo, we always have like a humanitarian open label extension arm, which

02:35:23.300 | allows for anybody who is in placebo can get access to the drug.

02:35:27.920 | So both Antonio and I feel very strongly about making sure that if we're doing a medication

02:35:32.320 | trial, everybody can benefit from it.

02:35:34.200 | Right.

02:35:35.200 | So-

02:35:36.200 | Afterwards, if they say, okay, I was in the placebo group, but I really want the chance

02:35:38.260 | to try this thing.

02:35:39.260 | Yes.

02:35:40.260 | We can, but then you also get more data.

02:35:41.260 | We get, right.

02:35:42.260 | So I think when the families are now aware that their child is on vasopressin and the

02:35:46.840 | clinicians are aware, you know, you really want, there's a huge placebo response rate,

02:35:51.520 | right?

02:35:52.520 | It's not a placebo response rate here, but we really would want to make sure that our

02:35:58.860 | evaluation of the social behavior is done unaware to the medication, but you can get

02:36:04.660 | good safety data, right?

02:36:06.200 | So you can have those, you know, 13 children who were on placebo.

02:36:11.000 | We can then also make sure that their blood chemistry labs look good, that their electrocardiograms

02:36:16.860 | look good, right?

02:36:17.860 | And so that also allows us to assess safety parameters in a greater number of children.

02:36:24.280 | In a fairly broad literature search, I was able to find, okay, microbiome, so fecal transplant

02:36:30.340 | is something that people are excited about as weird as that.

02:36:32.440 | And there are trials in people with autism ongoing.

02:36:36.160 | Using fecal transplants.

02:36:37.160 | Yes.

02:36:38.160 | Okay.

02:36:39.160 | Oxytocin, nasal spray, presumably still being investigated by some groups or it's been abandoned?

02:36:44.120 | Well, I think it's mostly been abandoned because there's no funding priorities for it, right?

02:36:49.520 | So I know that maybe in Australia, because of Adam's positive findings that I don't know

02:36:55.100 | what his plans are, but maybe he's doing work there.

02:36:58.660 | There might be a little bit of work with behavioral therapy and oxytocin, but this is the problem

02:37:05.000 | when there's one big trial that fails, the funding just completely dries up.

02:37:09.680 | So even if there's promise, I don't know a single funding agency that's going to touch

02:37:14.280 | it.

02:37:15.280 | Got it.

02:37:16.320 | And then there's the vasopressin administration work that you're doing.

02:37:20.120 | Right.

02:37:21.120 | I think it's worth contrasting that work with the fairly large trial that was done by a

02:37:26.440 | major pharmaceutical company exploring the role of vasopressin for the treatment of autism.

02:37:32.380 | You could tell us what they did because it's basically the opposite of what you did.

02:37:40.580 | And you can tell us the outcome because I think that if anything, that study inadvertently

02:37:46.460 | provides support for the results that you observed, which is that administering, let's

02:37:50.760 | say increasing vasopressin levels in the brain seems to ameliorate some of the social deficits

02:37:55.980 | of autism.

02:37:56.980 | Right.

02:37:57.980 | So, for example, Roche had a compound called balovaptan, which was a vasopressin V1A receptor

02:38:04.720 | antagonist, which basically means there's, I think I mentioned there's these four neuropeptide

02:38:08.840 | receptors, and oxytocin and vasopressin bind to each other's receptors, but the V1A receptor

02:38:14.880 | is the one that is most implicated in social behavior.

02:38:21.560 | And so they had, and this is the tricky part about when medications are developed in pharma

02:38:27.080 | versus in academics, in academics, there's definitely this transparency.

02:38:31.600 | We write grants, the abstracts are publicly available, we register our trials.

02:38:36.000 | They do too, but a lot of the, shall we say, early development is all put out in publications.

02:38:41.320 | And then it's also peer reviewed and there's an open trail of why we're doing what we're

02:38:46.840 | doing.

02:38:47.840 | But in a pharmaceutical company, they have the ability because also they have all the

02:38:51.740 | funding to be able to do all kinds of development that may never see the light of day because

02:38:56.480 | of the proprietary basis of it, right?

02:38:58.900 | And so when you go back to, so it's not, it still is not clear to me why they took the

02:39:06.280 | approach of using an antagonist to the main vasopressin receptor in the brain.

