Dr. Noam Sobel: How Smells Influence Our Hormones, Health & Behavior

Andrew Huberman:
Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, my guest is Dr. Noam Sobel. Dr. Noam Sobel is a professor of neurobiology in the Department of Brain Sciences at the Weizmann Institute of Science. His laboratory studies olfaction and chemosensation. Olfaction is, of course, our sense of smell. Chemosensation is our ability to respond to chemicals in our environment. Today, you are going to learn some absolutely incredible facts about how you interact with the world and other people around you. For instance, you will learn that humans can smell things around them as well as dogs can. In fact, humans are incredibly good at sensing the chemical world around them. You also learn, for instance, that every time you meet somebody, you are taking chemicals from that person, either from the chemical cloud that surrounds them or directly from the surface of their body, and you are actually applying it to your own body, and you are processing information about that person's chemicals to determine many things about them, including how stressed they are, their hormone levels, things that operate at a subconscious level on your brain and nervous system and that impact your emotions, your decision-making, and who you choose to relate to or not to relate to. You will also learn that tears, yes, the tears of others, are impacting your hormone levels in powerful ways. You will also learn that every so often, actually on a regular schedule, there is an alternation of ease through which you can breathe through one nostril or the other, and that alternation reflects an underlying dynamic of your nervous system and has a lot to do with how alert or sleepy you happen to be. The list of things that Dr. Noam Sobel's laboratory has discovered that relate to everyday life and that are going to make you say, "Wow, I can't believe that happens," but then go out into the real world and actually observe that that happens in ways that are incredibly interesting just goes on and on. In fact, his laboratory discovered that we are always sensing our own odors. That's right. Even though you might not notice your own smell, you are always sensing your own odor cloud, and throughout the day, you periodically smell yourself deliberately, even though you might not realize it, in order to change your cognition and behavior. I first learned of Dr. Sobel's laboratory through a rather odd observance. That observance took place when I was a graduate student many years ago at UC Berkeley. At the time, Noam Sobel was a professor at UC Berkeley. As I mentioned before, he has since moved to the Weizmann. Well, I was walking through the Berkeley campus, and I saw people on their hands and knees, but with their head very close to the ground, and their eyes were covered, their hands were covered, their mouths were covered, and only their nose was exposed. And what I was observing was an experiment being conducted by the Sobel laboratory in which humans were following a scent trail. That scent trail was actually buried some depth underneath the earth, and yet they could follow that scent trail with a high degree of fidelity. It was from that experiment and other experiments done in Dr. Sobel's laboratory at Berkeley and at the Weizmann, involving neuroimaging and a number of other tools and techniques, that revealed the incredible power of human olfaction and humans' ability to follow scent trails if they need to. And that, of course, led to many other important discoveries, some of which I alluded to a few moments ago, but you are going to learn about many, many other important discoveries in the realm of olfaction and chemosensation that have been carried out by Dr. Sobel's laboratory through the course of today's episode. And by the end of today's episode, I assure you that you will never look at or smell the world around you the same way again. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast.

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Andrew Huberman:
And now for my discussion with Dr. Noam Sobel. Dr. Sobel.

Dr. Noam Sobel:
Noam.

Andrew Huberman:
Noam, welcome.

Dr. Noam Sobel:
Thank you.

Andrew Huberman:
I must say, I am extremely excited for this conversation. I've been a huge fan of your work for more than a decade or two. Yes?

Dr. Noam Sobel:
Kind of frightening.

Andrew Huberman:
Yeah.

Dr. Noam Sobel:
But yeah.

Andrew Huberman:
We overlapped at UC Berkeley some time ago, although we did not meet, and we-

Dr. Noam Sobel:
Although we lived in the same apartment.

Andrew Huberman:
And we just learned that the amazing apartment that you moved out of was the apartment that my girlfriend and I at the time moved into in 2006, I believe.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
So, we've shared quite a few things.

Dr. Noam Sobel:
Certainly.

Andrew Huberman:
And today I'd love for you to share with us all about the amazing landscape of chemosensation, in particular olfaction, or sense of smell, and some related perceptual abilities or subconscious abilities, including pheromones, et cetera. To get everybody on the same page, I'd like to just start off by asking, what are the major components of our ability to smell? Obviously, or I like to think it involves the nose at some level.

Dr. Noam Sobel:
It does.

Andrew Huberman:
To what extent is that mixed in with other senses, like taste? And perhaps more importantly, what about the chemicals that we are sensing through this thing, and for those of you listening and not watching, I'm tapping my nose, that we are not aware of? The chemicals that we're inhaling and making sense of without our awareness. If you could just give us the top contour Or even deep contour, if you like, of the parts list and the various roles they play.

Dr. Noam Sobel:
So you've asked a lot of questions at once. I'll start with a little comment on the way you said smelling through our nose, which we indeed do, but we also smell through our mouth, actually. There's a process referred to as retronasal olfaction, where odorants come up through the back of our throat and out of our nose, the reverse way, and we smell things that way as well. And in fact, a big part of the contribution of olfaction to food and taste comes from that, from retronasal olfaction. But primary olfaction is referred to as orthonasal olfaction, that is through our nose. We sniff, and sniffing is a big thing. Well, I have a sense we might talk about that a lot today in all sorts of contexts. So we sniff in through our nose. And to answer your general question of the organization of the system, so airborne molecules travel up our nose, a distance in the human of about six or seven centimeters to about here, where they interact with, I will use the word sheet of receptors, but sheet is a bit misleading here. It's not a sheet. It's very convoluted. We have about seven million such receptors lining a structure known as the olfactory epithelium. This is the sensory surface of the olfactory system, the olfactory epithelium. Again, probably about six or seven million receptors in the human, probably of about 350 different kinds. So that's amazing. That means a meaningful percentage of your genome is devoted just to this, just to the kinds of olfactory receptor subtypes you have in your nose. By the way, I can share an amusing story. I would imagine amusing stories are good for podcasts. So that number of six or seven million receptors is probably not very well-grounded. It's hard to count, but it's reasonably grounded. And there was this thing roaming around in the literature about bloodhounds having a billion receptors in their nose, which is why they're so amazing. And this number, it sort of propagated through the literature. And our lab has written, over the years, a few review chapters, and we were repeatedly writing the olfaction chapter for one of these large textbooks, the "Gazzaniga Handbook of Cognitive Neuroscience," I think it's called. And we had that in there as well somewhere, and one time when we were renewing the chapter for a new version of the book, I told the graduate student who was leading that at the time, Araya Sharoun, she's now a professor at Tel Aviv University, I told her, "Check that reference out. Where in the world did that come from?" And we started going back and back. And it turns out it comes from a textbook, an Australian textbook. And we found the author of the textbook, and we wrote her, and I said, "Look, there's this thing in the literature of a billion receptors in the bloodhound. Where did that come from?" And surprisingly, she answered me. And I was hoping to get a reference, right? But it wasn't a reference. And this is where it really becomes funny for us, because she said, "I was once at a lecture of an olfaction geneticist by the name of Doron Lancet, and he said that in the lecture." Now, this is really funny because she's in Australia, this is all over the world, this number, and I'm writing her from Israel, and Doron Lancet is in the building next to me, okay? He's in Weizmann Institute of Genetics. He used to be. He's retired now. And he had meaningful contributions in the history of olfaction. So I picked up the internal phone and I said, "Hey, Doron. Did you say that there's a billion receptors in the bloodhound nose?" And he said, "What's a bloodhound?" And so this is totally made up, right? It totally made up, and it propagated. You can probably go into Google and type, like, a billion receptors in the bloodhound, and you'll get a lot of hits. But there was absolutely no evidence for that.

Andrew Huberman:
Amazing. And not just amazing in light of what it tells us about olfaction in bloodhounds or otherwise, but amazing because it sheds light on just how much of what is in textbooks, scientific and medical, is absolutely wrong.

Dr. Noam Sobel:
Things propagate, and you cite yourself. So we fixed that in that version of the-

Andrew Huberman:
Great

Dr. Noam Sobel:
... and so to finish the line, so odorants interact with these receptors, here in our epithelium, where they undergo what is referred to as transduction. That is, the odorants dock at a receptor and turn into a neural signal or force the receptor to respond in a neural signal. And this neural signal, in fact, action potentials, not gradient potentials of any kind, propagates via the olfactory nerve. Now, this is a nerve that goes from our epithelium, right here.

Andrew Huberman:
Behind the forehead.

Dr. Noam Sobel:
No. Well, yeah.

Andrew Huberman:
Yeah.

Dr. Noam Sobel:
Here, through the thinnest part of our skull, an area referred to as the cribriform plate, which is perforated. It has a lot of holes. The nerve goes through those holes and synapses at the first target in the brain, which is the olfactory bulb. In humans, that forms an interesting point of sensitivity, because a lot of people lose their sense of smell due to trauma because of that structure.

Andrew Huberman:
A head hit type trauma.

Dr. Noam Sobel:
Well, yes, although, you denoted hitting on the front of the head, which is where all this real estate is, but actually, the more common cause for losing your sense of smell for trauma is the back of the head because of what's referred to as a contrecoup injury. So as your listeners probably know, our brain is floating in liquid, in CSF, in cerebrospinal fluid inside our skull, and when we get hit in the back of the head, the brain has this forward and backward movement

Andrew Huberman:
In the liquid in the skull, it sort of crashes. It can crash against the front of the skull, which is why, in a contrecoup injury, you also often have frontal damage. But what happens is that this generates a shearing motion on the cribriform plate, and the olfactory nerve is severed. And if it's completely severed, it's lost. Forever? Because my understanding is that the olfactory sensory neurons are among the few central nervous system neurons in adult humans that can regenerate. So- Or replenish themselves. Right. So again, there are a few questions in one. Yeah, that's okay. So first of all- We will spin many plates simultaneously If it's completely severed, completely, then yes, you're lost. Forever. Yeah. If it's completely severed. Because even if you'll have regeneration at the basal cell level at the epithelium, they won't manage to find their way back to the bulb. If you have partial or something left, or something shows up in a short while after the injury, then you have a good chance of recovery. Ah, because they grow along the trajectory of the other axons- Yeah ... sort of pioneering the way for them. Assumingly, yeah. Interesting. And basically, the timeframe, and it's funny, I get a lot of emails on this, although I'm not a medical doctor, but I get a lot of emails from people who have lost their sense of smell because it's very distressing. And now more people know this because of COVID, that it's very distressing. And basically, the rule of thumb is that if you don't get it back within a year to a year and a half, you'll never get it back. My understanding of the statistics on olfactory loss and COVID and other viral type infections is that, first of all, I experienced that when I got COVID. Including total anosmia? For one day, and not total. There was a remnant of an ability to smell or perceive the smell of a lemon, and I was huffing as hard as I possibly could. Oh. There's an over-the-counter remedy, and this is not pseudoscience because there's a number of papers published about this on PubMed, that alpha-lipoic acid can accelerate the recovery of smell. Yeah. And so that's something that worked successfully for me. I'm not saying that that's the only route. You don't know if it worked successfully for you or if you would've recovered anyway. You didn't do a controlled study . True, but I was not willing to do the control experiment. Exactly. So yeah. Let me say two things on this front. First, the data on the alpha-lipoic acid is eh. Yeah. It's not overwhelming. Yeah. But losing your sense of smell is overwhelming. Yeah. No, no, I know. And so I think people feel desperate, and they- And I'll say one word about smelling the lemon. Mm-hmm. I'll take that opportunity to share more information. When we smell things, it's the result of more sensory subsystems than the olfactory system alone. So you have several chemosensory sensitive nerves in your nose. A primary one beyond the olfactory nerve is the trigeminal nerve, the fifth cranial nerve. So the trigeminal nerve has sensory endings in your nose, in your throat, and in your eye. It has three branches. That's why an onion has a smell and burns your eyes and burns in your throat. Is that why? It's trigeminal, yeah. The tearing of cutting an onion is due to the trigeminal. It's a trigeminal reflex. Amazing. We talked about trigeminal in the context of headache during a headache episode. It's a trigeminal reflex. So the lemon you were smelling may have been a trigeminal sensation. So smelling the lemon with my eyes is what you're saying. Well, no, with your nose. With my nose. But with your trigeminal receptors and not your olfactory receptors. So within olfaction researcher jargon, there's what we refer to as pure olfactants. These are odors that will stimulate your olfactory nerve alone. They won't influence your trigeminal nerve at all. And an example, just to get a sense of what that might be, would be the coffee right here- Mm-hmm ... is a pure olfactant. Vanilla is a known pure olfactant. These things have no trigeminal activation. Right. As long as we're on this topic, and we'll weave back and forth, but I'm glad we are on this topic because a tremendous number of people wrote to me during the pandemic, and continue to, about olfactory loss. I've heard of this olfactory training whereby if you have a partial or even a complete loss of primary olfaction- Right ... that one is encouraged to smell a number of different smells. I grew up studying activity-dependent wiring of the nervous system. It makes total sense to me why keeping neurons active keeps them alive. So this is not fire together, wire together type thing. By the way, that's a quote from Carla Shatz, not Donald Hebb, folks, or me. But this is about keeping neurons electrically active, in this case, olfactory neurons, in order to maintain their connections, because otherwise they will die. Olfaction is a definite use it or lose it system. And so that makes total sense. And indeed, there's very strong evidence for success of the training programs, more than the alpha-lipoic acid. Great to know. And so that's a real thing. Mm-hmm. And what's cool about that is that you don't need to go out and buy expensive things, although you can. Of course, there are people who are capitalizing on this commercially already. But you can just take things from your refrigerator or your makeup cabinet or whatever and smell them attentionally and constantly and sniff them, and that exposure will help you recover. There is good data on that by now. You made that point in passing about regeneration in the olfactory system. Indeed, one of the cool things... So in olfaction, you can study many things through olfaction, and indeed, one of them is neural regeneration, because the olfactory neurons are really the only neurons that do that systematically in the adult mammalian brain. And whether the human olfactory system shows the same level of regeneration as it does in other mammals is and was somewhat questionable, and I'm just bringing that up to share a really cool study that was published in "Neuron," I think somewhere around 2014

Dr. Noam Sobel:
Where to address this question, I just really like the idea of doing that. What the authors did was in postmortem, they looked at levels of C14 in adults who were exposed to atomic bomb experiments. So you can actually look at these neurons and time them based on exposure to radiation. And that paper suggested that there's not as much turnover in the human olfactory bulb as there is in other mammals. Other lines of data suggest otherwise. So this is kind of a debated question as to what extent of neurodegeneration you have in the human olfactory system as opposed to other mammals. But that was just a really cool paper, I think, of doing that.

Andrew Huberman:
Fascinating.

Dr. Noam Sobel:
Should I finish the path just so we have the-

Andrew Huberman:
Please.

Dr. Noam Sobel:
So we said information then synapses at the olfactory bulb from the olfactory epithelium. And the pattern of that synapsing follows what's referred to as the most extreme case of convergence in the mammalian nervous system. More specifically, what happens is that all the receptors of a given subtype, and remember, in humans, we said we have about 350, in the mouse, we have about 1,200 probably. So all the receptors of one subtype converge to one location in the bulb, and this location is referred to as a glomerulus or in plural, glomeruli. And that may be a slight oversimplification. It's in fact two glomeruli. There is a sort of a mirror cut line, and so all the receptors of one subtype will converge to two mirror glomeruli on the olfactory bulb. So you end up having two glomeruli that reflect that one receptor subtype. And so if, and this is as far as the... I'm giving you now the textbook view of how the system works, but then I'll happily share with you things that pose a problem for the textbook view of how things work. But the textbook view of how things work is that every such receptor subtype is responsive to a small subset of different molecular shapes, what's sometimes referred to as odotopes, the molecular aspects of the odorant. So each receptor is responsive to a different subset of odotopes, let's say 10, and each odotope will activate a different subset of receptors. So potentially, you have this insane combinatorics of this potentially 350-dimensional space in the human, potentially. But then because of this convergence, you end up having on the bulb, in a way, a map reflecting receptor identity. So let's say this coffee activates receptors of type one, three, and seven, so the glomeruli of receptors one, three, and seven will "light up," quote-unquote, when I smell the coffee. And if you can take a snapshot of that, theoretically, you would have the map of coffee, and so on and so forth. This is sort of the textbook view of how the system works. And then information goes from the bulb to several targets in the brain, what is referred to as primary olfactory cortex, is piriform cortex and entorhinal cortex. This is on the ventral surface of the brain, the lower portion of our temporal lobe. And information goes there directly, but it also goes directly to the amygdala. It probably goes directly to the hypothalamus. It may go directly to the cerebellum. It goes all over the brain. So information projects widely from there, and as far as people understand, the map that may exist on the bulb doesn't exist in the rest of the brain, and the understanding of how coding occurs in the rest of the brain is murky.

Andrew Huberman:
Commonly, one hears that the memories that we have of odors are somehow more robust than the memories of other perceptual events in our life. I don't know if this is true or not, but people will say, for instance, "I can still remember the smell of my grandmother's hands," or "The smell of cookies in her kitchen." At a minimum, it points to the fact that smell and memory are closely linked, and you just mentioned a direct multi-station, but nonetheless, somewhat direct path from the nostrils to the hippocampus, one of the primary encoding centers of memories in the brain.

Dr. Noam Sobel:
Two synapses away.

Andrew Huberman:
Yeah. Which is a remarkably short pathway considering that, for instance, just by example, because some of our listeners won't be familiar with this, but some will, that sound waves that are transduced into neural signals at the level of the inner ear go through many stations before they arrive at the location in the brain where we make sense of those sound waves as voices or music, et cetera. Whereas olfaction is more of a direct route to the memory centers. Is there any just-so story or real objective truth to the idea that olfactory memories are formed more easily or maintained longer or more robustly than other sorts of memories?

Dr. Noam Sobel:
So, yes. But first, I should say that I'm not an authority on olfactory memory. Olfactory memory is a huge field of research, and somehow our lab has never really gone much into that. Although, again, the same student I happened to talk about before, Yariv Sharon, who's, again, now a faculty at Tel Aviv, ran a study, a paper we, I think, we published in "Current Biology" called "The Privileged Representation of Early Olfactory Associations." Basically, there's something about the first time you experience a smell that generates a particularly robust representation more than other sensory stimuli, and that's what she, in fact, compared. So there's something about the first exposure to a smell In terms of the brain encoding that etches it into our being. And this is an effect that has echoes, of course, in literature. I mean, the biggest cliche in this is to bring up the Proust effect, right? So, the Proust effect is when he ate the madeleine, and the taste and smell immediately reminded him of an event in his childhood where the same madeleine appeared. So that's something very real. There's a lot of research on it not coming from our work. So I'm not an authority.

Andrew Huberman:
But it does sound like there's something special about olfaction, and that doesn't mean that there isn't something special about vision or audition.

Dr. Noam Sobel:
No.

Andrew Huberman:
Each one has its own unique tone.

Dr. Noam Sobel:
I'm the last to argue that there's something special about olfaction. My students make fun of me because they say, and there's some truth to that, that I try to explain everything through the olfactory system. I mean, for me, everything is olfactory. So, yes.

Andrew Huberman:
Through the lens of the nose.

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Andrew Huberman:
When I was at Berkeley, I was walking across campus one day, and I saw, I think students, but I saw people on their hands and knees with goggles on, gloves on-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... and I think their mouths were covered, too?

Dr. Noam Sobel:
Everything was covered.

Andrew Huberman:
Was covered, and they were crawling along the ground, and I thought this was peculiar, but then again, it's UC Berkeley, and the joke is to get noticed on the UC Berkeley campus, you have to be naked and on fire, right? One or the other would not be sufficient. Please don't run this experiment, everybody.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
It's that kind of place.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
But nonetheless, a paper came out a few years later describing the results of what turned out to be your experiment that your laboratory was running, which was having people follow an odor trail with their nose. And my understanding is that people can improve their ability to track scents quite robustly, especially if we deprive them of vision and somatosensation, that is touch and some other sensations. Maybe you could just tell us a little bit about that study and-

Dr. Noam Sobel:
Sure

Andrew Huberman:
... I think in our audience, I'm suspecting that many people have a keen, keen sense of smell. I have a family member who just can detect any negative putrid odor in the environment, but also good odors exquisitely well, and I have other family members whose sense of smell is quite poor. I'd love for all of those people to learn a bit about what is possible in terms of training up or-

Dr. Noam Sobel:
Right

Andrew Huberman:
... improving our ability to smell, and perhaps in the context of that study, if you will.

Dr. Noam Sobel:
Yeah. So first, before even talking about improving, just off the bat, humans have a remarkable sense of smell. And this is something, again, in our lab, we already said, "Yeah, we know this. This is old news." But to people who come from different worlds, we have to reiterate this. Sometimes when I give public lectures to non-olfaction audiences, I reiterate this. Humans have an utterly remarkable sense of smell. To put that a bit into things that are tangible. So, for example, mercaptans, which are added to cooking gas so that we smell it, because otherwise it wouldn't have a smell. So that the smell of gas is not the smell of gas, of propane. It's an additive.

Andrew Huberman:
Mercaptan?

Dr. Noam Sobel:
Yeah. It's mercaptan.

Andrew Huberman:
The sulfur-like smell?

Dr. Noam Sobel:
Yeah. So our detection threshold, that is the level at which we can detect it, is 0.2 parts per billion. Okay? There's no machine that can really do that that effectively. No gas chromatograph, nothing. Now, to give you another sense of making this, again, really tangible, we're working with an odorant in our lab called estra tetraenol that our participants can detect when we have it mixed at 10 to the negative 12 molar in the liquid phase. To give you a real sense of that, we did the math. If you would take two Olympic-size swimming pools and you would pipette one ml, one drop, into one pool versus the other, you could smell the difference between the pools.

Andrew Huberman:
Incredible.

Dr. Noam Sobel:
That's the detection threshold that you have with your nose. People have an utterly amazing nose, okay? So that's just in terms of its detection abilities, which are just remarkable, really up there in the mammalian world. We're not a bad mammal at olfaction. And beyond that, we can improve, okay? And the example you're talking about actually started off as a lab bet. Okay? We were having a lab picnic, so I guess I should here fill in because I'm your guest from the Weizmann Institute of Science in Israel. But before going back to my home in Israel, I was a faculty at UC Berkeley in the Helen Wills Neuroscience Institute, and this study was done during that time. And we were on a lab picnic, and we were having, indeed, one of these lab discussions, arguments on what humans can and can't do with their sense of smell. And I said that humans could truly even track odor like a dog, and people there said, "No way." And we ran this quick experiment, which I have video of, but I don't think we'll show it here. But I actually have original, the picnic video, we have it And a graduate student by the name of Christina Zelano, a brilliant graduate student at that time, she's now a professor at Northwestern. And she's really leading the field of olfaction imaging today. But she was the volunteer, and we dragged a chocolate bar across the grass and blindfolded her, and checked if she could track the track we made with the chocolate, which she did very effectively. Right? And as far as-

Andrew Huberman:
Did you place her at the starting point of the line, or?

Dr. Noam Sobel:
I think we did. I don't exactly remember what we did on that sort of picnic tryout. But I assume she never practiced that in her life before, right? And yet, she did it really, really well. And then this went on as a lab bet in a way that I said to my students, "Okay, we have to make this into an experiment, put it in an experimental setting, and quantify what's going on." And they all said that it would be uninteresting. That was the bet. And I told them it would be in Nature, which is a bet I won in this case.

Andrew Huberman:
Nature, of course, being one of the three apex journals in science.

Dr. Noam Sobel:
It was Nature Neuroscience, to be fair.

Andrew Huberman:
Yeah.

Dr. Noam Sobel:
So then we turned it into an experiment, and what the experiment was, is that we brought in participants, naive participants, not graduate students from our lab, completely deprived them of any other sensory input. So we blocked their eyes, we blocked their ears, we blocked everything. They were wearing heavy gloves. They couldn't sense anything. And we generated a consistent odor path in the grass, which is what you saw. We did that by burying twine under the grass, an odor-impregnated twine, so that way we could generate a consistent odor trail every time.

Andrew Huberman:
Was it at the base of the grass or in the dirt itself?

Dr. Noam Sobel:
It was buried under the grass.

Andrew Huberman:
Really?

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
Wow.

Dr. Noam Sobel:
And-

Andrew Huberman:
I did not know that

Dr. Noam Sobel:
... it was buried under the grass, and we conducted aerial photography, and participants also had this sensor pack that they were wearing, where we measured nasal airflow in each nostril in real-time. And, we also used something called RTKGPS, which is a way to lay a radio frequency grid over the GPS grid so that you have millimeter resolution in space, basically. It's used by surveyors mostly, so that we could track behavior. And we found a few things doing this. One is that people could just do this right off the bat. The second thing we found that is when we trained them up, then within average of four days, the rate-limiting factor became the speed at which they could crawl. So as fast as you could crawl, you could scent track. Of course, you can't crawl as fast as a dog can run, but as fast as you can crawl, you can scent track. And then to sort of add what made it really interesting from a systems neuroscience perspective is that we asked whether having two nostrils contributes to this. So we built, we constructed a nasal prosthesis, if you will, that had two versions. One is that it combined both nostrils into one big nostril, centered, and the other is that it maintained two separated nostrils. And we compared performance under these two conditions, and people performed better with two nostrils over one centralized nostril, although the flow remained the same. So you're taking advantage of the information that comes from your two separate, totally separate nostrils. By the way, the system I described before of your epithelium and bulb and connection to cortex, you have two of those, right? It's a completely unilateral, well, almost completely unilateral system. There are some very small exceptions to that, but-

Andrew Huberman:
So a representation on both sides of the brain. Much in the same way we have two eyes, we're not a Cyclops. We can gain depth perception information, we can perceive motion better as a consequence, and a number of adapt, especially stereopsis.

Dr. Noam Sobel:
And we can locate sound because of the difference between our ears and how the head blocks them between and-

Andrew Huberman:
Amazing. Another question about the mechanics and strategies that you observed, because I think there's information about the system, the brain, as a consequence. Were you in a position to measure sniffing frequency? And the specific question I have is, were people doing something along the lines of a quick sniffing, or a like a long-

Dr. Noam Sobel:
Right

Andrew Huberman:
... drawl inhale?

Dr. Noam Sobel:
So, yes, we were measuring sniffing and recording it, and we have all the data. There was nothing very remarkable in that data, in that study, although it may reflect that we didn't analyze it carefully enough as well. It wasn't a major component of our analysis, although we did look at it, to some extent. Again, you're asking me about a paper from quite a few years ago, so I may be forgetting parts of it as well. But-

Andrew Huberman:
I'm sure if it was a major component of it, it would've risen to the top.

Dr. Noam Sobel:
It definitely wasn't a major finding-

Andrew Huberman:
Mm-hmm

Dr. Noam Sobel:
... the sniffing behavior in the paper. Although again, sniffing behavior is a huge portion of our life in lab. And it's taking us to places, and it's re-emerging now in our work. We're doing tons of sniffing work. I can share with you something that I think will interest your listeners and viewers as well, and we think is really one of the most overlooked things in neuroscience.

Andrew Huberman:
Please do.

Dr. Noam Sobel:
I'll invite you to do the following experiment.

Andrew Huberman:
Okay.

Dr. Noam Sobel:
So occlude one nostril by pressing on it from the side and sniff in. And then occlude the other and sniff in. Do you sense a difference in flow?

Andrew Huberman:
Yes.

Dr. Noam Sobel:
Okay. Do you know why that is?

Andrew Huberman:
No, and it was the next question-

Dr. Noam Sobel:
Okay

Andrew Huberman:
... on my list, so-

Dr. Noam Sobel:
Then don't feel badly about not knowing why that is.

Andrew Huberman:
Mm-hmm.

Dr. Noam Sobel:
Most people don't. But that is a reflection of something referred to as the nasal cycle. So in fact, if you were to do that repeatedly, you would find that your high-flow nostril and low-flow nostril alternate every two and a half hours on average.

Andrew Huberman:
In an absolute way, or is it like a sine wave, like gradual shift to the one and then gradual shift back?

Dr. Noam Sobel:
It can vary.

Andrew Huberman:
Mm-hmm.

Dr. Noam Sobel:
It can vary, and we don't yet know all the rules. But you have this constant shift from side to side. The shift becomes incredibly pronounced in sleep, so we can measure the power of the difference. And in sleep, you have this phase shift of power. You have a huge... One closes and one opens totally. And it turns out that this is linked to a balance in the autonomic nervous system. So as you and your listeners know, we have an autonomic nervous system that has a sympathetic and parasympathetic component to it, and they're in balance or imbalance in many diseases, for example. And this interplay between the sympathetic and parasympathetic nervous system drives the switch from left to right nostril.

Andrew Huberman:
Just to remind people, sympathetic nervous system has nothing to do with sympathy- ... has everything to do with generating patterns of alertness. It's sometimes called the fight or flight system, but any pattern of arousal, positive or negative, and then it's balanced in a coordinated way or at least in parallel with the parasympathetic nervous system, which is sometimes called the rest and digest system, but is associated with all sorts of things, the sexual arousal response, and a number of other aspects of our physiology. So think of it like a seesaw of alertness and calm. Yeah.

Dr. Noam Sobel:
Perfect. So now imagine you would walk around living your life, right? Half of the time with one eye closed like this and the other half with one eye closed like this, and you had this eye cycle, right? And that was linked to autonomic arousal. I assure you, you would go to PubMed, there would be 5 million papers on the eye cycle, right? And the eye cycle in every disease you can name and what it denotes and what it tells us and what we can do with it. You have exactly this marker. You're walking around with a marker on balance in your autonomic nervous system, and we do nothing with it. So we're in fact now doing a lot with it. Okay, so we built a wearable device that is pasted to your body and measures airflow in each nostril separately and logs it for 24 hours. And we're collecting these 24-hour recordings. We're calling it the nasal halter. So we measure with the nasal halter, and we're finding it is a disease marker. I can give you a nasal halter measurement as an adult, and I can say, this is work by Tim Nasserroka, a graduate student in our lab now. So we can tell the difference between ADHD and non-ADHD adults, and we can tell just from the recording, we can tell if the adults are on Ritalin or not. So I can measure your nasal airflow and say if you are or are not with ADHD and if you are or are not on Ritalin.

Andrew Huberman:
Incredible. I have a couple of questions about this. Is it the case that airflow through one nostril is reflective of a sympathetic nervous system dominance versus parasympathetic?

Dr. Noam Sobel:
Yes.

Andrew Huberman:
Or is it simply the case that this alternating left-right nostril periodicity, which you said I think is on the order of about every two hours-

Dr. Noam Sobel:
Two and a half

Andrew Huberman:
... two and a half, it switches to maximal on one side versus the other. Is that simply reflective of an overall balancing? Maybe is it the hinge in the seesaw, or is it the tilt of the seesaw?

Dr. Noam Sobel:
So I don't have a good answer. I could say that to some extent, right nostril more open is more sympathetic and the left nostril more open is more parasympathetic, but that wouldn't be very correct. I mean, it's a super-

Andrew Huberman:
I'm sure that the yogis are going to be all over this, right?

Dr. Noam Sobel:
So, right. I have to-

Andrew Huberman:
Because I get this quite-- My lab does do some stuff on breathing, and the yogis are always saying, okay, because there's this thing... I don't do yoga anymore. Not for any particular reason-

Dr. Noam Sobel:
Pranayama

Andrew Huberman:
... but where they'll have you breathe through one nostril or the other, and I've probably been asked this question on social media 10,000 times.

Dr. Noam Sobel:
Okay, wait. I'm going to become public enemy number one of the yogis right now. So listen, so we-

Andrew Huberman:
They'll come at you with yoga mats, which are not very dangerous.

Dr. Noam Sobel:
So since we're so interested in this mechanism, one of the things we'd really like to know how to do is to gain control of it somehow. And there's this world out there of yoga who claims to have control over this. So we said, "Okay, let's bring really serious yoga practitioners and see if they can shift their nasal cycle from left to right, but by will alone, right? Not by manipulating themselves somehow. And if yes, we'll learn from them how they do this, and then we might use this to cure ADHD or whatnot, right?" So we posted on all the lists of the yoga teachers and had this parade of yoga teachers walking into our lab. This was one of the strangest experiments.

Andrew Huberman:
A lot of sandalwood odors and bare feet.

Dr. Noam Sobel:
Exactly.

Andrew Huberman:
You know?

Dr. Noam Sobel:
White clothing and so on. And so we studied 14 yoga teachers. All 14, by the conditions of enlistment for this, came in saying that they can control shifting from left to right nostril.

Andrew Huberman:
Without plugging a nostril with their finger.

Dr. Noam Sobel:
Yeah, by the power of thought alone.

Andrew Huberman:
Yeah.

Dr. Noam Sobel:
And you know how many of 14 succeeded? Zero. Including one, the most extreme one was we had this guy And we're recording, and we know how to record this really well, right? And he's sitting there saying, "Yeah, I'm switching now, and it's switching." And you're looking at the monitor and, no, it's not switching. And so no yoga teacher that we found could willfully switch between left and right nostril flow.

Andrew Huberman:
And yet they are convinced that they are, and I have to imagine there's no incentive for them to lie, right?

Dr. Noam Sobel:
Yeah. No, even the opposite. This puts them in an awkward position once... Yeah, I don't know what the deal is, but none of them can do it.

Andrew Huberman:
Given that the alternating flow through one or the other nostril is reflective of the autonomic nervous system, has this two-and-a-half-hour periodicity, if I suddenly enter a bout of stress, for instance, does it switch? Because that's reflective of the autonomic nervous system.

Dr. Noam Sobel:
Yes.

Andrew Huberman:
And the reason I'm asking this question is not because I think that's necessarily important as it relates to stress, but I'm trying to understand the direction of causality. In other words, is the-

Dr. Noam Sobel:
As are we

Andrew Huberman:
... the unilateral nostril smelling periodicity, we named it something. I named it the wrong thing, I'm sure. Is that driving the shift in the autonomic nervous system, or is it merely reflective of the shift?

Dr. Noam Sobel:
So you've very concisely now worded aim two of a grant that was probably just rejected. But basically, we're trying to answer exactly that question, and we're currently running experiments on that line. So we have one experiment where we're exposing participants to pain. We're using cold water hand exposure. It's a really cool paradigm because there's huge individual differences. We just started this. We built the setup just now, and you have a lot of meat to work with there because there's a lot of individual differences. It's capped at three minutes, so for safety reasons, because you have participants putting their hand in two-degree Celsius water. But there'll be participants who will pull it out at 10 seconds, nine seconds, and then you'll have three minutes as well. So there's lots of... And so now I'm sharing pilot data with you-

Andrew Huberman:
Got it

Dr. Noam Sobel:
... so when this ends up being published, it might be the opposite, but so far it seems that the exposure to cold generates a shift in nasal balance.

Andrew Huberman:
So autonomic arousal can drive the shift, potentially. Earlier, you were describing the architecture of these smelling systems, and you mentioned these glomeruli where the olfactory receptors converge-

Dr. Noam Sobel:
Right

Andrew Huberman:
... in the bulb. And then later you mentioned that the system is unilateral, but with a mirror representation on both sides of the brain. So for those who don't think in terms of neuroanatomy, what Noam was describing is the fact that, of course, there are two nostrils and then a bunch of receptors. They converge in these glomeruli, but you have a mirror representation of that on both sides of the brain, and that most of that information is kept on one side of the brain or the other. There isn't a lot of extensive intermixing at the first order of processing.

Dr. Noam Sobel:
Right.

Andrew Huberman:
So the question I have is whether or not you believe, I'm not asking for data. First, I just want to know what you believe, that this alternating nostril airflow phenomenon has anything to do with preferential processing of olfactory information in terms of right brain, left brain, with the caveat that anytime we hear right brain, left brain, we've covered this in a previous episode, most of what people hear out there about right brain, left brain, emotionality, logical stuff, is completely wrong. Doesn't exist, is a total fabrication, and we'd like to abolish that myth. But with that aside, or set aside rather, what are your thoughts on why the information would switch from one side of the brain to the other at all?