02:39:13.440 | What's interesting is if you go back and you look at the animal literature, there are hamsters

02:39:19.480 | that if you give them vasopressin, they become aggressive, right?

02:39:22.640 | And if you give male prairie voles vasopressin, they can become aggressive.

02:39:26.780 | But let's think about the context that they're doing this in.

02:39:29.920 | These hamsters that show aggression are asocial.

02:39:33.420 | They live by themselves.

02:39:34.740 | If you give them vasopressin and the only social repertoire they have is to have sex

02:39:40.900 | with a female or to fight a male that they see, they have a very limited social repertoire,

02:39:45.880 | right?

02:39:46.880 | So if a prairie vole male is being given vasopressin, it's often in the context of like protecting

02:39:53.080 | his mate and his offspring.

02:39:54.960 | And so then it's actually species appropriate for him to attack a maraudering male on his

02:39:59.760 | territory who's going to, you know, kill his babies, right?

02:40:03.380 | And so my thinking in reading the preclinical literature, the animal literature, was that,

02:40:08.800 | all right, that makes a lot of sense in the context of those species, but we've never

02:40:13.620 | seen any evidence in our trial.

02:40:16.320 | Vazopressin didn't change.

02:40:17.320 | We also have an aggression measure in the current trial as well.

02:40:20.760 | But, you know, for me, the vast majority of evidence from the animal literature suggested

02:40:26.680 | that vasopressin was prosocial and that, you know, especially given our CSF findings, like

02:40:34.400 | over and over, across species, across studies, across ages, that we should be giving vasopressin,

02:40:40.400 | especially given the correlations between vasopressin in CSF and symptom severity and

02:40:46.360 | autistic traits, you know, the former in people and the latter in the monkeys.

02:40:51.960 | And so they had some preliminary studies that I believe were maybe single dose, one that

02:40:58.120 | they published, but then they had a trial where the primary outcome measure, the social

02:41:04.080 | responsiveness scale, was negative, and then they had some secondary measures that maybe

02:41:09.820 | showed some promise, and then they were conducting another trial, and then they did a futility

02:41:16.260 | analysis and I know they stopped the trial, and I don't think it was for safety reasons,

02:41:20.280 | but again, you know, a lot of this isn't made public, right, because it's a pharmaceutical

02:41:24.540 | company.

02:41:25.540 | So, you know, we will see, because we are going to be completing our larger trial, you

02:41:30.800 | know, this year, and, you know, as they say, the proof is in the pudding, so we will see

02:41:34.240 | if, you know, we can replicate our initial pilot findings.

02:41:37.720 | Well, it sounds like they got it backwards, that blocking vasopressin pathways would just

02:41:42.380 | make things worse, and that augmenting vasopressin makes things better, although that last statement

02:41:49.180 | needs to be supported by this more extensive population.

02:41:52.180 | Right.

02:41:53.180 | Well, I think, you know, there's been a lot of speculation and maybe there are people

02:41:55.740 | closer to the trial than me who might be able to speak to mechanism, but, you know, I would

02:42:00.320 | meet the Roche people at conferences and they would come to my talks and I would always

02:42:04.380 | ask them, like, "What's the mechanism of action, why are you antagonizing the system when we're

02:42:08.540 | giving, you know, a vasopressin agonist, if you will?"

02:42:11.840 | And you know, some people had said, "Well, maybe by blocking the vasopressin receptor,

02:42:16.340 | you know, there's a way to have oxytocin be more bioavailable."

02:42:21.380 | That sounds like some gymnastics to me.

02:42:22.740 | Yeah, yeah, I totally agree.

02:42:23.900 | And so I've never had a, I've never received a compelling response from anybody about why

02:42:31.100 | they did their trial and then, you know, the differences.

02:42:34.700 | I mean, when this was ongoing and, you know, there was potentially room for both, right,

02:42:41.320 | you know, maybe I thought that maybe there's some optimal band of vasopressin signaling

02:42:45.260 | in the brain, right?

02:42:46.640 | And so maybe there's some people where they have too much vasopressin and some who have

02:42:51.100 | too little, right?

02:42:52.100 | And so this was a lot of maybes, but it doesn't to me seem like that's the case, especially

02:42:57.160 | if our current trial has a positive readout.

02:43:00.800 | I'd be remiss if I didn't ask for your stance and read of the landscape on the data about

02:43:09.660 | vaccines and autism.