Dr. Noam Sobel:
Yeah. I don't think that the nasal cycle is an olfaction story. So I don't think that this was shaped by the olfactory system, nor do I think this has a major impact on olfaction. I think the nasal cycle story is a different story about brain function. So we have this sort of pet theory we're calling now the sniffing brain approach, where basically we think that nasal inhalation is timing and driving a lot of aspects and patterns of neural activity and cognitive processing. And this theory is olfaction-inspired in its beginning. If you think of the mammalian brain, which evolved from olfaction, it's sitting there, and in olfaction, because olfaction depends on sniffing, you have this situation where you have a sniff, you have information, and then flat, nothing. Right? And then you have information, and then nothing. So information processing is one-to-one linked to nasal inhalation, and we think that this property evolved to be meaningful in brain processing in general, not only of olfactory information, but of any type of information because the brain evolved in this way, in this way that it processes information on inhalation onset. So a study led by Ofer Peril from our lab, two, three years ago, we looked at something completely non-olfactory. We looked at visual spatial processing, and we compared visual spatial processing on inhalation versus exhalation. And the brain does this completely different on inhalation versus exhalation. In that particular task- People performed significantly better on inhalation versus exhalation.

Andrew Huberman:
What was the task? Was it an olfactory task?

Dr. Noam Sobel:
No, no, it's a visuospatial task.

Andrew Huberman:
Oh, excuse me, yeah.

Dr. Noam Sobel:
So this is a task where the specifics of the task were that you see a shape, and you have to determine if it's a shape that can or cannot exist in the real world. So some of them were these Usher shapes, where one facet doesn't reach the other facet.

Andrew Huberman:
The impossible figure type stuff.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
Yeah.

Dr. Noam Sobel:
But structural shapes.

Andrew Huberman:
Mm-hmm.

Dr. Noam Sobel:
And so a pure visuospatial task. We intentionally went for a task that is not considered a ventral temporal task, an olfactory cortex task in any way. And people performed much better on inhalation versus exhalation at doing this task.

Andrew Huberman:
Was there a both nostrils occluded version where people were forced to mouth breathe?

Dr. Noam Sobel:
Yes. And in this particular task, they also did better on mouth inhalation versus mouth exhalation. But the difference wasn't as pronounced as it was with nasal inhalation versus exhalation.

Andrew Huberman:
So, I'm a big proponent of nasal, not mouth breathing whenever possible-

Dr. Noam Sobel:
For sure

Andrew Huberman:
... for many health-related reasons. I'm a big fan of the book "Jaws: A Hidden Epidemic" written by colleagues of mine at Stanford.

Dr. Noam Sobel:
Familiar with it.

Andrew Huberman:
Yep. And this idea that people who mouth breathe experience more colds, more infections of various kinds. It's not good aesthetically or for the dentature. I never know... The teeth, the gums. It's stuff, folks.

Dr. Noam Sobel:
Yeah. Stuff.

Andrew Huberman:
Sorry, my dentist is going to come after me. Need to go to the dentist anyway. The nose breathing is great for your health relative to mouth breathing.

Dr. Noam Sobel:
So I think it's also good for your cognition, not only for your dental health. I think that nose breathing shapes cognition, and there are other labs who are finding the same. Again, Cristina Zelano is doing work on this line. She had major contributions here and Johan Lundström is doing work on this line. There's lots of studies suggesting that nasal inhalation is timing cognitive processing and modulating it.

Andrew Huberman:
Incredible. Perhaps not surprising given what you've taught us about the olfactory system. These two holes in the front of our face, these nostrils, are a pathway to the brain, right? I love to tell people, because I work on the visual system in my lab, that your eyes are two pieces of brain extruded from the cranial vault-

Dr. Noam Sobel:
Right

Andrew Huberman:
... which they are. The retinas anyhow. And then you never look at anyone the same way again. It's okay. But the olfactory sensory neurons are right there at the tops of those caverns that we call nostrils, and they are brain.

Dr. Noam Sobel:
Yeah. Definitely. It's the only place where your brain meets the outside world, because in your retina, they're protected by a lens.

Andrew Huberman:
Mm-hmm.

Dr. Noam Sobel:
And here you have neurons in contact with the world. This actually has been the source for some theories on a potential route for neurodegenerative mechanisms. So, as you may know, loss of the sense of smell is one of the, if not the earliest sign of neurodegenerative disease. So, for example, in Parkinson's disease, there's a loss in the sense of smell probably 10 years before any other symptom. But people have failed to make this a diagnostic tool because it's nonspecific. So it's not as if you could come to your doctor and say, "I'm losing my sense of smell" and they'll say, "Oh, early sign of Parkinson's." Because you can have many reasons to lose your sense of smell and so on. But olfactory loss, again, is an early sign of neurodegeneration, and there's at least one theory, particularly about Alzheimer's disease, suggesting that Alzheimer's may be the result of a pathogen that enters the brain through the olfactory system.

Andrew Huberman:
Hmm. Oh, interesting.

Dr. Noam Sobel:
It's not, of course, a mainstream or widely accepted theory of any type, but it just highlights this notion that the nose is a path to our brain.

Andrew Huberman:
I think these non-invasive readouts of potential neurodegeneration, such as visual tests, because of the fact that the retinas are part of the brain, and loss of neurons in the retina is often associated with other forms of central degeneration, Alzheimer's, Parkinson's, et cetera. As it's a little more invasive than what you're describing, I'm beginning to wonder why we don't have a olfactory task every time we go to the doctor that would allow tracking over time. Because, of course, as you mentioned, someone can lose their sense of smell. Does that mean they're getting Alzheimer's? Not necessarily. But if their sense of smell was terrific the year before and it's 50% worse the next year-

Dr. Noam Sobel:
That's a really bad sign

Andrew Huberman:
... yeah, that's a bad sign. And so what we're talking about is something completely non-invasive, and could be relatively pleasant to innocuous-

Dr. Noam Sobel:
Right

Andrew Huberman:
... depending on the odors used.

Dr. Noam Sobel:
So yeah. So first I can answer that, right? And the reason that that's not happened, and that may be changing right now, but the reason that has not happened is because olfaction has not been effectively digitized, right? So if you need to generate really precise visual information, you can buy a monitor for 100 bucks that is at the resolution of the visual system, basically. And if you want to generate auditory stimuli really precisely, then you can buy an amplifier for maybe a bit more than 100 bucks, but not that much more. And you'll be at the resolution of the auditory system. In our lab, we build devices that generate odors. We call them olfactometers, which is a misnomer because they don't measure anything, but that's what they've always been called, so we call them olfactometers as well. And we've already built at least one olfactometer that cost a quarter of a million euro, and it's pathetic. So it's pathetic. It's slow, it's contaminated, it's nowhere near the resolution of your system. So one of the reasons that's not happened is just the utterly poor control of the stimulus. Mind you, to some extent, it has happened in that there are standard clinical tests of olfaction, basically two that sort of control the world in this respect. The older one is a test called the UPSIT, which stands for the University of Pennsylvania Smell Identification Test. It was developed by Richard Doty in Penn, and it's a test where you scratch and sniff, and it's a four alternative forced choice test with 40 odorants. So you have these 40 pages that you page through and you sniff and smell and it's been normed on gazillions of tests. I'm always amused by it because, so Richard Doty made a ton of money on the UPSIT, but he needed it because he has a habit. He has a NASCAR. So every time we buy UPSITs in the lab, I say, "There's another gallon of gas into Richard Doty."

Andrew Huberman:
He races NASCAR?

Dr. Noam Sobel:
Not like NASCAR, but one lower than that. I don't know, some sort of Formula A or Formula Ford or something. He races a car, and so that's where all the UPSITs went. So I always feel good about buying UPSITs because I know they're going to that good cause. But-

Andrew Huberman:
Keeping him in the fast lane.

Dr. Noam Sobel:
Yeah. But so that's one test that's out there and indeed has been shown as a-- so there's reduced UPSIT in Alzheimer's and Parkinson's and in a host of other diseases.

Andrew Huberman:
Mm.

Dr. Noam Sobel:
And there's a European version called Sniffing Sticks that Thomas Hummel has developed, and it's basically the same sort of concept of ... That one isn't scratch and sniff. It's like these pens that you open up and sniff. But those exist, but they're not as convenient as delivering stimuli in vision and audition, and that's why you don't have what you've just suggested.

Andrew Huberman:
Interesting.

Dr. Noam Sobel:
Another place where you don't have it, which I think would've been even more meaningful is olfaction is not tested in newborns. Where vision and audition is. There's this thing called congenital anosmia, which is being without the sense of smell from birth, supposedly. Congenital , which is a half a percent of the population.

Andrew Huberman:
It's not a trivial number.

Dr. Noam Sobel:
Not totally, yeah. But nobody knows if that really is true because here's an amazing factoid. Guess the average age at which congenital anosmia is diagnosed, and this is a horrible statistic for me, for the way I see the world. But what do you think the average age of diagnosis is for congenital anosmia?

Andrew Huberman:
Five years of age?

Dr. Noam Sobel:
Fourteen.

Andrew Huberman:
Incredible.

Dr. Noam Sobel:
Fourteen.

Andrew Huberman:
So most people who are one half of a 1% of the human population, presumably-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... is without the sense of smell and doesn't realize that until they're 14 years old.

Dr. Noam Sobel:
Well, I don't know when they realized it first, but it's formally diagnosed at 14 on average. Which means some of them even later, right? After.

Andrew Huberman:
And right. It's a distribution. Do they suffer?

Dr. Noam Sobel:
Yes. So first of all, they suffer socially. And there's a host of deleterious life events associated with congenital anosmia. They die younger. This is work out of Ilona Croy in Germany. And amongst the various things that are predicted by anosmia is shorter lifespan. But things like reduced social contacts, reduced romantic social contacts. It's not a good thing.

Andrew Huberman:
And do they lack olfactory bulbs? I'm presuming they have noses and nostrils.

Dr. Noam Sobel:
They have noses.

Andrew Huberman:
There is a condition I'm aware of where children are born without noses and nostrils.

Dr. Noam Sobel:
Those are rare.

Andrew Huberman:
Very rare.

Dr. Noam Sobel:
Yeah. Those are rare things.

Andrew Huberman:
Very rare. We won't focus on that because it's exceedingly rare.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
So-

Dr. Noam Sobel:
But they're born with noses and nostrils. And here's the thing, we don't know if they're born with olfactory bulbs. Most of them, although not all of them, but most of them don't have olfactory bulbs in adulthood. Or I should rephrase that, have remnant olfactory bulbs, really shriveled olfactory bulbs. But nobody can say the cause and effect here.

Andrew Huberman:
Before we talk about the role of the requirement for olfactory bulbs for olfaction, a very interesting topic in its own right. I'm curious as to whether or not their endocrine system is altered, because as we'll soon talk about, there's a lot of signaling through the nose-

Dr. Noam Sobel:
Right

Andrew Huberman:
... from between individuals that triggers things, everything from the onset of puberty to feelings of romantic attraction, attachment, these sorts of things.

Dr. Noam Sobel:
Right.

Andrew Huberman:
Is it known whether or not-- And I should say, excuse me for interrupting myself, but as long as I'm interrupting you every five minutes, I might as well interrupt myself, too. That we are well aware of the proximity of the olfactory system to some of the hypothalamic systems that regulate the release of gonadotropins-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... which control testosterone and estrogen production, et cetera. So, are they hormonally normal?

Dr. Noam Sobel:
So some are and some aren't, and I'll be specific. So there is a condition known as Kallmann syndrome.

Andrew Huberman:
Mm-hmm.

Dr. Noam Sobel:
Which is hypogonadic development in men. And in Kallmann syndrome, they're practically all anosmic. So, to answer your question, yes, there's a direct link, and it materializes in Kallmann syndrome. That said, not all congenitally anosmic individuals have Kallmann syndrome, and not all, but almost all people who have Kallmann syndrome are anosmic. So, Kallmann syndrome goes with anosmia. I think there's a female equivalent of Kallmann's, or I don't remember its name.

Andrew Huberman:
It's not in the Turner syndrome family, is it?

Dr. Noam Sobel:
I'm not sure.

Andrew Huberman:
Okay.

Dr. Noam Sobel:
And I think it's also associated with anosmia, but I'm not confident of that. But Kallmann's is associated with anosmia. So the answer is yes. And olfaction and reproduction are tightly linked, and they're tightly linked in all mammals. And we are big terrestrial mammals, and olfaction and reproduction are linked in humans as well.

Andrew Huberman:
Yeah, we will definitely get into that. I have a story/question that I'd like to tell you, ask you, as a segue to that, noting, of course, that we'll get back to the requirement for olfactory bulbs, yes or no, for olfaction. And this relates to when I was growing up, I grew up at the end of a street with a lot of boys of my age, who, just by coincidence, had a lot of older sisters that were my older sister's age. It was fortunate, so I had a lot of kids to play with. We would hang out at each other's houses, bike, build jumps, and do all those things, like kid stuff, fort stuff, get into trouble or whatnot. And oftentimes, we would end up leaving our articles of clothing at each other's houses all the time, like T-shirts and jackets, and so my mom was constantly coming in and saying, "There's these clothes. Someone left this here. I don't know who it was." We were all more or less the same size. And from as far back as I could remember, six, seven years old and onward, I could pick up a shirt or a jacket, smell it, and say, "Oh, well, that's Eric Eisenhart's shirt." A friend of mine there, I just gave his name. Or, "Oh, that's Scott Matson's shirt." I could just smell the shirt, and in a conscious way, know who it belonged to, having never, I promise, not that I would pretend I hadn't if I had, but having never actually done the exercise of going and taking and smelling my friend intentionally.

Dr. Noam Sobel:
Right.

Andrew Huberman:
Okay? In fact, if anything, I had all the reasons in the world to avoid smelling the other young boys-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... in my neighborhood. Okay, so-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... that raises a question of whether or not we are consciously and/or subconsciously coding identification of people that we interact with frequently or infrequently in terms of their smell, or some other aspect of their chemistry.

Dr. Noam Sobel:
Yeah. So yes. We're doing that all the time, in my view, and a lot of this processing, almost all of it, is subconscious, and I don't know why. I'll already put that out there. I have no idea why human nature, or nature or culture or whatnot, has pushed this into the realm of subconscious and something we're unaware of. But we do it all the time, and our lab has lots of studies on this front. One of them you may be familiar with that had gained some notoriety because it's amusing. So, we look at human behavior a lot. We try to look at it through our nose in the way we look at what people are doing. We try to think, "If I was a dog, what would I think of this?" And if you look at dogs, when they interact, they visibly sniff each other. It's very obvious. They walk up to each other, and they sniff each other. And yet humans don't typically walk up to a stranger and carefully sniff them, right? I mean, we're sort of obliged to sniff our babies. That's considered almost something you're supposed to do.

Andrew Huberman:
Mm-hmm.

Dr. Noam Sobel:
And it's not culturally taboo to sniff our loved ones. It sort of doesn't seem like an odd thing to do. But we don't sniff strangers, right? Well, or do we? So we're finding more and more mechanisms where we do this, and the one I'm referring to now for one example is we started looking at handshaking. Handshaking is this really odd behavior, and it's not only in the West, by the way, as some people think that it's only a Western thing. It's not. It's almost everywhere. And there's really poor understanding of how this behavior evolved, like where did this thing come from? So if you look for the Wikipedia version, then they'll tell you that it's to show that you're not holding a weapon in your hand. But there's really no good evidence for that. It's a bit like the trillion bloodhound receptor story. I mean, we tried to find it. Why do people say that? They just do. And we started looking at people handshaking, and we noticed, or it seemed to us that we're noticing, that people will shake hands and then go like this and like this.

Andrew Huberman:
For those of you listening, not watching-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... Noam is taking his hand and wiping it on his face.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
Rubbing his nose or-

Dr. Noam Sobel:
Touching myself

Andrew Huberman:
... touching the side of his cheek.

Dr. Noam Sobel:
Yeah, these things that we do all the time.

Andrew Huberman:
After a handshake.

Dr. Noam Sobel:
Well, so first of all, we do them all the time just period. The baseline here is really high, and we'll get to that in a second. But these behaviors that you could easily not notice. And so we asked whether that's a real thing. And this was a study led by Dan Frumin in our lab at the time. And what we did first, and if you want, we can link. So this was published in eLife, and one of the nice things about eLife is that it has a very effective way to embed videos in the publication. So if you want, we can link this to your system later on, the eLife-

Andrew Huberman:
We put it in the show note captions as a link on YouTube and the other four platforms, Spotify, Apple

Dr. Noam Sobel:
So what we did is we brought in participants to our lab, and we sat them in the room, experiment room, and told them the experiment would start soon and they should wait for us there. They didn't know what they were coming from. Unbeknownst to them, they were already being videoed. Of course, later on, they had the opportunity to not agree to us saving the video, in which case, we would delete it immediately, or letting us use it for science, or some letting us use it for more than science, for the video that's now on eLife. And we would walk into the room and say, "Okay, just wait here. We'll be right back with you to set up our experiment." And they would sit there for three minutes, and during those three minutes, we could later quantify how much indeed they, just by baseline, how much they touch their nose or their forehead or their chin, or how many times their hand reaches their face. And by the way, that baseline is not low. Okay? And then three minutes later, an experimenter would walk into the room and would share a consistent text. It would be, "We're still setting up our equipment in the other room, and so just wait here and we'll be right back with you. But in the meantime, just wait here." And the experimenter went through this 20-second fixed text, and in half of the cases, it included a handshake. This was a new experimenter, not the one who put them in the room, so it's the first time they met. So it would be, "Hello, I'm so-and-so." They would put out their hand and shake their hand or not. Okay? And we did all possible interactions in terms of gender, so we matched male participants with male and female experimenters and female participants with female and male experimenters, and so you had handshake and no-handshake conditions, and then you can quantify that behavior of the hand going to the nose after a handshake. And there was a remarkable increase in the hand going to the nose after a handshake. And this is one of the nice cases. The paper includes statistics, but you don't need statistics here. Just look at the video. It's unreal. The video is unreal.

Andrew Huberman:
So interesting.

Dr. Noam Sobel:
So the hand goes to the nose. Now, we did a few controls here to verify that this is an olfactory behavior. One is, unbeknownst to the participants, we measured nasal airflow. And people not only bring their hand to their nose, they sniff it. So, and this is perfectly timed. They go like this, okay? So they're sniffing their hand. And in an additional control study, we manipulated it. So we built this little James Bond thing of a watch on the experimenter's hand that could emit an odor. And the experimenter didn't know what odor they were emitting, and they could emit either a pleasant or an unpleasant odor, and we could drive the self-sampling afterwards up or down. So this was an olfactory behavior, no doubt about it. We're quite confident that-

Andrew Huberman:
So people, in that case, people must have been sensing the odor on their own hand because they had shook the hand of the experimenter, pleasant odor, and they're more frequently bringing that hand to their nose versus unpleasant odor that had been introduced to their own hand by the experimenter. Correct?

Dr. Noam Sobel:
No, I think they were sensing the ambient odor that came in with the hand that shook, and then that either drove them to sniff their hand more or less.

Andrew Huberman:
The odor cloud-

Dr. Noam Sobel:
And-

Andrew Huberman:
... of the experimenter.

Dr. Noam Sobel:
Yeah. And there's an interesting thing going on here too, because people didn't only smell the hand that shook, they also smelled the other hand. And we think that there's something going on here comparing self to other, and we think a lot of self-sampling might reflect that. There's, on the same line, and again, to link to your childhood story of identifying your friends by smell, a study we published just last year by Inbal Ravrebi in our lab, where Inbal came with this basic interest in this phenomenon that's loosely referred to as click friendships. So people you meet, and you click right away, right? You immediately become close friends. And this is a phenomenon that is poorly described in literature as an entity, and yet anybody will tell you they know what you're talking about, right? If somebody you click with right away, you become intimate within five minutes, right? Everybody experienced this in their life, to some extent. And the question is, what was there, right? What was it? Was it because you look the same? Could be. Was it because you had the same sports team that you liked, or is there something deeper here? And Inbal's theory was that a similarity in body odor may contribute to this, that people who smell the same will click in some way. And so to address that, she actually recruited click friends from all over Israel. She posted all over social media to identify pairs of friends. So these are same-sex, non-romantic dyads. So these are friends, men and women, whose friendship started as a click, where here this becomes sensitive because it has to be a mutual click, right? Later on, we discovered there could be one-sided clicks. So somebody's sure they clicked with somebody else, but the other person-

Andrew Huberman:
There's a name for that in neurology that our common friend, the late Ben Barres, taught me, which is there's a phrase that neurologists use-

Dr. Noam Sobel:
Okay

Andrew Huberman:
... called sticky. These are people that come up to you and-

Dr. Noam Sobel:
Mm-hmm

Andrew Huberman:
... start asking you questions and then won't leave you alone. They're so-called sticky people.

Dr. Noam Sobel:
Okay.

Andrew Huberman:
And if you ask these sticky people, sticky in air quotes because they're not physically sticky-

Dr. Noam Sobel:
They may be

Andrew Huberman:
They could be. "What do you think of this person?" They'll say, "Oh, they're great. We're really good friends." And so they've made a unilateral clique friendship.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
And yes, neurologists are talking about you. If you're one of these people, neurologists are talking about you. There's an informal diagnostic code, sticky.

Dr. Noam Sobel:
So she recruited clique friends, and then she sampled their body odor. And we have a protocol for this. So they're given an odorless shampoo and soap to use for three weeks or something, and then they sleep two nights in this T-shirt where they have to sleep alone, and then we extract the body odor from the T-shirt. And so we have a method to extract body odor. And then she first asked whether indeed clique friends are more similar in their body odor than you would expect by chance. And she first tested this with a device, a machine we call an electronic nose. So an electronic nose is sort of a very poor effort to mimic what the mammalian nose does. Basically, it's a bunch of sensors that respond to airborne molecules, in this case, sensors referred to as MOxSors, as metal oxide-covered sensors. And so she used an electronic nose to sample these body odors, and she found that clique friends are indeed more similar to each other than you would expect by chance, by random dyads. And this was a significant difference. And after she found that a device could do this, she had other participants do this. So she had people smelling the clique friends versus non-clique friends, and they judged them as being more similar to each other than not. Now again, you might wonder, is this causal or not, right? Because maybe clique friends go to the same restaurant together all the time or whatever, or live in the same neighborhood, and that's why they smell the same. So to address causality, she recruited total strangers, and first smelled them with the electronic nose, and then engaged them in a social interaction, something called the mirror game. So in the mirror game, one person moves their hands, and the other person is really close to them, like right here, so they can smell each other, and has to move their hands with the other person. And one prediction there panned out, but another didn't. The one that didn't, so she predicted that people who would smell more similar to each other would be better at the mirror game. That is, they would follow each other better. That did not pan out. However, the interaction was completely non-verbal. They were not allowed to speak with each other, and she did an entire round robin, so everybody played with everybody else. This was an insane experiment to run. And she then, at the end of the experiment, each person rated each other person as to how much they think they would want to be their friends, and also on a bunch of ratings, how nice they think they are, how affectionate they think. A bunch of ratings, okay? All of this was predicted by the electronic nose. So people who smell more similar to each other think that the other person is more likely to be their friend, is more likely to be a nice person, et cetera. So we could actually predict friendship using the electronic nose. So this is not a result of friendship. It plays into the causal elements of building friendship. So this is to relate to your childhood story. There's something going on here. We're constantly smelling ourselves, constantly. Constantly. The reason I'm smiling, and your viewers or listeners will understand why I'm smiling, I'll send you a video to link into your podcast here. The fact that people constantly sniff themselves, we thought of calling this the Low effect. So in America, this won't pass effectively, but in the rest of the normal world, Joachim Low is the national soccer coach of the German soccer team. So, I don't know who would be a very famous coach here, but Steve Kerr.

Andrew Huberman:
Good choice.

Dr. Noam Sobel:
This is a super, super famous name all around the world where soccer is the primary sport that people watch. And once people will see this video, they'll understand why we thought of calling this the Low effect. It's very graphic. But people are constantly smelling themselves. They're smelling themselves with their hands. They're smelling themselves explicitly. People are constantly smelling themselves, constantly smelling others.

Andrew Huberman:
I find this topic so interesting. And first of all, confession, I definitely smell myself multiple times per day.

Dr. Noam Sobel:
Everybody does.

Andrew Huberman:
Okay, good.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
Well, then I would do it anyway. I think I, like most people, I either find my own smell to be neutral to pleasant, right? Occasionally I'll be like, "Whoa, I need to take a shower." As long as we're talking about smelling oneself and friendship, kinship, and its relationship to smell, we have to talk about the relationship between smell and romantic attraction and bond. So my understanding is that if, for instance, a mouse is given the option to mate with any number of other different mice, they will bias their choice toward the mouse that has the immune composition, the so-called MHC-

Dr. Noam Sobel:
MHC

Andrew Huberman:
... major histocompatibility complex-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... which reflects immune diversity, the immune system that is most distant from theirs. The evolutionary argument being that were they to produce offspring, that the array of immune genes would be much broader than if they were to select an animal very close to them. And in addition to that, that one of the most strongly selected against behaviors, not just culturally, but at the level of eliciting a sense of disgust maybe even from the activity of the hypothalamus, is mating with very close kin, AKA incest, because that, we know, produces a higher rate of mutations. In other words, whereas you described the relationship between smell and choice of friends as you choose people who smell more like you, my understanding is that in the context of choosing romantic partners or sexual partners or both, that you choose the person whose odor, and therefore immune composition, is most different.

Dr. Noam Sobel:
Right. So the way you describe the animal literature is correct, and there's evidence to similar mechanisms in humans. Our lab has not worked directly on this issue of romantic selection based on odor. There's a bunch of papers, Wedekind et al. and the Wedekind lab, and also Porter, I'll email these to you later on, that have done a lot of this work and find exactly as you say that romantic odor preferences in humans are influenced by body odor, and that this is linked to MHC, histocompatibility complex makeup of the portion of our genome that shapes our immune system to some extent. So this effect has been studied and reported on, again, extensively in mice and also in humans. Not work that we've done. The one sort of tangent work we've done, and I'd like to maybe tell you about, it relates to an effect that is one of the most remarkable effects in mammalian social chemosignaling. So it's not related to romanticism in any way, but it's related to reproduction. And indeed, in our lab, we've not looked at romanticism, we have looked at, or are looking at reproduction. They're not always the same.

Andrew Huberman:
Certainly. But they can.

Dr. Noam Sobel:
They can. Animal mammalian or terrestrial mammalian reproductive behavior is dominated by the sense of smell in mammals. And here, remember initially when we started off, I noted that there are several subsystems in our nose that transduce odorants, and so primarily the main olfactory system, which is cranial nerve number one, and the trigeminal nerve, which is cranial nerve number five. Most terrestrial mammals have another subsystem referred to as the secondary olfactory system that has a separate sense organ in the nose. This organ is known as the vomeronasal organ. It's a small pit in the nasal passage of most terrestrial mammals. Sometimes it's described as a communicating pit because sometimes it connects the nasal passage to the roof of the mouth. Sometimes it connects both. And so there's this sense organ with its specific receptor subtypes, VNRs, vomeronasal receptors, and this is linked to a sort of separate portion of the olfactory bulb, not really the main olfactory bulb, but it's referred to as the accessory olfactory bulb. And from there directly to the limbic system, to the portions of the brain that control reproductive behavior and aggressive behavior. And in most terrestrial mammals, this subsystem processes odorants that are sometimes referred to as pheromones, although that's in many ways a problematic term. But odorants that are referred to as pheromones, namely odorants that are emitted by another member of the species to influence that member of the species and alter behavior or hormonal state. And some of these pheromonal effects are utterly remarkable, and in my view, the most remarkable of all is an effect known as the Bruce effect. This was an effect discovered by Margaret Bruce in 1959. She was a British scientist. And in the Bruce effect, when you expose a pregnant mouse at an early critical stage of the pregnancy, I think up to about day three, if you expose the pregnant mouse to the odor of what is referred to in technical terms as the non-stud male, that is a male who did not father the pregnancy, she will miscarry the pregnancy. She will abort it. Now, that's an insane decision made by the female here, right? Because she's invested quite a lot in this, right, in biological terms, in forming this pregnancy and maintaining it, and yet she drops it on the basis of an odor. And this effect is remarkably robust. And what do I mean by remarkably robust? So this will occur on about 80% of exposures. Now, as you know, 80% is 100% in biology, right? There's nothing that happens at more than 80%. So it's a remarkably robust effect, this dropping of the pregnancy.

Andrew Huberman:
And we know it's mediated by chemosensation through the nose.

Dr. Noam Sobel:
We know for sure, and we know in the following way. So first, it's enough to just bring the odor of the non-stud male. You don't have to bring the male himself, right? So you just can bring bedding from a non-stud male, and that will induce the Bruce effect. But of course, the most telling set of experiments is that if in the female mouse you ablate the vomeronasal organ, you just burn this tiny structure in the nose, then the effect disappears. So the effect is completely dependent on the vomeronasal organ. And I find this utterly a remarkable effect. Again, because of the extent of cost that the female takes on here based on this information and smell. Now, humans, the going notion in olfaction is that humans don't have a functional vomeronasal organ. So we don't have that functional organ in our nose. Now, I'll point out, we actually do have the pit. So the structure or the outlining structure is there, but the pit that we have is considered vestigial and non-functional.

Andrew Huberman:
And what about this thing I learned about at Berkeley, in Integrative Biology class, that we have something called Jacobson's organ?

Dr. Noam Sobel:
This is the same organ. So Jacobson organ is the vomeronasal organ. It's also called Jacobson because I think Jacobson was a military physician in the 1800s in Holland or something, and he found it in a soldier he was operating on or something like that. The story comes from something like that. But Jacobson organ is another name for the vomeronasal organ. These are one and the same. The sensory organ of the accessory olfactory system. And again, the going notion is that the human Jacobson organ or vomeronasal organ is vestigial. It's non-functional.

Andrew Huberman:
Does that necessarily mean that we don't have these pheromone effects?

Dr. Noam Sobel:
No, it does not. So first of all, we know that lots of what are considered pheromonal effects, namely social chemosignaling in rodents, are mediated by the main olfactory system. We know that for sure. There are several examples for this in mice and rats and rabbits and so on and so forth. So A, these can be mediated by the main olfactory system, and I'll come back to that in a second. But first, to finish the Bruce effect. And second, and I'm going out on a limb here, but I'm willing to take that risk. For me, the jury is still out on human vomeronasal organ. The decision or the notion that it's non-functional relies on about one and a half papers postmortem, looking for the nerve that connects this thing to the brain and failing to find it, using staining and so on and so forth. But staining postmortem studies in humans are notoriously complicated. Basically, for many reasons, one of them is that the material has gone through... It's not ideally set as it is when you sacrifice an animal and study its tissue. So based on really a paucity of studies that fail to find this nerve, the notion is that the structure is vestigial in humans. I don't have any evidence that it's functional, mind you, but I'm just not sure that it's not. But what we do have a suspicion is that humans may experience something similar to Bruce effect. So first of all, humans have an enormous number or ratio of spontaneous miscarriage.

Andrew Huberman:
Are they occurring more often in the first trimester? Because you mentioned-

Dr. Noam Sobel:
Yes

Andrew Huberman:
... that in the Bruce effect in the mice is in the first three days or so following pregnancy-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... which in the mouse gestation, as I recall, is about 21 days in the mouse. So you're talking about one-seventh of total gestation, so I'm-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... I'm not quick enough to, nor is it important to translate, but this will be first trimester in humans.

Dr. Noam Sobel:
Yes. Which is indeed-

Andrew Huberman:
Early first trimester

Dr. Noam Sobel:
... when most miscarriage occurs. Now, humans have, again, a huge number of miscarriages, and the numbers, I'll soon share them with you. They sound odd, and the reason they sound odd is because if you have what's sometimes simply referred to as failed implantation, this can occur in days one, two. Nobody ever knows, okay? So some papers talk about 90% of all human pregnancies end in miscarriage. This is counting a failed implantation in day one, two, et cetera. More conservative studies talk about 50%. Nobody will argue 30%. Okay? So a huge number of human pregnancies end in miscarriage. Now, out of these, there's a portion that are unexplained. So nobody knows why. There are a portion that are explained by all sorts of genetic factors, developmental factors, and so on and so forth. But there's also a proportion that are unexplained. And so all I'm saying is that there's a statistical backdrop or setting, if you will, for something like a remnant Bruce effect in humans. Now, with that in mind, we enlisted a group of, they're not really patients and participants in a study of people who, or couples who are experiencing what is referred to as unexplained repeated pregnancy loss. So formally, if you have two consecutive unexplained miscarriages, then that is sufficient for the diagnosis of unexplained repeated pregnancy loss. However, in our cohort of 30, we had couples who experienced 12 consecutive unexplained repeated pregnancy losses. So the two is just the formal. All of our cohort was like 12, five. So this is an emotional, difficult place to be. And these are couples who are losing their pregnancy for no apparent reason. So they've gone through all the tests that you can imagine of genetic incompatibilities and all sorts of issues, clotting, all the known suspects for pregnancy loss. And the medical establishment remains totally at a loss as to why these pregnancies aren't holding. And so we hypothesized that perhaps here there's something akin to a Bruce-type effect. Obviously, it's not going to be the same as in mice, but something like a Bruce effect. Now, of course, at that stage, we could not do anything causal to test this, right? But what we could do is to seek circumstantial evidence to see if where there's fire, maybe there's smoke. And what we did was we tested olfaction, and more specifically, the response to male body odor in the couples experiencing repeated pregnancy loss. And we found a few things. First of all, if you think of the mechanisms behind the Bruce effect, the Bruce effect implies that the female has to have a very clear memory of the fathering male, because if she's going to miscarry in response to the non-father, she has to know father, non-father. That means that there's a pronounced olfactory memory at the moment of mating. Okay? And in mice, this has been very well-characterized and attributed to the anterior olfactory nucleus, a structure in the brain. But you'd have to have this memory in order to make that decision. Now, so to address that, and here you're going to see that you and your childhood story from before stand out a bit as skillful, is that the first thing we did was just behaviorally test whether these women and control women could identify the smell of their spouse. And you might be disappointed, or we would all are probably a bit disappointed to learn that control women are very poor at this. So you would think that women would be good at identifying the body odor of their spouse. They're not. They're not far from chance. However, the women who experience repeated pregnancy loss, they're double at their performance level. So this is not a nuance effect. Women who experience repeated pregnancy loss can identify their husbands' or their spouses' by their body odor.

Andrew Huberman:
With much greater acuity than the typical person?

Dr. Noam Sobel:
Double. A bit more than double, and way above chance.

Andrew Huberman:
Yeah. No, sorry, I posed it as a question, but I meant yes, with much greater acuity, and double is-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... a significant improvement. Are they much better at detecting any odor?

Dr. Noam Sobel:
No, they're not. We did the controls, and they're not. And then, using fMRI, we measured their brain response to stranger male body odor. And this was quite remarkable because we approached-- So this was a full brain analysis. So without a region of interest analysis, so it's not as if you're tweaking your statistics to look at one part of the brain. You're just looking at the entire brain in the response to male body odor and asking de novo, "Is there a difference between these two groups of participants?" And there was one huge difference, and it was in the hypothalamus. And so there was a difference in response to stranger male body odor between the two groups. So olfaction is altered in repeated spontaneous pregnancy loss. We don't know this is causal, right? But that was enough for us to approach the ethics committee to run a causal experiment, and we're at the beginning of that now.

Andrew Huberman:
Incredible. I can't wait to hear the results of that experiment.

Dr. Noam Sobel:
It'll probably take years.

Andrew Huberman:
Mm-hmm.