02:43:10.660 | I'm not talking about COVID vaccines here, I want to be really clear about that.

02:43:13.800 | But there was a theory running about, not just in the press, but in the scientific literature

02:43:21.020 | for a while, that vaccines could cause autism.

02:43:26.040 | That was proposed.

02:43:28.720 | My understanding is that was debunked.

02:43:31.960 | That idea still lives on the internet.

02:43:36.740 | But what is the evidence or let's say, let's go through this sequentially.

02:43:41.600 | What was the idea?

02:43:43.460 | What was the evidence for that idea?

02:43:45.340 | And then what caused the demise of the, at least the scientific support for that idea?

02:43:51.780 | Leaving open, of course, that new data may come, but let's talk about what is known now.

02:43:57.040 | Right.

02:43:58.040 | So what I will say is being evidence-based is something that all scientists should strive

02:44:05.260 | for.

02:44:06.260 | Right?

02:44:07.260 | And so the backstory on this is there was a guy named Andrew Wakefield who published

02:44:10.680 | a paper and he basically said the preservatives and vaccines are causing autism.

02:44:16.580 | So not the specific vaccine, but the adjuvant, the stuff that's preserving, the stuff that's

02:44:21.380 | keeping the vaccines bio-effective.

02:44:24.220 | Right.

02:44:25.500 | At least that was my understanding.

02:44:27.060 | Yeah.

02:44:28.060 | That's mine as well.

02:44:29.060 | And so, and then it turns, I want to be clear because the internet is a, is a, is a cruel

02:44:33.320 | and diabolical place.

02:44:35.700 | My stance is that that was the hypothesis.

02:44:38.720 | I don't agree with that stance.

02:44:40.920 | Right.

02:44:41.920 | Okay.

02:44:42.920 | Right.

02:44:43.920 | And so, or if we want to just back up a little bit broader, there was this idea that something

02:44:47.800 | about vaccines were causing autism, but the study was debunked.

02:44:52.480 | He lost his medical license and the paper was retracted, right?

02:44:56.200 | He lost his medical license on the basis of the fact that the study was wrong.

02:44:59.820 | Or was there ever-

02:45:00.820 | I think he faked the data.

02:45:01.820 | There were, that's what I recall as well, that there was evidence of him literally making

02:45:05.980 | up the data.

02:45:06.980 | Right.

02:45:07.980 | Right.

02:45:08.980 | So it wasn't a case of like sloppy technique.

02:45:09.980 | It was a case of intentional fraud.

02:45:12.860 | Right.

02:45:13.860 | That's my understanding.

02:45:14.860 | Again-

02:45:15.860 | What was his, does anyone ever like look into what his motivation for what it was?

02:45:19.820 | Like why someone would, I mean, he threw away his whole career.

02:45:22.540 | Right.

02:45:23.540 | Yeah.

02:45:24.540 | I don't, I don't know.

02:45:25.540 | I don't know.

02:45:26.540 | But I think the hard part about that is understandably, people got very frightened, right?

02:45:31.840 | That we're doing something to our children that could have unanticipated consequences.

02:45:38.200 | And when something like that happens, then we dump, we spend a lot of money investigating

02:45:43.640 | it.

02:45:44.640 | And so the good news is at this point, there have been multiple, multiple studies that

02:45:48.520 | haven't shown a correlation between vaccines and autism.

02:45:53.980 | I do believe that preservatives have been changed as a result.

02:45:56.980 | So that's something we should check that, you know, that might be something where, you

02:46:00.960 | know, there's been a public health change on preservatives that are in vaccines.

02:46:04.760 | That's interesting in its own right.

02:46:06.240 | I mean, we don't want to cause alarm.

02:46:08.240 | But that's, that's interesting, you know, that, that in this data fraud case, it might

02:46:12.600 | have cued people to the idea that certain things might have been needing change, even

02:46:18.140 | though it wasn't the specific issue that this, this fraudulent researcher was focused on.

02:46:23.100 | The change was made to make sure people would vaccinate their children, right?

02:46:26.320 | Like, so this is something that I think we should have lots of caveats here, like, you

02:46:30.320 | know, post the, post the studies, like make sure that what we're saying is accurate, right?

02:46:35.240 | But I, but I think that my concern is that we've spent, you know, so the good news is

02:46:40.240 | that, you know, the, like every single study that I'm aware of does not show a relationship

02:46:46.600 | between vaccination and autism, right?