Dr. Noam Sobel:
A few. Because these are slow experiments to run. Recruitment is complicated. But basically, we're blocking smell in couples who are trying to maintain a pregnancy.

Andrew Huberman:
I want to touch on some other so-called pheromone effects. And one thing I heard you say during a talk, which I think really captures this whole issue of are there pheromone effects in humans very nicely is you said, whether or not it's a classic pheromone effect or whether or not it's olfaction or something else, this is chemosensory signaling-

Dr. Noam Sobel:
Yep

Andrew Huberman:
... between individuals. The reason this is important to me is a few years ago, I did a social media post about pheromone effects in animals and some potential pheromone effects in humans. And a couple of the human olfactionistas, more from actually who work on animal models, really came after me with intense sniffing, saying there is no evidence for human pheromone effects, human pheromone organs, and I think today you've beautifully illustrated how, regardless of the answer to that, humans are contained or are emitting chemical signals that influence each other's physiology and behavior.

Dr. Noam Sobel:
For sure. For sure. And the term pheromone is a problematic term in any case. The term was put forth to describe insect behavior. Right? So, if you were given a hard time by the mouse people, you could've given them an equally hard time if you were an insect person. Right? Because really, the place the term is accurate is, so the first pheromone that was discovered was Bambiclol, which is the pheromone that has the male moth follow the scent trail of the female moth. Bambiclol is a pheromone. Insect pheromone people will argue that this stuff that people talk about in mice and rats is not pheromones.

Andrew Huberman:
I see.

Dr. Noam Sobel:
And it all becomes semantics, right?

Andrew Huberman:
Yeah, sort of like nerdy inside ball. Yeah.

Dr. Noam Sobel:
It's all semantics.

Andrew Huberman:
Yeah.

Dr. Noam Sobel:
So in our publications, we don't use the term pheromone, because it would not help me, and it would probably only hurt us. And so, we talk about chemosignals.

Andrew Huberman:
Mm-hmm.

Dr. Noam Sobel:
And humans definitely emit chemosignals from their body, and these chemosignals influence other humans and influence their behavior. And there are several examples of this. One of them I'll point out first, which is sort of the most widely studied and not mostly from our lab, actually. The flavor of the month for the past 10 years in this field is what's referred to as the smell of fear. Right? So, this is probably true of many mammals and humans. It's true of we emit a specific body odor when we're in a state of fear. This was first discovered in humans by Denise Chen out of, I think, Brown. I'm not sure.

Andrew Huberman:
I think that's right.

Dr. Noam Sobel:
Yep. Humans emit a particular body odor when they're in a state of fear, and this body odor influences other humans, in effect, increasing their autonomic arousal, their sympathetic state. So in effect, you could say that fear is contagious a bit. So the smell of fear is contagious. By the way, culturally, we know for ages that dogs can smell fear in humans, but actually that was only really shown about a year and a half ago in a study. So it was always said, but it wasn't really shown effectively. It was shown about a year and a half ago in a study that dogs indeed can smell human fear. And humans can smell human fear. So several labs, starting from Denise Chen and Haveline Jones, and then in our lab and in other labs, if you collect body odor from people in a state of fear, and collect body odor from the same people when they're not in a state of fear, other people can determine which is the state of fear or not, and this influences their behavior.

Andrew Huberman:
What about the smell of safety, or is that simply the absence of the odor corresponding to fear? And the reason I ask this is-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... somewhat woven into our prior discussion about mate choice. Again, I'll ask the question in a form of brief anecdotes. I'll use the I had a friend who approach here. But one phenomenon that has nothing to do with me in particular, I think this is a common phenomenon, is romantic partners leaving articles of clothing at each other's homes. Now, this could have other purposes to mark territory. Visually marking territory, but also scent marking territory is very common in the animal kingdom.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
It's not uncommon for romantic partners when one is traveling or away, for the other partner to smell their article of clothing in order to bring about positive connotations-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... of the other partner.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
Very common behavior. If you're doing this, folks, other people are doing this, too.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
It raises questions, for instance, about whether or not the mourning period part post-breakup, whether by decision, by death, or by some other phenomenon that's forced the breakup, whether or not that mourning period has something to do with an olfactory unlearning of and mate selection, and on and on and on.

Dr. Noam Sobel:
With all these insights-

Andrew Huberman:
Right

Dr. Noam Sobel:
... I would offer you to be a post-doc in my lab.

Andrew Huberman:
Well, I was going to say, listen, I have a sabbatical-

Dr. Noam Sobel:
But I know they've got to finish

Andrew Huberman:
... coming up, so I would love to do a sabbatical.

Dr. Noam Sobel:
But it's going to kill me, so I don't

Andrew Huberman:
No, exactly. Exactly. You don't want me to work for you. We talked about this earlier.

Dr. Noam Sobel:
That's what I'm saying.

Andrew Huberman:
For other reasons. Exactly.

Dr. Noam Sobel:
That's the thing.

Andrew Huberman:
There's a story there. What Noam is referring to, I'll just tell people, because inside jokes on a podcast don't really work. Earlier, I was referring to the fact that I've had three incredible scientific mentors, undergraduate, graduate, and post-doc. But for reasons that are unclear to me, the first one died of suicide, the second one cancer at 50, and the third one pancreatic cancer in his early 60s. And the last one before he died, who was an MD and a common friend of Noam's and I, turned to me and said, "Andrew, you're the common denominator." So-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... the joke-

Dr. Noam Sobel:
I prefer not to-

Andrew Huberman:
The joke in my business is you don't want me to work for you. So nonetheless, I would love to do a sabbatical in your lab.

Dr. Noam Sobel:
No. So what I was trying to say in that roundabout way is that those are all really keen observations and good ideas, for sure. And they just highlight again, that we're incredibly olfactory animals. And you're even talking about the nuance. We're very olfactory even not in the nuance. When people tell me that we don't use our sense of smell and we don't need it and all that, and I have to deal with this a lot. Right? I have to deal a lot. You study vision. Nobody will tell you that vision is unimportant, right?

Andrew Huberman:
I'm very visually dependent. I don't need a dog to take over my olfactory system if I lose olfaction, but I'll tell you from having lost my sense of smell-

Dr. Noam Sobel:
For, yeah

Andrew Huberman:
... for one day-

Dr. Noam Sobel:
Right

Andrew Huberman:
... I was in intense fear.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
I love blueberries. I'm like a drive-by blueberry eater. If they're there, I just kind of pick them up like a grizzly bear and cram them in my mouth. So keep them away from me if you don't want them eaten.

Dr. Noam Sobel:
Mm-hmm.

Andrew Huberman:
But I almost can't help myself. I bit into a blueberry or a handful of blueberries, and it was the sensation of little bags of water, and I-

Dr. Noam Sobel:
Right

Andrew Huberman:
... immediately felt tremendous grief.

Dr. Noam Sobel:
Yeah. I'll tell you a sort of a throwaway line that I use when I talk with people. Take the two most basic behaviors That sustain us, right? Let's say I give you a choice between a beautiful-looking layer cake with strawberries and blueberries and whipped cream, but that smells of sewage versus some gray-brown mix that smells of cinnamon. Which do you eat?

Andrew Huberman:
Oh, simple. The latter.

Dr. Noam Sobel:
Right. You eat the latter. Right? Now, imagine I offer you a mate. Choose the gender of your liking, that looks like a Greek god or goddess, but smells of sewage, or an ordinary-looking individual that smells of cinnamon itself. Who do you choose?

Andrew Huberman:
The latter.

Dr. Noam Sobel:
Right. So in the two most basic behaviors we have, we follow our nose, not our eyes. Right? Definitely-

Andrew Huberman:
And not always in predictable ways, because you offered an extreme example, which is the best example. But I, for instance, for reasons I don't know, I've never liked the smell of perfume, ever. In fact, I find it aversive. But I confess, I do like the smell of certain body odors very much. And I'm very particular about that, and I know within an instant. And so, this is a problem for any romantic partner who likes perfume for me, but I know many people like perfumes and colognes and things of that sort.

Dr. Noam Sobel:
I like perfume .

Andrew Huberman:
And in fairness, I've also been told by someone that they couldn't spend time with me because they do not like my smell. In fact, they dislike it. And fortunately for me, there's at least one person on the planet who said the opposite. So I completely agree with what you're saying.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
I can also say that I imprinted on the smell of my... I had a bulldog mastiff that I raised from the time he was a puppy, and I imprinted on his smell immediately. And even though to other people, he was a bulldog mastiff after all, his smell was rather aversive, to me, he smelled delicious. Right? It smelled like home, and he was my-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... best animal friend-

Dr. Noam Sobel:
Right

Andrew Huberman:
... for a long time. And on and on and on. The smell of children, as you said. We had a guest on this podcast who I'm sure you're familiar with, Charles Zuker.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
A professor at Columbia, has done incredible work in vision and olfaction-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... thirst sensing. And I talked a little bit about this, that there's something in the breath of romantic partners that's hopefully appetitive, not aversive, as well as in children. He was talking about the smell of his grandchild, the back of their neck, and how he misses that smell because when he thinks about missing his grandchild or children, it's that smell that's associated with that feeling.

Dr. Noam Sobel:
So, hexadecanal.

Andrew Huberman:
Hexadecanal?

Dr. Noam Sobel:
Yes.

Andrew Huberman:
Charles Zuker, your grandchildren smell like hexadecanal.

Dr. Noam Sobel:
Yes, they do.

Andrew Huberman:
He's going to come after me now.

Dr. Noam Sobel:
They do. And so this is a study ran by Eva Michor, who was a graduate student in our lab. And Eva was interested in aggression. She was really into aggression. And so when she started off, we said, "Okay, let's do chemo signaling of aggression." She actually was going to MMA clubs and collecting body odors. And we had all sorts of ideas going, and she worked on that for quite a bit. It never went anywhere, really. And then at the same time, we had a colleague of ours from Germany. When I say colleague, primarily a friend or acquaintance I met at conferences, Heinz Briere. And he was studying in his lab a molecule, hexadecanal, that was a chemo signal in mice, where in mice it was described as a chemo signal that promotes social buffering. Where social buffering, as far as I understand, it's not my field, but as far as I understand, it's basically a feel-good together thing. So when lots of mice are together, they feel good about being in a group, and that's social buffering, and it's promoted by hexadecanal, which they emit in their feces, mice. And in his work on hexadecanal, so Briere and his colleague, Storzman, they discovered the receptor for this, and then they went and discovered that the receptor is very highly conserved throughout mammalian evolution, and therefore, they hypothesized that maybe this is a universal mammalian signal. Now, which is unusual because in chemo signaling, typically, you tend to think of things as being very species-specific. But here they hypothesized that maybe hexadecanal, which promotes social buffering in mice, may do something in all mammals. Again, because this receptor is very highly conserved, OR37B, I think. So he approached us and said, "Look, you got to study this stuff in humans." Because he knows us as the human people, right? We go to these olfaction conferences where lots of people study mice and zebrafish and whatnot, and we're the human group. And eventually, he just FedExed us hexadecanal. And so we had this thing sitting around, and Eva was not going anywhere with her aggression studies with sweat from human participants, and yet she built the entire paradigm to study human aggression. So they're standard paradigms. This is a paradigm known as the TAP, the Tyler Aggression Paradigm. I'll soon describe it And so we said, "Okay, we have this hexadecanal stuff here, and it promotes social buffering. Social buffering sounds like it would make you less aggressive. Why don't you run your tap experiment using hexadecanal?" What's the tap experiment? So basically, what you do is you bring in a participant to lab, and you have them thinking that they're going to be playing against another person in this game. And you can do something like have another person walk into the other room playing online, so connected. So you can fool them into being quite convinced that this is what's happening. And they go into their own room, and in the initial game they play, on each round, they're provided with a sum of money. And this is real money that they'll receive at the end of the experiment. And by turn, each one of them decides how to divide the money up between the two. So they're playing against another person, they think, but that's actually a computer algorithm that they're playing against. And the computer algorithm is programmed to be, in scientific terminology, a jerk. So let's say they have to divvy up 100 shekel, which is the Israeli currency. So the other player would say, "Okay, I'll keep 96, and you get four." And then you can either accept it or not accept it, and then neither of you get anything. So basically, you're being shafted by the other side all the time. And this is called the provocation phase. You're really getting angry at this person because they're really not nice. They're shafting you on every trial, or almost. And you play this game, and it goes to its end, and then you play a second game, as far as you know, against the same participant. And the second game is a reaction time game. So a target shows up, and the first to press it wins. And on every trial where you win, if you want, you can blast the other participant with a loud noise. And it's a really loud noise. So you're also wearing earphones. It's 90 dB, and it's a screeching, horrible sound. It's the most punishment that an IRB committee will let you endure on a participant in an experiment, unless you're in Stanford 70 years ago or whatever that was.

Andrew Huberman:
No, I was referring to the classic prisoner experiment, which took place in the building next door to where I work, by the way.

Dr. Noam Sobel:
So you can blast the other participant with varying levels of sound, and you have a selection box from something very low to something very high. And what's nice about this is that then allows you to quantify aggression, because the more volume you're blasting the opponent with, the more aggressive you are towards your opponent. And so you have a measure of aggression. Again, the Tyler aggression paradigm, obviously invented by Tyler. Very well-validated, studied all over, a very standard protocol. So we brought in participants and had them play the Tyler, the tap, either under exposure to hexadecanal or control. Now, hexadecanal, it's incredibly difficult to even detect hexadecanal, but just in case, because it's considered a semi-volatile. It doesn't have a strong smell. But we buried both the control and the hexadecanal in a control odor that hid them in a mask. And she ran lots and lots and lots and lots of participants, men and women. And I'll first tell you the result with men, which is that hexadecanal consistently reduced aggression. People were less aggressive under hexadecanal. The effect size was quite meaningful, and later on, we learned, because I'm no specialist in the world of aggression, but compared to effects seen in the aggression world in research, really, really strong effects. So unusually strong. So hexadecanal lowered aggression in men, and we were like, "Cool." This is sort of what we were hoping to see, consistent with the hypothesis, and consistent with what it seems to do in mice. But then we looked at the data from women, and hexadecanal increased aggression equally significantly.

Andrew Huberman:
Is this thought to be something related to maternal protectiveness?

Dr. Noam Sobel:
We're getting there. So you got there really fast. It took me a year, and Eva got to it, really, I'll tell you, because remember, we're reaching the back of the head of your, whose was it? Grandchildren?

Andrew Huberman:
Charles Zucker.

Dr. Noam Sobel:
Charles Zucker. Just go with grandchildren.

Andrew Huberman:
The Charles Zucker.

Dr. Noam Sobel:
The. Yeah.

Andrew Huberman:
One of the kingpins of the New York neuroscience mafia.

Dr. Noam Sobel:
Yes. So this was really odd to me at that time. So I didn't have the intuition you just had, and I was like, "Eva, there is some bug here. It makes no sense to me. Why would something increase aggression in women and decrease aggression in men? This is really, really strange." And I said, "Okay, I want to see this happen again before we go ahead with this." So she went and did the entire experiment again, and this time she did it within the fMRI magnet so that we can also track brain activity while this was happening. And first of all, it replicated again. So once again, hexadecanal made men less aggressive and women more aggressive. And the extent of more than the effect alone, the dissociation was remarkable. It's almost like a chromosomal test. You look at the data on the unit slope line, and all the men are below, and all the women are above. There's this figure in the paper. Then she also looked at the brain data, and although our lab does a ton of fMRI, it's one of the major tools we use to measure brain activity. I'm quite cognizant of the limitations of fMRI, and this is, sadly, I think the only study in my career at least, where I actually managed to also get a mechanism out of fMRI, not only an area that's involved in activity. And so here's what we saw, that hexadecanal alone increased activity quite pronouncedly in an area of the brain known as the left angular gyrus. Now, this is an area involved in what's referred to as social appraisal. So that was kind of cool in that a social odor activated the social brain, not the olfactory system per se, and very pronounced. So on one hand, that was cool, but then what was uncool was that it did the same in men and women, and this was in contrast to behavior, which you don't like seeing, right? Because you would expect brain activity to reflect behavior, and it increased activity in the left angular gyrus in both men and women. But then she did a follow-up analysis, which was look at what's referred to as functional connectivity. That is, how does this region of the brain talk with the entire brain, as it were, under hexadecanal versus control? And here, the dissociation reemerged powerfully, whereby the connectivity from the angular gyrus was mostly to the classic neural substrates of aggression, so the amygdala and the temporal pole, and the connectivity went in opposite directions in men and women. So hexadecanal increased functional connectivity in men and decreased it in women. So in a way, this is almost saying that the default brain reaction is aggression. Right? The default is to aggress, and in men, hexadecanal increases the control that the left angular gyrus is holding over your aggression and keeping you back, and in women, it let it roam free, and they became more aggressive. But I was still puzzled. So I was convinced this happened twice. The MR data provided not only a pattern but a mechanism, which is unusual. And yet, I was telling Eva, "But this makes no sense to me." And then her insight, which, of course, afterwards is like, duh, is, no, there's a place where this makes perfect sense, and that is if you're a mammalian offspring because paternal aggression is often directed at you. There's infanticide all over, and sadly, there's male aggression towards human children as well, and maternal aggression is often protective. So if you're an offspring, if you have a molecule that will make your mother more aggressive and your daddy less aggressive, both of those are good for you. So you're winning. So we remembered a recently published paper from a group in Japan that looked at the odors emanating from baby heads. We now come full circle to Zucker's grandchildren. They used a method known as GC-MS, gas chromatography-mass spectrometry, to measure the volatiles from baby heads because baby head odor is a cultural thing across cultures, even in Japan. And so we quickly went to that paper to see if one of the molecules they report is hexadecanal, and we were very disappointed that it wasn't one of the molecules they reported in the paper. And so we wrote to the authors, who are since then our co-authors, and we said, "Look, we're studying this molecule, hexadecanal, and we don't see it in your results, and we were wondering maybe you had some results that you didn't publish or some supplementary materials or whatever." And this lab, which is a hardcore GC lab, said, "No, no. Hexadecanal is a semi-volatile," which we knew, "and our previous paper was not directed to the semi-volatile range, but we can now use what's called GCxGC, double GC, that is directed at semi-volatiles, and we can do this again. We just studied 11 babies, and we can see if this is an issue." So we said, "Yeah, please do." The bottom line of all this is that hexadecanal is the most abundant semi-volatile in baby heads. It's tons of it coming out of baby heads. So babies, again, speaking about if humans do or don't chemosignal, babies are conducting chemical warfare, right? They're reducing aggression in their fathers or males around them and increasing aggression in their mothers or females around them, and both of those things are good for them.

Andrew Huberman:
Incredible. This is somewhat different than what we're talking about, and yet similar in other ways because it's built off of anecdotal evidence, but it's anecdotal evidence that you hear all the time, and yet when you look in the scientific literature, at least by my read, the data are not clear, maybe even contradictory, and that relates to the coordination of menstrual cycles among co-housed-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... women or women who are friends. The many women listening to this, and maybe some men who are aware of this effect, will say, "Oh, yeah, absolutely. When I spend time with my friends or go away camping or even spend a day with them, our menstrual cycles become coordinated." However, my understanding is that the early literature, Barbara McClintock?

Dr. Noam Sobel:
Correct.

Andrew Huberman:
Discovered this phenomenon, published a paper in Science as an undergraduate?

Dr. Noam Sobel:
1971, "Nature."

Andrew Huberman:
Amazing. "Nature" paper. Again, one of the three apex journals, and as an undergrad, fantastic. So discovered this, described this, and probably women all over the world who became aware of this one way or another probably said, "Yes, absolutely. This gives validation to what we've observed-

Dr. Noam Sobel:
Right

Andrew Huberman:
... over and over again." And yet, as subsequent papers have been published, this result has been called into question. Is there any final word on whether or not menstrual cycles become coordinated among women who spend time together? And if so, is there any role of olfaction in this, or chemosensing through the nostrils-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... and/or mouth

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... to support this idea?

Dr. Noam Sobel:
Yeah. So I'll start off, indeed, to echo The background is that this study was conducted by Martha McClintock when she was an undergraduate at Wesleyan College, and she noticed that she thought her menstrual cycle and her co-inhabitants in her dorm room were coordinated in time. And I should say that this comes on the basis of similar or related type effects in rodents. Now, rodents don't have a menstrual cycle like humans do, but there's an effect in rodents referred to as the Whitten effect, which resembles this type of effect. And she published indeed that paper as an undergraduate in "Nature" in 1971. And to answer your question, she published a follow-up in 1998, also in "Nature," with then her graduate student at Chicago, Stern. So this is Stern and McClintock, 1998, and here's what they did. They collected sweat from donor women and deposited it on the upper lip of recipient women. So this would be a fun experiment for you at least, because you said you like body odors, but for many others, perhaps it would be daunting.

Andrew Huberman:
Well, I like certain body odors from certain individuals.

Dr. Noam Sobel:
Okay.

Andrew Huberman:
I don't think I uniformly like all body odors, although I do seem to uniformly not like the smell of perfume. Although I should, just to clarify, because I put this out there- ... and I learned the hard way in the comment section on YouTube, some of those perfumes I find downright aversive.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
I think the great Marcus Meister, a great neurobiologist, once said there's basically three responses. It's either yum, yuck, or meh. So some are truly yuck.

Dr. Noam Sobel:
Yeah, I never heard that one. Okay.

Andrew Huberman:
Kind of like that one, right? In terms of animal behavior-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... human behavior-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... we're either a move forward-

Dr. Noam Sobel:
We're an animal

Andrew Huberman:
... move back, or a-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... stop or a pause. So some are truly a yuck. Many are meh. Zero, to date, are yum for me.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
Now, body odors, the distribution is shifted. It could be any one of those three, yum, yuck, or meh, so just to be clear, but the yum category is definitely included.

Dr. Noam Sobel:
So-

Andrew Huberman:
Thank you for allowing me to do that.

Dr. Noam Sobel:
Yeah. So she did this study. So because right in the original McClintock study, you might suspect other drivers of the effect. Let's say you accept the effect, but still there might be other social drivers of the effect that are not body odor, right? There might be some dominant woman who's dominant in some other way, and this might be driving the coordination. So here, there was no direct link between these women other than body odor, so if the effect reemerged, it would definitely be an olfactory effect. And what she found is that if she took sweat from the follicular or the ovulatory phase of the donors, one extended the cycle in recipients and one shortened the cycle in recipients. I don't remember which was which, but basically, definitely denoting a chemosignaling effect, with opposing effects on duration based on the time it was collected from. Again, published in "Nature" in 1998. That said, there's a quotation, I think this is from... I'm not sure, but that if something's published in "Nature" or "Science," that doesn't necessarily mean it's not true. So with that in mind, the findings were since called into question widely. One reason is just statistics of cyclic events are surprisingly complicated, so it's tricky. Once you have a cyclic event, statistics become tricky. And so Martha took a lot of heat on the statistics of claiming an effect, and I think there was at least one effort of replication that didn't really work out. If you ask me, I'm on the fence, but I may be in a minority in my field. I think a majority in the field is currently negative. I'm not. And we've said in lab that we should do a planned replication. We will. Again, it's a horrible study to run. It's tons of work, and you have to run it for a really long time. And so it's just completely non-trivial. But we have a graduate student now in lab interested in these exact things, Ruth Weisgrosp, and she's doing similar stuff, and I hope we'll do that. I hope we'll try to replicate this.

Andrew Huberman:
Very interesting result, and I think interesting because of its real-world, meaning outside the laboratory, of course, or experiment analog, but also because pheromone effects and olfactory effects in humans seem unique among neurobiological/endocrine phenomena because there seems to be so many stories that we all have of the smell of our grandmother's hands, or the recognizing the scent of somebody, or I knew from the moment that I smelled their breath, or I just liked their smell kind of thing.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
These kind of things that inform the deep potential for a real biological phenomenon, as opposed to the kind of thing like, oh, you just throw something out there, oxytocin is bonding. And all of a sudden, the general public, to no fault of their own, comes to think that every aspect of bonding is oxytocin, and every defect in bonding is lack of oxytocin. But- The general public provides a sort of a rich fodder for exploring all these things, and a lot of times they turn out to be true, right? In the context of olfaction.

Dr. Noam Sobel:
Yeah. No, it's a very primal system. So, it's linked to the most limbic, primal mechanisms in our brain, and it drives primal behavior.

Andrew Huberman:
It's an incredible system. I have a question about a particular study, but I'm just going to cue it up, and you'll know immediately what I'm cuing up. And that is, what is the relationship between odors and hormones, and in particular, crying?

Dr. Noam Sobel:
As I pointed out previously, the sort of flavor of the month in human social chemosignaling research is the smell of fear, and the media of the month is sweat. Right? So, the few, maybe tens of labs in the world that study human social chemosignaling all collect sweat, and that's the media they look at.

Andrew Huberman:
Is it always from the armpit, or are there meaningful differences in terms of the sweat emitted from different locations on the body? I already know the answer to that as I ask it, but let's just stay above the waistline and-

Dr. Noam Sobel:
Oh, no. Yeah

Andrew Huberman:
... or below the waistline.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
I mean, we're biologists after all.

Dr. Noam Sobel:
Yeah, so it's funny. We're working on a paper on that right now on the smell of fear. So we have a nice paradigm for generating fear. We throw people out of airplanes. It's a very effective way to generate fear.

Andrew Huberman:
I have to come to your lab. It sounds like the greatest lab in the world.

Dr. Noam Sobel:
We didn't invent that, by the way. The first to do that was, and I hope I'm pronouncing her name correctly, I think it's Mujica Perudi. But that's our paradigm for generating fear, and we started that on our own, but we've since entered into collaboration with the Israeli Paratroopers Brigade, and we now collect body odor from every first-time jumper. So, we went that path because we, like everybody else in this field, the holy grail there is finding the molecules, right? If you'll have the fear molecules, that's a bonanza, right? Because you could think of many reasons why it would be a bonanza, but for me, if you find the molecules, you can then try and find the receptors. And when you find the cognate receptors, you can then develop blockers, and you can imagine, what's the term I'm looking for? I'm switching into Hebrew. It's about midnight now, right? I'm sorry. It's 2:00 in the morning.

Andrew Huberman:
You're doing incredibly well, considering the inversion of the circadian clock.

Dr. Noam Sobel:
It's definitely 2 in the morning, yeah.

Andrew Huberman:
We would never know. Noam traveled in today from Israel, so he's a circadian inverted, as we say.

Dr. Noam Sobel:
Anxiety. So, you can imagine developing a nasal spray against anxiety, right? Where you would quell those receptors and kill the fear response, right? Which, rather than going the current path, which is through neurotransmitters that then have effects all over the place, you would be getting fear at its source, right? So that would be why I would want that. And we figured out that doing that, collecting fear from three, four, or five people in an experiment, you'll never be able to do analytical chemistry on that. So we now have a setting we call Fear Bank, which now has more than 1,000 samples in it. So we're trying to do analytics on that. But in doing that, we've joined the crowd. Everybody's doing fear, and everybody's doing sweat. And in one of our discussions in lab, we were saying, well, there's got to be, or there potentially definitely could be additional bodily media that are playing into social chemosignaling. Now many of these, you can't really study, right? So just to throw out, most terrestrial mammals communicate social information through urine. But starting doing experiments with humans with smelling urine, it would be difficult both in IRB and in agreement. And then this is a rare case where we actually hypothesized what we set out to do, and then only claim in retrospect that it was hypothesis, is tears. We started thinking about tears and looking into tears because tears are a bodily liquid, emotional tears, that we emit in emotional situations where these are situations where non-verbal communication is critical and key. And tears are a liquid that is puzzling beyond ocular maintenance, right? And so the most influential text, I think, till this day in emotion research is Darwin's book, "The Expression of the Emotions in Man and Animals," I think is the full name of the book. And an entire chapter, chapter six, is devoted to tears. An entire chapter of this book. Why? With no conclusion. Why? Because the book revolves around describing the functional antecedents of emotional expressions. So, for example, showing of the teeth is a sign of aggression, right? So animals first bit with their teeth, and Darwin argued that through evolution, just showing the teeth alone became an aggressive sign because it started from biting. Or what I find is a beautiful example, and this is work partly done by Adam Anderson, now at Cornell, is the emotional expression of disgust. So disgust, which comes from Latin disgustia, distaste, right, is spitting something out of your mouth. Now, what Adam showed is that The musculature patterns of activation and the temporal sequence of activation when you experience moral disgust are the same as when you spit a bitter taste out of your mouth. So again, so there's a functional antecedent, spitting something out, and through evolution, the argument was that it became an expression of emotion, and you express disgust just as if you're spitting something out of your mouth, even though in the case of moral disgust, there's nothing you're spitting out of your mouth. So Darwin systematically went through the expressions of emotions, and for each one went to their functional antecedent and explained everything very nicely. And then he got stuck with tears, because tears are an obvious emotional expression, and he could not find a functional antecedent. So he ended up saying, "This is an epic phenomenon," basically. I don't know.

Andrew Huberman:
What all scientists do when they don't have a good explanation, blame it on nature.

Dr. Noam Sobel:
Right. But he bothered to write this entire chapter on the ocular sort of maintenance function of tears and so on and so forth, but nothing emotional. So we thought, well, maybe the function is a chemical signal. So with that in mind, we harvested emotional tears, which was also an amusing event on its own. Because we posted messages on all sorts of boards that we're seeking experiment participants who cry with ease. Now, this generated an unfortunate gender bias in our study. Because we received about 100 women volunteers and about one man. And I think this is not a problem only in macho Israel. Probably anywhere in the West, definitely in America it would be the same, I think.

Andrew Huberman:
My guess is that there are probably men out there who cry easily, emotional tears easily-

Dr. Noam Sobel:
Oh, I'm sure

Andrew Huberman:
... but they're not going to show up.

Dr. Noam Sobel:
Yeah. That's what I'm saying.

Andrew Huberman:
Yeah.

Dr. Noam Sobel:
It's a cultural thing. You're not going to come to a lab and say, "I cry all the time." It's just not going to happen. And then, what we did is, for each one of these participants, we would ask them, "Is there a particular film event that you know of, or a scene that makes you cry?" And interestingly, in these effective criers, there was always, "Oh, yes, the scene in so and so. I always cry profusely from that." They have their-

Andrew Huberman:
Can you give me an example of one of the more commonly named scenes?

Dr. Noam Sobel:
Yeah. With ease. The movie "The Champ."

Andrew Huberman:
Hmm. I know that one.

Dr. Noam Sobel:
The champ dies. He's a boxer, and he dies literally in the hands of his about eight-year-old son, and his son is standing next to his bed and saying, "Champ, champ," and he dies. It's a winner. Okay? And-

Andrew Huberman:
Waterfalls.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
Got it.

Dr. Noam Sobel:
So, we're probably the neurobiology lab with most sad movie films on the shelf in the world, right? We have a whole huge collection.

Andrew Huberman:
There is such a thing as tears of joy, by the way.

Dr. Noam Sobel:
So, no.

Andrew Huberman:
No?

Dr. Noam Sobel:
Well, we're getting ahead of ourselves-

Andrew Huberman:
Sure

Dr. Noam Sobel:
... but let's just say we tried to collect them and failed. Even people who think they shed tears of joy and laughter, their eyes water a bit, but it's not the same thing.

Andrew Huberman:
Ah.

Dr. Noam Sobel:
In the effective criers we end up screening, we collect a full ml of tears in about 15 minutes.

Andrew Huberman:
Wow.

Dr. Noam Sobel:
So that's pouring, right?

Andrew Huberman:
Yeah.

Dr. Noam Sobel:
And that doesn't happen from laughter.

Andrew Huberman:
Correct.

Dr. Noam Sobel:
We've never seen that happen from laughter. We tried. So we have all these sad films, and by the way, one of the amusing things is, when we ultimately published this paper in Science, we were forced in retrospect to go out and actually buy the films. Originally, we downloaded them here and there, but you can't because you'd be violating copyright.

Andrew Huberman:
Copyright laws.

Dr. Noam Sobel:
Right. So we had to purchase all these films that the participants watched.

Andrew Huberman:
And watch them.

Dr. Noam Sobel:
So we actually have these in lab, DVDs, that we actually purchased. But, so-

Andrew Huberman:
Nice coverage of potential legal fallout there, Noam.

Dr. Noam Sobel:
No, we did. We did.

Andrew Huberman:
No, I believe you. I believe you.

Dr. Noam Sobel:
Yeah, it was that-

Andrew Huberman:
I believe you.

Dr. Noam Sobel:
And, well, we can touch on that later. But, so most of these volunteers who come saying they can cry with ease actually don't meet the bill. And so out of the about 100, at least, more women that we screened, we ended up with about six who could really come to lab week after week and pour tears.

Andrew Huberman:
There's a name for this in psychiatry. They call it a narrative distancing. Some people, when they watch a film where someone's getting hit, they flinch quite a lot. It's almost as if they're experiencing it. But it works in the opposite direction, too. I know someone like this-

Dr. Noam Sobel:
Okay

Andrew Huberman:
... where if they watch a film that someone's experiencing something even mildly positive, their mood elevates. So they can quickly bridge.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
And it's not always adaptive, as you can imagine. So there's lack of narrative distancing.

Dr. Noam Sobel:
Right. Yeah. One issue you can bring up with this entire line of studies in our lab is, I don't know if there's something very unique about the donors. We're assuming these are tears, and it's-

Andrew Huberman:
No, this is pretty common. I think that the numbers I saw out there, about five to 8% of people.

Dr. Noam Sobel:
That's exactly what we got about, right?

Andrew Huberman:
Interesting.

Dr. Noam Sobel:
About 6%. So we collected tears, and we exposed participants to these tears. And we found a few things. First of all, the tears are completely odorless. You cannot detect them at all, completely odorless. And yet, when you sniff them, you have a pronounced reduction in testosterone within about 20 minutes, half an hour.

Andrew Huberman:
This is men and women smelling women's tears?

Dr. Noam Sobel:
Men. Just men. Yeah.

Andrew Huberman:
Men smelling women's tears-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... but not perceiving any odor.

Dr. Noam Sobel:
Nothing. Just sniffing them. And you have about a 14% drop in free testosterone. Free.

Andrew Huberman:
Okay, so this is testosterone that's already been liberated from the testes.

Dr. Noam Sobel:
Free testosterone.

Andrew Huberman:
And so that we've done a few hormone edits, either bound or unbound. It's unbound, excuse me-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... from sex hormone, binding globulin, et cetera, and it's the active form. So it's subject to very short timescale changes.

Dr. Noam Sobel:
Yeah. And people who study testosterone, which is not me, but they tell me this is a really strong effect.

Andrew Huberman:
Mm-hmm.

Dr. Noam Sobel:
It's hard to even pharmacologically get an effect like that, that fast.

Andrew Huberman:
Yeah.

Dr. Noam Sobel:
I know in pharmacology.

Andrew Huberman:
Yeah, years ago, I spent time studying endocrine effects of this sort, and that's a tremendously-

Dr. Noam Sobel:
Right

Andrew Huberman:
... sized effect.

Dr. Noam Sobel:
And so here I'll point out in passing that one of the concerns we had because of the effort to run this study is that nobody would ever try to replicate it. And to our joy, about two years later, an independent group from South Korea, Oh et al., who I don't know at all, replicated the testosterone effect to a T. Same numbers. So it lowers testosterone. And we then also looked, using MR, at the effect on brain activity and saw a pronounced effect on activity, a dampening, a lowering of activity under an arousing state. A lowering of activity both in the hypothalamus and in the fusiform gyrus, for whatever reason, I don't know.

Andrew Huberman:
Face recognition area.

Dr. Noam Sobel:
Amongst other things, yes. And we don't know why.

Andrew Huberman:
Interesting.

Dr. Noam Sobel:
But pronounced. And currently, Shania Gronin in our lab is replicating this again, and this time with a stronger behavioral component. And I can share with you unpublished data now under review that as you would expect, given the effect on testosterone perhaps, sniffing tears lowers aggression in men.