02:46:48.960 | And so I think that most scientists and medical doctors that I know that are part of like

02:46:53.660 | the, you know, standard biomedical research community do not believe that vaccines cause

02:46:59.620 | autism.

02:47:00.620 | They vaccinate their own children.

02:47:02.540 | You know, they recommend vaccinations to other people's children.

02:47:06.980 | And so I think that's where we are, you know.

02:47:10.120 | Could I just ask a question?

02:47:12.680 | And I feel more than obligated to do this because I don't, you know, I think I have

02:47:16.860 | a pretty good finger on the pulse of the listenership of this podcast, but I think there's a range

02:47:20.940 | of, of stances on this where some people have a lot of trust in the standard medical establishment,

02:47:28.120 | others have less trust in the standard medical establishment.

02:47:31.280 | And I wouldn't be doing my job if I didn't try and represent all those sides.

02:47:37.600 | And you know, one thing that I've heard is that over the last 20 or 30 years, there's

02:47:43.240 | been a dramatic increase in the number of vaccinations that kids get.

02:47:47.180 | And I don't know if that's true, but when we say vaccinations, we could be talking about,

02:47:51.420 | you know, measles, mumps, rubella, polio.

02:47:55.560 | We could also be talking about measles, mumps, rubella, polio, flu shots every year, rabies

02:48:01.420 | vaccine, tetanus vaccine, you know, HPV, right?

02:48:05.040 | With one that wasn't even available when I was in college, you know, as everyone in college

02:48:09.560 | was well aware, there wasn't an HPV vaccine, didn't change people's behavior a whole lot.

02:48:14.580 | But you know, there's, there's a vaccine, there's multiple vaccines, and then there's,

02:48:23.240 | you know, all the vaccines, right?

02:48:25.200 | And I think that one of the concerns that I hear about is the idea that, okay, there's

02:48:30.560 | some critical vaccines, but then which ones are perhaps less critical, if any.

02:48:35.640 | And these are the kinds of discussions that are starting to surface, and that, you know,

02:48:40.800 | have parents and potential parents, you know, rightfully thinking about this stuff.

02:48:45.160 | And no one really knows where to get the information.

02:48:47.320 | But like, I've tried, and I can't find a pediatrician that says, hey, listen, these, but not those,

02:48:54.380 | or you can certainly find board certified physicians that say many, and certain board

02:48:59.540 | certified physicians that say none, you actually can find those.

02:49:02.880 | The none category tend to hide themselves a little bit more than others for obvious reasons.

02:49:07.120 | But it's hard to get a sense of like, which, which vaccines are critical and which ones

02:49:11.680 | aren't, if you're a parent, and you're not versed in this stuff.

02:49:15.080 | And so you could imagine that like, people are, you know, kids are taking many more vaccines,

02:49:20.460 | and only some of those are critical, and maybe all of them are critical.

02:49:23.340 | I think, I guess the way I would maybe turn it on its head is that, you know, because

02:49:28.280 | of this, this study that did, in some ways, so much harm, right, like we spent, we spent,

02:49:37.080 | I don't even want to hazard a guess about how much money worldwide went into studying,

02:49:42.760 | you know, the, you know, vaccines and autism based on a fraudulent data, right?

02:49:47.700 | Like that's, to me, a real tragedy.

02:49:49.520 | But at the time, they didn't know it was fraudulent.

02:49:51.280 | No, right.

02:49:52.280 | Exactly.

02:49:53.280 | So they went after this thinking it was true.

02:49:54.280 | Okay.

02:49:55.280 | So I think, I think the thing, the consequence of all this that I think is also extremely

02:50:00.400 | sad is that everybody, because everyone got so riled up and so fearful, there has been,

02:50:10.280 | historically until recently, many researchers who are like, oh, man, I don't want to touch

02:50:14.500 | immunology and autism with a 10-foot pole, right?

02:50:17.720 | And yeah.

02:50:19.040 | You know, and I wouldn't consider myself fearless, but like my lab never had any reason to work

02:50:23.240 | on those, on those important problems.

02:50:26.040 | But I'll tell you, like, yeah, it seems like it's not a kettle of fish.

02:50:28.840 | It's a ball of barbed wire with a bunch of, you know, napalm burning around it.

02:50:33.080 | You know, I mean, you say one thing, your career is ending.