Andrew Huberman:
Very interesting.

Dr. Noam Sobel:
Using again the TAP, the same experiment used by Irvine in the hexadecanol experiment.

Andrew Huberman:
The TAP, I'm going to think of that as the sadist-

Dr. Noam Sobel:
Tyler aggression

Andrew Huberman:
... the titration, the sadist titration experiment-

Dr. Noam Sobel:
Yeah. Tyler aggression paradigm

Andrew Huberman:
... with the lab rats. Not unlike the Milgram experiments of the 1950s, which this was looking at sort of post-Holocaust behavior.

Dr. Noam Sobel:
Right.

Andrew Huberman:
People basically, in American laboratories, thinking they were torturing other people-

Dr. Noam Sobel:
Yep

Andrew Huberman:
... simply because they were told to, and a lot of people did that, even though most people would report that they would never torture somebody else.

Dr. Noam Sobel:
Yeah. No, humans are not a wonderful species.

Andrew Huberman:
No. Or as we could say, I think it was the great Carl Jung that said we have all things inside of us, but the goal is not to experience them all, certainly. It's an incredible study, and it points again to the power of these chemosensory systems and pathways. And obviously, there's so much here.

Dr. Noam Sobel:
I don't know if you want me to tell about this or not, and I guess you can edit it out-

Andrew Huberman:
Please

Dr. Noam Sobel:
... if you don't want. But-

Andrew Huberman:
Please

Dr. Noam Sobel:
... this is just sharing stories about the politics of science. And so whereas the effect on testosterone was replicated by an independent group, in the original study in science where it had three components. One was the effect on testosterone, which was robust, the second, which was brain activity, which was robust, and there was a significant but weaker effect on behavior, and I don't think we studied the right behavior in retrospect. What we looked at then was ratings of arousal associated with pictures. And there was an effect, it was significant, but it was not what carried the story. Now, there's a lab in Holland of a guy by the name of, I'm probably mispronouncing this, but I think it's Vingerhoets.

Andrew Huberman:
For the non-Dutch.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
Dutch names are always a little bit of a challenge, but-

Dr. Noam Sobel:
And I shouldn't say that. Being an Israeli, I shouldn't go too much on that line. But that lab really didn't like our original tear story. And the reason they didn't like it is because they've built a career on this notion, including a book with this title, that "Emotional tears are uniquely human." Now, here I should share, so one of the things we really liked about the tear result is that partially before we did our work, but more afterwards, and we like that because usually things-- So usually in our chemosignaling work, like what I told you before about the Bruce effect, we look at what happens in rodents, and we see if the same thing is happening in humans. This was a rare case where after we did this work, more or less identical effects were discovered in rodents. So a paper published in "Nature" two years later found that mouse tears Mouse pup tears lower aggression in male adult mice towards them.

Andrew Huberman:
In a smell-dependent way.

Dr. Noam Sobel:
Yeah. And they also actually found the actual component in tears, so the tear pheromone that lowers aggression. You can think of tears as like a chemical blanket in a way, that you're covering yourself up to protect against aggression. And so our finding, which to me, this is consistent with how I think about behavior in general. I don't think beyond language, there are very few things, definitely sensory things, that are uniquely human. I'd be hard-pressed. So our finding went against their story. Because here we're saying, no, tears are this chemo signaling mechanism like all animals. And by the way, just after this entire debate, about six months ago, there was a paper in "Current Biology" that dogs emit emotional tears. And the dogs emit emotional tears when they reunite with their owners.

Andrew Huberman:
Mm.

Dr. Noam Sobel:
And you were talking before about oxytocin. So I think what they showed there is that not only that, but that the view, seeing the tears in the dog influences oxytocin in the humans.

Andrew Huberman:
I absolutely-

Dr. Noam Sobel:
I hope I'm getting this right. But that's-

Andrew Huberman:
No, I absolutely believe this. From the time I brought Costello home at eight weeks old-

Dr. Noam Sobel:
Costello's your dog

Andrew Huberman:
... he is my dog. Unfortunately, he passed away about a long time. Actually, the only time I can recall crying... Listen, I've certainly cried before, many times in my life. Many, many times. The only time I ever recall crying to the point where I wasn't sure that I could keep producing tears, but somehow did, is when I had to put him down.

Dr. Noam Sobel:
Oh, yeah.

Andrew Huberman:
It's just like, and if I talk about too long now-

Dr. Noam Sobel:
You'll tear up

Andrew Huberman:
... I'll start crying today. It's one of those things-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... and I think it's a healthy-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... emotional state.

Dr. Noam Sobel:
For sure.

Andrew Huberman:
But I recall when he was a puppy, thinking, "This oxytocin thing must be real," because I can recall being in faculty meetings, which fairly stated are not always that interesting, but they could be pretty interesting, and someone presenting data, and my mind thinking, "I hope Costello's okay. What's he doing down in my office?" This is when he was very little. And also not needing to eat, not being able to focus on anything else except my attachment to him for about the first two or three weeks that I had him. Then it was easy. Then I could focus off on other things. And I think that dogs, perhaps through oxytocin, hijack the circuitry that's intended for child rear.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
I really do. Otherwise, why would people be so ridiculously attached to their dogs? Hence all the posts of everyone thinks their dog is the cutest dog-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... the same way everyone thinks their children are the cutest children.

Dr. Noam Sobel:
Yeah. Mine are-

Andrew Huberman:
Costello, by the way, was a very handsome bulldog.

Dr. Noam Sobel:
So yeah. So even to put another nail in that story of tears are uniquely human, so they're not, dogs shed emotional tears. And so that group really didn't like this, and they went ahead and tried to replicate. And to your listeners, I'm showing double quotations on the replicate, only the behavioral part, the ratings of arousal-

Andrew Huberman:
Mm

Dr. Noam Sobel:
... of women, and failed to replicate that.

Andrew Huberman:
I see.

Dr. Noam Sobel:
Now, this was just sharing on how science works and doesn't work in my notion in this case. So at the time, after they got this accepted in some journal, not a field journal, in a journal of memory of something, they contacted me for a response. And I wrote to the author, and I said, "Look, this is very odd to me. Why don't we replicate this again together and see if it doesn't work? If it doesn't work, I'll publish it with you that it doesn't work." And so I said, "Why don't you send over a graduate student or the lead author, and we'll do it here, and we'll show them how it's done," because they did it very wrongly in the paper. And so they replied that no, they don't have money to send over a graduate student to do it. So I replied saying, "Okay, I'll fund the graduate student coming over, and I'll fund the entire study and their stay," and so on and so forth, "and let's do this together." And they replied, no, they're not willing to do that, which I don't think is the way things should work. And they published this sort of failed behavioral effect in that paper. So I'm just sharing this, that there was that successful replication with the effect on testosterone, but there was supposedly this failed replication on the effect in behavior. And then I published a rebuttal on that, which I don't know if I should've done, but I did.

Andrew Huberman:
Well, I think it's interesting. I think provided studies are done correctly, the positive result almost always trumps the negative result, and yet I think replication is key. The problem, as you point out, is that replication is rarely pure replication of the exact study.

Dr. Noam Sobel:
Yeah. This one is not even remotely. So actually, they hid something in their data that did partially work. So I asked for their data, and I reanalyzed it, and that's what I published in the rebuttal. But this is just sharing on how science works. I took advice. It's not that I'm friends with him, but at that time, I was communicating a bit because we were on some board with Daniel Kahneman, who's Nobel laureate.

Andrew Huberman:
"Thinking, Fast and Slow."

Dr. Noam Sobel:
Right. And so I asked him, "How should I deal with this? Give me some advice here." It was emotionally not fun to be in that position. And he said, "Don't Never publish a rebuttal. Don't do anything." And I was, "How can I? I have to do something." He said, "No, don't. Because once you do that, then people don't go into the details. They won't read the details of your rebuttal. They'll be like, 'Well, there's a group that says this, and there's a group that says that,' so it's unclear."

Andrew Huberman:
Well-

Dr. Noam Sobel:
And-

Andrew Huberman:
Yeah. I appreciate that you're bringing it up today, and I do appreciate that you published the rebuttal, and that you offered, in a very magnanimous way-

Dr. Noam Sobel:
So-

Andrew Huberman:
... to do a collaboration

Dr. Noam Sobel:
... that's what he then said. So Carmen's advice after that was that, well, if you insist, then just publish. Write a response that you offered them to come do it together. They refused, and there's nothing you can do about that.

Andrew Huberman:
It's a lot like fight sports, right? People talk a lot of trash. Although in science, I will say this, as long as we're on the sociology of science. Science is very different-

Dr. Noam Sobel:
The stakes are lower.

Andrew Huberman:
Science is very different than podcasting or social media or other fields, because in science, people generally are very kind to your face, and then they- ... you get it in the neck on grant reviews or anonymous reviews.

Dr. Noam Sobel:
Yep.

Andrew Huberman:
I was on a grants review panel this morning. I'm a nice reviewer, meaning I judge things objectively, but I try to always think from the perspective of the graduate student or author of the proposal. Listen, I think that science is a game of people who, most of them are seeking facts. However, the ego is strongly woven into it like anything else.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
So I think it was very magnanimous of you to offer the collaboration. So I'm going to tell this lab whose name I can't pronounce, please accept the collaboration. Then we can invite everyone on here-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... for a round table. I appreciate that you shared that story, and I know a number of other people will for a number of reasons. I have a couple more questions. And I realize, and thank you by the way, for your willingness and stamina, because it is probably 1:00 a.m. Israel time now, and you just arrived.

Dr. Noam Sobel:
Later, I think.

Andrew Huberman:
But you're doing terrifically well. So if you'll indulge us just a touch further, there are two topics that I want to touch on, and if you want to cover these in shorter thrift, that's fine, although don't feel any obligation to. The first one is, I think most people are familiar with the scent of food or foods as a signal of the nutrient contents of those foods. An orange that smells great or the smell of something baking, it suggests something about the contents and quality of that food. After all, you and I both separately lived in the same apartment in Berkeley above The Cheese Board, which-

Dr. Noam Sobel:
Oh, it's crazy.

Andrew Huberman:
... the smell of cheese wafting up through The Cheese Board is something I will never forget.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
And the breads, never forget it. Amazing bread and-

Dr. Noam Sobel:
I don't know if you've conveyed that clearly enough to listeners or watchers-

Andrew Huberman:
No, the probability is-

Dr. Noam Sobel:
... that we really just discovered that we lived in the same-

Andrew Huberman:
Exactly

Dr. Noam Sobel:
... we've never met like this before.

Andrew Huberman:
Yep.

Dr. Noam Sobel:
And we lived in the same apartment.

Andrew Huberman:
Exactly.

Dr. Noam Sobel:
What are-

Andrew Huberman:
Are we clique friends?

Dr. Noam Sobel:
In a lingering way, I guess.

Andrew Huberman:
Absolutely. Through the-

Dr. Noam Sobel:
Floorboards. It had a great floor, that place. It had a great wooden floor.

Andrew Huberman:
Yeah, it was an amazing place. I lived there with my girlfriend for a year and a half, and then- It was an amazing place. We won't give out the address-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... out of respect for the people that live there now. But do check out The Cheese Board if you're ever in Berkeley. Their hours are weird, so you have to look online. But it's a unique place-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... with great bread and cheese and some good flavors of pizza. In any case, I'm wondering whether or not smell can signal things about the nutrient contents of foods in a way that's divorced from the smell that we are perceiving. So for instance, I could imagine, based on what you've told us about smell today, that I I don't know. I smell a piece of meat cooking, and it smells great to me, and I think of it as, "Oh, that's so savory," and my mouth is watering and I love the smell of this. And I'm thinking, "Okay, this is protein and fat, and I love the taste of steak and a little bit of char," but that nature has co-opted that to ensure, or I should say increase the likelihood, that I will ingest some other thing that's in steak that has no odor but whose nutrient content is very important to me. For instance, amino acids.

Dr. Noam Sobel:
Right.

Andrew Huberman:
Right? Amino acids are essential to life, and yet we don't go around sniffing for amino acids. We go around sniffing for savoriness, umami-type tastes and things of that sort. So I could imagine a million different examples of this, in the same way I could imagine that the scent of somebody that we fall in love with or become romantically attached to or sexually attracted to is signaling all sorts of things about, sure, the potential for offspring of a particular immune status. That's a long-term game, but also something about pleasure and safety of a potential interaction. So what I'm asking here is about whether or not there are subconscious signals that the olfactory system has learned to seek, but learned to seek through more overt signals. Sort of the tip of the iceberg phenomenon.

Dr. Noam Sobel:
Yeah. So, I don't have a good answer for you, although I think it's a really good question. Or a good idea, in fact. So whether there's odor cues on nutrient value is a really good idea. Moreover, it's probably good to the extent that somebody probably did it, and I should know and don't. We haven't done anything on that line, so I don't know. I don't know if the nutrient value of food is systematically encoded in odor. If that's not been done, and I will check after our meeting today, then it should be. It's a really good idea.

Andrew Huberman:
One of the reasons I ask this is because the obesity crisis in the US is a huge issue, and elsewhere. And highly processed foods have a lot of things that are problematic, but one of the things that they don't have often is a direct relationship between the scent, the taste, and the nutrient content. And I don't mean macronutrients, sugar, fat-- Excuse me. Carbohydrates, fats, and proteins, but the vitamins and micronutrients, things that support the microbiome. Whereas foods that are not highly processed, for instance, meat or a piece of fruit, contain many micronutrients that are vital to aspects of our biology, but we don't go around sniffing for probiotics.

Dr. Noam Sobel:
I'll tell you one sort of factoid that may support your hypothesis here, and that is that there appears to be potential olfactory perceptual similarity in metabolic products. So something that's metabolized from something else has perceptual similarity across those two things. So metabolic cascades play into the coding of olfactory space, and that is consistent with the direction you're implying. But again, I don't know of a direct test of nutritional value in smell. And again, the fact that I don't know doesn't mean, of course, that it doesn't exist, and in this case, I would suspect that it should exist in scientific press, and if not there, then with the companies that have vested interest in this, which are many.

Andrew Huberman:
Briefly share, just-

Dr. Noam Sobel:
Please. An amusing anecdote to share with you is that we've received two independent companies who have turned to our lab recently, asking for help to bring odor to engineered meat. That's a growing thing. And all these meats that are-

Andrew Huberman:
Oh, boy. You had to bring it up. This audience is going to be very polarized along the lines of engineered meat.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
You're not promoting.

Dr. Noam Sobel:
Oh, no, I'm agnostic. But we've had two companies turn to us and say, "Look, we have this great product, but it just doesn't smell like meat, so help us make it smell like meat."

Andrew Huberman:
Interesting. The reason it's so polarizing is that anything related to nutrition on social media is a total barbed wire topic. We've had experts-

Dr. Noam Sobel:
Okay

Andrew Huberman:
... on nutrition come on here, we'll have more, but-

Dr. Noam Sobel:
I know nothing about nutrition

Andrew Huberman:
... don't worry, you're safe. No, don't worry. No, he's not promoting this. He hasn't even said whether or not he's going to help them out.

Dr. Noam Sobel:
No. We're not, actually. No, because it didn't happen.

Andrew Huberman:
Yeah.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
No, whether or not those engineered meats are yum, yuck, or meh is a personal issue to people in terms of taste. Whether or not they are better for, neutral, or worse for you and the planet than, given the ingredients that are required, that's a whole world we'll avoid now.

Dr. Noam Sobel:
I will, but I'll take the opportunity to highlight something related, maybe, because on what we were saying on the scale. I'll take the opportunity to dispel another misconception about olfaction. There's this common notion that our sense of smell is incredibly subjective, and that what you might like in a smell, I will not like in a smell, and that we all have our own totally subjective world of olfaction.

Andrew Huberman:
I think I know the study you're going to tell me.

Dr. Noam Sobel:
There are many.

Andrew Huberman:
The cross-cultural similarity.

Dr. Noam Sobel:
There are many. That is utterly untrue. Many, not only from my lab, there are many from many labs.

Andrew Huberman:
Please clarify for those that don't follow this literature.

Dr. Noam Sobel:
Yeah. So humans are incredibly similar to one another in their olfactory perception, and this is in contrast to what most people think. So why is there this misconception? The misconception is there for two reasons. First of all, or for several reasons, but two stand out. First of all, we're attracted by outliers because I'll tell somebody, look, for example, olfactory pleasantness is highly correlated amongst humans. And let's first put this in numbers. You'll take a bunch of humans and a bunch of odorants and have them rate pleasantness. The correlation across the humans will be about .8. That's incredibly high.

Andrew Huberman:
What you think is pleasant, I think is pleasant.

Dr. Noam Sobel:
Yeah. Now, why does that go against what culturally people think? For two reasons. First of all, we're attracted or biased by outliers, but that shows, in fact, the result. What do I mean? So you'll tell somebody, "Look, people are very similar in their pleasantness estimates." And they'll say, "No, that can't be. I love cilantro, and my girlfriend hates the smell of cilantro." Or, and there are a few classic examples there. Guava is another polarizing odor. So there are a few polarizing odors, and that's true. So that's true that half of the population loves the smell of cilantro and half hates it, half loves guava, half hates it. That's true.

Andrew Huberman:
Microwave popcorn.

Dr. Noam Sobel:
However, I assure you that you can come to our lab. We have about 1,000 odorants in our lab. We won't smell the thousand. But I assure you, take 100 odorants from our mixtures in labs. And we'll smell them, and out of the hundred odors, 90 Will totally agree on. And including universe. Nobody will say they like the smell of feces or fecal smells, and everybody will say they like the smell of rose and flowery smells. There will be rare exceptions. Again, the correlation is about 0.8 across individuals. So on 90 of 100 will usually be in high agreement, then five odorants will be in sort of intermediate agreement, and yes, there'll be the five odorants that we're in total disagreement on. But I ask you, if we agree on 95 and disagree on five, are we the same or are we different? We're the same. They're just outliers to this rule. And so one reason is this issue of outliers attract how we think about things, but no, we're actually much more similar than what we think. And the second thing that drives this cultural effect is our poor application of language to olfaction. So, in other sensory systems, we develop with anchors. So since you're a little kid, your mother shows you a cow and says, "What does a cow do?" "Moo." And we all know moo. And "What color is this?" Well, this is kind of an odd black, but it's black. Or, "What color is that?" It's red. So you have these anchors. But as you well know, the red that I'm seeing is not necessarily the red that you're seeing. We just both know to call that red. And since you say red and I say red, I think, wow, we're seeing the same thing. But no, we're not seeing the same thing. And in odor, we don't have those anchors. From childhood, our mom doesn't tell us, "So what's this smell and what's that smell?" And so we don't have these language anchors that make us think that we're perceiving the same thing. Now, how can you quantify that? The most important term in measuring sensory systems is similarity. That's the measure. So let's say we take 10 odorants and I have you rate all the pairwise similarities. So you end up with 45 numbers. So how similar is one to two, one to three, one to four, and all the possible pairwise similarities. Let's say you rate similarity from one, which is totally dissimilar, to 100, exactly the same. So now I have a similarity matrix that describes Andrew's perception of smell. Based on these 10 odorants that I selected. Now I can run my similarity matrix, and then I can see if the similarity matrix are correlated. And then we've gotten rid of the issue of names and odors. It doesn't matter if I'll call this lemon and this orange, and you call this sweet potato and this marshmallow. It doesn't matter. If I think that these two are highly similar and you agree, and I think that these two are very different and you agree, we perceive the world in the same way if our similarity matrices are aligned. And what's nice about that is that then you can do that for vision, audition, and olfaction in a common group. And you can see where we're more like each other or not. And we've done that for color vision, olfaction, and tonal audition. Okay? And we are most dissimilar in color vision. Okay? In color vision, the variance is about 100%.

Andrew Huberman:
Amazing.

Dr. Noam Sobel:
It's-

Andrew Huberman:
That's quite different.

Dr. Noam Sobel:
And there's tons of literature on this. Tons of it. And in olfaction and audition, they're about the same. So we're not different, we're very similar. We're just very poor at appreciating this. And mind you, not that there's not variability. There is variability. And of course, the system is malleable, as all sensory systems are, so you can learn to like an odor, and that will change you, and learn to dislike an odor. But just the way you can learn to like a sound or dislike a sound. So this doesn't take away from the hardwired link of a structure to its perception that they're malleable. And we're not very variable. We're actually kind of similar.

Andrew Huberman:
That's a perfect segue to the question I have next, which is if, in general, people perceive certain odors similarly, you could imagine that odors could be manufactured, co-opted, et cetera, in order to elicit richer sensory experiences and drive choice-making.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
That's obvious at the level of the smell of a hot dog stand or freshly baked bread, et cetera, but what I'm talking about here, and I'd like to ask you about, is doing this at scale, and scientist geeks like to say in silico, through computers. So for a long time now, there's been this idea that there will soon be Google Smell. Not to call out Google as the only search engine, but DuckDuckGo Smell, for those of you that don't want to hear smell-

Dr. Noam Sobel:
ChatGPT smell.

Andrew Huberman:
ChatGPT, and on and on. In other words, visual information is sent through computer interfaces-

Dr. Noam Sobel:
Right

Andrew Huberman:
... as is auditory information. Not so much haptic somatosensory, although it can. Our lab uses VR. It can be done.

Dr. Noam Sobel:
Right.

Andrew Huberman:
But it hasn't really taken hold. However, smell being such a rich source of behavioral and hormonal and other sorts of deep information that can drive people into yum, yuck, or meh-type decision-making-

Dr. Noam Sobel:
Yeah

Andrew Huberman:
... seems like an amazing candidate. So what is your experience with generating smells in silico in computers? And here, folks, for those of you that aren't catching on to this, and I don't expect that everyone would, because what we're really alluding to here is the idea that you'll put into a search engine "blueberry pancakes recipe," and that not only will you get photos of those blueberry pancakes and a recipe, but you will get the hopefully validated odor of those pancakes and that recipe coming at you in real-time through the computer.

Dr. Noam Sobel:
So I'll start off answering from the name you threw out there, Google. So probably about five years ago, Google had an April Fools' spoof.

Andrew Huberman:
Oh, right.

Dr. Noam Sobel:
And they put out this video of Google Smell, okay? And it had all these classic sales images of holding up your phone to a rose and it generating rose and all these things, right?

Andrew Huberman:
Mm-hmm.

Dr. Noam Sobel:
So Google is now trying to do that. And they just published-- I know they've been trying to do it for a while. They visited our lab. But they just sort of went public with this, really just about a month ago or something, that they have this offshoot startup, I think it's called Osmo or something like that, that started off with a ridiculous sum of money for a startup. I don't know, tons of money.

Andrew Huberman:
There's a lot of money in that world.

Dr. Noam Sobel:
Yeah. In Google, yeah. To digitize smell. And there are other companies that are trying to do this as well. And we've been talking now for quite a while about our lab's chemosignaling work, but actually half of our lab is devoted to this question of ultimately digitizing smell. And so this is a very, very active field of research. And I'll say one thing that dovetails with what you were talking about before, in many ways, COVID is going to be one of the best things that ever happened to olfaction research, because suddenly all the world is-- Or all the world. Lots of people are very cognizant of the importance of smell, and smell is way up there in people's awareness because of COVID. And this is driving a renaissance of olfaction research, and awareness to olfaction as something that's worth paying attention to. And our lab has been involved in this way, in this effort for a long time, where the initial part of this effort is in fact to develop a set of rules that link odor structure to odor perception. That is, the going saying was that until recently, at least, there was no scientist, or perfumer for that matter, who could look at the structure of a novel molecular mixture and predict for you how it will smell, or smell something and tell you what its molecular structure could or should be. So in contrast, let's say, to trivial color vision, let's say. So if you know what the wavelength of the light is, you more or less know what perceived color it's going to be. Of course, there are exceptions to that and all sorts of issues, but as a rule, you would know. Or the other way around, you can generate a wavelength, and you would know at what color of light it's going to be perceived. So that's an example of where the rules linking structure, in this case measured by wavelength, and perception, in this case experienced as color, the rules are well known. In olfaction, we didn't have that until recently. But over the past few years, a bunch of labs have really pushed this forward. There's a bunch of work out of Leslie Vosshall's lab at Rockefeller, and Andreas Keller working with Leslie, who've done a lot of work on this front. Also work from Joel Mainland's lab at Monell. And fair discovery, Joel was a graduate student in our lab. And recently in our lab, we've had, and I hope this doesn't come across as overly arrogant, but we've had a sort of mini breakthrough on this front.

Andrew Huberman:
To call something a mini breakthrough is far from arrogant.

Dr. Noam Sobel:
And this is a paper led by Arun Ravia from our lab, and Kobi Snitz, also a major contributor there. A paper published in "Nature" about a year and a half ago in the height of a COVID pandemic, so nobody really, or I won't say nobody, but it wasn't noticed in the way it otherwise would've been. It was published in "Nature," really on a week where the whole world was going berserk over COVID. And in this paper, we develop an algorithmic framework where we can predict the perceptual similarity of any two molecular mixtures with very, very high accuracy. So if you give me two molecular mixtures, I can predict how similar you will smell them to be.

Andrew Huberman:
Mm.

Dr. Noam Sobel:
Okay? Now, not only could we predict that, but we could design it. So we can generate mixtures with known similarities. And the result was highlighted, and you'll appreciate this coming from vision, is that using our algorithmic solution, we generated olfactory metamers. So we measured mixtures completely non-overlapping in their molecular structure, but they smell exactly the same. Okay? Now, if you would come to a classic perfumer, or most classic perfumers, and tell them that you can generate two mixtures with zero molecules in common but smell exactly the same, they would tell you no. And yet we did, and anybody can recreate them. This is simple, actually. And in the paper, we do a few things, like we generate a metamer for Chanel No. 5. So you don't like perfume, so this one-- But so we generate a Chanel No. 5 with no component from Chanel No. 5 in it. Okay. And we actually have a publicly available website. I'll give it to you for your links if you want. Anybody can do this. We built an engine that you can generate these metamers. Now, once we did that, in a way, we've generated the infrastructure for digitizing smell. Because again, what our algorithm predicts, our framework predicts, is similarity. But in a way, that's enough for you. Why is that enough? We have a map of 4,000 molecules. For each one, we know their perceived smell. Now you can make up any mixture you want for me. I can project it into that map and measure its pairwise distance from all the points in the map. If it falls on lemon, then what you generated smells like lemon. And if it falls on tomato, then what you generated smells like tomato. So we now solved that problem. We can predict the odor of any molecular mixture. We can say how it's going to smell. What we can do is then find a set of components, which we call odor primaries, that can be used to mix any odor that you can perceive. And that's what we're working on now. And about a month ago, so this is in collaboration with a lab of Jonathan Williams at Max Planck in Munich. Jonathan Williams is an atmospheric chemist, but he's really good at using GC-MS, these tools that measure molecules. So Jonathan Williams measured odorants in Germany, transmitted the information to us over IP. We fed that into our algorithmic framework and recreated it from a device that mixes primaries. And we tried to do four different odorants in our proof of concept test. One of them was rose, and we failed at recreating rose. We, in fact, recreated something that had a percept, but most people perceived it as bubblegum. The second one we tried to do was anise, and we failed at recreating anise, and most people said it was cherry, which is not very far, but it failed. The third was gasoline, and we were slightly but significantly better than chance at recreating gasoline. And the fourth was violets, and 15 of 16 people said violets. So the first odor ever transmitted over IP is violets, and we did that last month. Of course, this is not anything near a practical solution. The device that Jonathan was using to measure is a $1.5 million device, bigger than this table.

Andrew Huberman:
That's right. I remember when VCRs, half the audience won't even know what that is, but VCRs were this big.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
So we're all good.

Dr. Noam Sobel:
Oh, yeah.

Andrew Huberman:
I'm all good with the prediction that-

Dr. Noam Sobel:
I'm just saying-

Andrew Huberman:
... things will come down in size and cost.

Dr. Noam Sobel:
Yeah. I'm just saying, don't hold your breath for this to be on your table tomorrow. And again, all we have in hand is this very initial proof of concept. It's not even yet close to being a paper we are submitting because there's still lots of work to be done. But we're on the path. We're on the path, and Google will probably beat us to it. They got a lot more-

Andrew Huberman:
I don't know. You seem pretty dogged in there.

Dr. Noam Sobel:
Yeah, but they have so much more resources that at this stage-- And they've already published two papers from that effort that are good. Yeah.

Andrew Huberman:
They definitely have a lot of dollars and a lot of people, a lot of good neuroscience and other biology, engineering graduate students, and post-docs go there.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
But the real question is, are they getting the best people? Because as you and I both know, in science, oftentimes it's small groups of the very best and most creative people that can outrun and outgun large groups. And here, I don't have anything against Google, by the way.

Dr. Noam Sobel:
Yeah.

Andrew Huberman:
I use it all the time.

Dr. Noam Sobel:
I'm not a betting man, but I would put my money on Google on this race. But I'll try and give them a run for their money.

Andrew Huberman:
There you go.

Dr. Noam Sobel:
Let's put it that way.

Andrew Huberman:
Well, it seems like most of you just want to see the problem solved, regardless of who gets there first. What I'll say is you better get going, Google, because Noam's being-

Dr. Noam Sobel:
I don't know

Andrew Huberman:
... he's humble, and he's dogged, so-

Dr. Noam Sobel:
I don't know

Andrew Huberman:
... better get cracking. There, we just cost the weekends of and broke up the relationships of a bunch of scientists. I remember when I was a graduate student at Berkeley, I remember hearing there was a guy in our common friend, Irving Zucker's lab, that worked 100 hours a week. So I was like, "Oh, I'll work 102 hours a week," which was not a good choice, folks. In any case, it's abundantly clear that you're making progress here.

Dr. Noam Sobel:
Oh, we are.

Andrew Huberman:
And I go to some of the earlier discussions we had, and I think we're not just talking about transferring recipes and smells of food, gasoline from the people watching the F1 race or something, but I'm thinking dating apps. I'm thinking nowadays everyone knows that when you travel, and you want to see your family, your grandkids, or kids, you better to get on FaceTime and see them or Zoom, than to just hear their voice.

Dr. Noam Sobel:
Look-

Andrew Huberman:
We're also talking about being able to smell them in real time

Dr. Noam Sobel:
... I'll tell you more than that. I'll tell you more than that. We're talking now of trying to achieve the olfactory equivalent of circa 1956 black and white TV, okay? Basically, right? I'm not dreaming, let's say, of being able to transmit to you the difference between a Cabernet or a Merlot, right? But if I can generate something that's vaguely wine, that will be an amazing success from my perspective, right? But jump ahead in your imagination to 4K odor transmission Then medical diagnostics is what you want to be talking about. Because this is over extension, but you can almost say that every disease will have an odor. Every disease is a specific metabolic process. Metabolic process have metabolites, metabolites have a smell. Olfaction, once it's digitized and high resolution, which again, in our hands, it's not going to be. We're talking, in my retirement, maybe I'll read about this one day if I'll still have vision. This is not close. But when olfaction digitization is brought to the equivalent of 4K of vision and audition that you have now, then it will be in medical diagnosis. You'll have, excuse me for the imagery, but you will have an electronic nose in your bathroom, each one of us will have in the toilet. And it will be doing diagnostics all the time. And that's where it's going to go. But again, not anywhere in the very close future.

Andrew Huberman:
Well, it's certainly an exciting proposition, and I'm delighted that you and other groups who are so strong are working on it. I really am. Noam, I want to say thank you for your time today. First of all, this was a tremendously interesting conversation. We touched on so many things, hormones, smells, the architecture of the olfactory system. I know that people listening to this are realizing, but I'm going to say it anyway, what an incredible gift you've given us-

Dr. Noam Sobel:
Thank you

Andrew Huberman:
... as a expert in this field, giving us this tour of the work that you and others, who you credit so generously, have done to elucidate this incredible system that we call olfaction and chemosensation.

Dr. Noam Sobel:
Thanks.

Andrew Huberman:
Also just for the incredibly pioneering work that you've done. I don't have many heroes in science. I have heroes outside of science and a few in science, but I'm going to purposely embarrass myself a little bit by saying that from the time I was at Berkeley and saw that experiment being done of people foraging, following scent trails, and then until I was a junior professor, I used that in my teaching slides in a class that I taught. That was sort of the early origins of this podcast in many way. And over and over again, when your laboratory publishes papers, I find like, "This is super interesting, super cool," and I find myself telling everybody about it, and that's really what I do for a living, is I learn, and then I blab about it to the world. So thank you so much for the work that you've done and the spirit that you bring to it. Whatever drives that spirit, as the great late Ben Barres used to say, keep going, because we are all benefiting tremendously. And I also just want to say that for people listening to this, the spirit of science is one of, as you mentioned, there's complex politics and all these things, but it's absolutely clear that you delight in the work you do. And so I delight in it. I'm grateful for it. I'm grateful for your time today. And so on behalf of me and many, many people listening to this, I just want to extend a huge debt of gratitude. Thank you so much.

Dr. Noam Sobel:
Oh. So I'm blushing. I don't know if this doesn't come across on the radio podcast, but thank you so much for very warm words. As you know, when you work in your lab, there's these moments where you suddenly discover that somebody cares a bit about it, and those are always very rewarding moments, because usually you function without that. I guess that's one of the things you need to be a scientist, is to have the drive to work without that, because it comes only rarely.

Andrew Huberman:
There's immense gratitude and appreciation for you and what you do from me, and now I know from a large segment of the world as well. So my only request is that you come back and tell us about the next results sometime not too long from now.

Dr. Noam Sobel:
Yeah. Well, I'm going to catch you live now, although you have the power to edit this, so I guess that's not fair. But first you come visit us in Israel and tell us both about the science and the public science work you're doing, and then I'll come again.

Andrew Huberman:
A good bargain, and I accept. Delighted. Thank you so much.

Dr. Noam Sobel:
Yeah. Pleasure.

Andrew Huberman:
Thank you for joining me for today's discussion about olfaction and chemosensation with Dr. Noam Sobel. If you'd like to learn more about the work in the Sobel Laboratory or read some of the papers described during today's episode, as well as learn about the current and future projects in the Sobel Laboratory, please go to the link provided in the show note caption. If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero-cost way to support us. In addition, please subscribe to the podcast on both Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five-star review. If you have questions for me or comments about the podcast or guests or topics that you'd like me to include in future Huberman Lab podcasts, please put those in the comments section on YouTube. I do read all the comments. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. Not so much on today's episode, but on many previous episodes of the Huberman Lab podcast, we discuss supplements. While supplements aren't necessary for everybody, many people derive tremendous benefit from them, for things like improving their sleep, their focus, and hormone support. The Huberman Lab podcast is proud to have partnered with Momentous Supplements. If you'd like to see the supplements discussed on the Huberman Lab podcast, please go to livemomentous, spelled O-U-S, so that's livemomentous.com/huberman. If you're not already following the Huberman Lab podcast on social media, we are hubermanlab on LinkedIn, Facebook, Twitter, and Instagram. And on all those accounts, I include information, some of which overlaps with content of the Huberman Lab podcast, but often which is distinct from information covered on the Huberman Lab podcast. So again, it's hubermanlab on all social media platforms. If you haven't already subscribed to our newsletter, we have a zero-cost monthly newsletter. It's called the Neural Network Newsletter, and it includes podcast summaries and toolkits or protocols for things like enhancing sleep, for exercise, for meditation, for dopamine, for focus, and many other topics. To sign up, you simply go to hubermanlab.com, go to the menu, and click on Newsletter, and provide your email. And I want to be clear that not only is the Neural Network Newsletter zero cost, we also do not share your email with anybody. Once again, I'd like to thank you for joining me for today's discussion about olfaction and chemosensation with Dr. Noam Sobel. And last but certainly not least, thank you for your interest in science.