02:50:36.560 | You say the opposite thing, your career is also ending.

02:50:39.120 | You know, it's, it's, it's, it's a, it's a mess.

02:50:42.840 | But, but I think this highlights that there are so many parents, you know, again, and

02:50:47.520 | I think we need to listen to parents' stakeholders, right?

02:50:50.400 | Like, you know, there's, there needs to be a dialogue whenever anybody's studying any

02:50:55.320 | illness to, to talk to the people who are involved, right?

02:50:59.400 | And, and I think that there are parents who will report, wow, like there are, there is

02:51:03.840 | immune system dysregulation in my child.

02:51:07.280 | And, but because of this historical issue with vaccines, it's only been very recently

02:51:14.080 | that I think people, scientists, medical doctors have said, okay, we're hearing a lot about

02:51:19.640 | this from parents.

02:51:21.400 | And are there a group of individuals who have, you know, immune issues that could be driving

02:51:27.520 | their autism, right?

02:51:28.520 | We don't know and everything should be evidence based.

02:51:31.040 | But I think that, like you said, with this cancel culture and all this fear, scientists

02:51:35.800 | sometimes will pick topics very judiciously based on, you know, like, hey, I just want

02:51:41.700 | to be left in peace and I'm trying to help this community.

02:51:45.520 | And if there is areas of the enterprise that you think are going to cause all kinds of

02:51:49.760 | grief, then people are going to be less reluctant to study them, even if it's critically needed.

02:51:54.840 | Well, that's a perfect place to say thank you.

02:52:00.320 | I realize you're not addressing the vaccine autism issue directly, but you're so clearly

02:52:05.920 | going after the target, trying to figure out what are the biological mechanisms that are

02:52:10.960 | disrupted in autism and by extension, other deficits of social function in kids and adults.

02:52:17.780 | You've identified this incredible relationship between vasopressin, which should have more

02:52:24.560 | prominence in my opinion than oxytocin, its lesser cousin, just kidding, oxytocin lovers.

02:52:32.480 | But also have shown, you know, yes, in a small study, but you're now extending this to a

02:52:37.360 | larger cohort, as you mentioned, a causal relationship when vasopressin is administered

02:52:44.140 | to these low vasopressin/low social functioning kids, their symptoms improve.

02:52:49.720 | So I know I speak for many people when I say that I truly appreciate your doggedness in

02:52:56.880 | going after this problem, especially on the complicated landscape of lack of funding for

02:53:01.680 | doing novel and truly high-risk work, especially on the backdrop of the sociopolitical landscape

02:53:09.980 | around autism.

02:53:10.980 | It's a complicated thing even to discuss, you know, as I mentioned in the introduction,

02:53:14.600 | you know, we had to have some fluency around autism, so we sometimes said autistic.

02:53:19.320 | Sometimes we said people with autism, you know, I mean, it's a tough one, but in order

02:53:23.760 | to make progress, real progress in this area, we need people like you.

02:53:27.840 | We need you and you're doing it to get in there and just go, okay, you know, let's get

02:53:32.200 | at the biological functions.

02:53:33.700 | Let's get at the novel treatments and you're making amazing progress.

02:53:37.040 | So I'm so grateful that you're doing it and that you'll continue to do it and that you

02:53:41.200 | came here today to teach us what you've been up to.

02:53:44.960 | I'm also grateful and I just want to say thank you for that and that we absolutely have to

02:53:49.720 | get you back here to give us an update on your progress really soon and again and again

02:53:55.340 | and again.

02:53:56.340 | Thank you so much.

02:53:57.340 | I love being here.

02:53:58.340 | All right.

02:53:59.340 | Well, I've loved this conversation and I'll sign off by saying, folks, this is how diseases

02:54:04.420 | are cured.

02:54:06.380 | Thank you for joining me for today's discussion with Dr. Karen Parker about the biological

02:54:10.040 | basis of social functioning and autism.

02:54:12.720 | To learn more about Dr. Parker's research, please see the links in our show note captions.

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02:56:15.220 | Thank you once again for joining me for today's discussion with Dr. Karen Parker.

02:56:19.060 | And last, but certainly not least, thank you for your interest in science.

02:56:22.140 | [MUSIC PLAYING]

02:56:24.000 | (upbeat music)

Dr. Karen Parker: The Causes & Treatments for Autism

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